@article {pmid40473116,
year = {2025},
author = {Su, CH and Chang, YT and Tseng, HS and Kuo, CY and Chen, JH and Yu Chien, P and Chang, YJ and Hung, CC},
title = {Comparisons of efficacy and safety of immunotherapies for Alzheimer's disease treatment: a network meta-analysis of randomized controlled trials.},
journal = {Clinical medicine (London, England)},
volume = {},
number = {},
pages = {100336},
doi = {10.1016/j.clinme.2025.100336},
pmid = {40473116},
issn = {1473-4893},
abstract = {BACKGROUND: Alzheimer's disease (AD) remains a major challenge due to limited effective therapies. Moreover, direct comparisons between newly developed and symptomatic drugs are lacking. This network meta-analysis aimed to compare the efficacy and safety of immunotherapies for AD.

METHODS: A systematic search of PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov was conducted for randomised controlled trials (RCTs) up to 29 June 2024. Eligible studies included adults with AD receiving immunotherapy versus placebo or symptomatic treatment.

RESULTS: Fifty-nine RCTs were included. Donanemab and lecanemab ranked among the most effective treatments for improving cognitive function (Clinical Dementia Rating Scale-Sum of Boxes P-scores: 0.88 and 0.77) and daily activities (Alzheimer's Disease Cooperative Study-Activities of Daily Living P-scores: 0.85 and 0.90), based on network meta-analysis findings.

CONCLUSIONS: Anti-Aβ mAbs, particularly donanemab and lecanemab, demonstrated superior efficacy over other immunotherapies in slowing cognitive deterioration, supporting their role in AD management.

PROSPERO REGISTRATION NUMBER: CRD42023461680.},
}

@article {pmid40473085,
year = {2025},
author = {Caldero-Escudero, E and Romero-Sanz, S and Álvarez-Illera, P and De la Fuente, S and García-Casas, P and Fonteriz, RI and Montero, M and Álvarez, J and Santo-Domingo, J},
title = {Calreticulin (crt-1) silencing reduces Aß1-42-induced toxicity and restores muscle function in C. elegans.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167946},
doi = {10.1016/j.bbadis.2025.167946},
pmid = {40473085},
issn = {1879-260X},
abstract = {Accumulation of aggregated β-amyloid peptide is a key histopathological feature of Alzheimer's Disease (AD). Experimental models of AD based on β-amyloid peptide display calcium (Ca[2+]) signaling alterations, and targeting key components of the cellular Ca[2+] signaling system has been postulated to modulate AD onset and progression. Here we have taken advantage of a C. elegans strain that over-expresses the most toxic human ß-amyloid peptide (Aß1-42) in body-wall muscle cells, to study the impact of calreticulin (crt-1) silencing on body-wall muscle performance. Crt-1 knockdown reduced the percentage of paralyzed worms in a dose-dependent manner and improved locomotion parameters in free-mobility assays in Aß1-42-overexpressing worms. At the cellular level, crt-1 silencing prevented Aß1-42-induced exacerbated mitochondrial respiration and mitochondrial ROS production without impacting mitochondrial sarcomere organization. Crt-1 knockdown reduced the number and size of Aß1-42 aggregates in body-wall muscle cells and prevented the formation of Aß1-42 oligomers. We propose that crt-1 depletion reduces the number of Aß1-42 aggregates, precluding Aß1-42-induced mitochondrial toxicity and improving muscle function. We identify C. elegans crt-1 as a gene involved in the toxicity associated with the expression of human Aß1-42, and thus a potential new target for treatment.},
}

@article {pmid40473076,
year = {2025},
author = {Fang, J and Shi, Y and Ba, L and Zhang, M and Li, M and Zheng, N and Qin, Y and Zhu, W},
title = {Gray Matter and White Matter Functional Connectivity Changes induced by rTMS concurrent with Cognitive training in Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111418},
doi = {10.1016/j.brainresbull.2025.111418},
pmid = {40473076},
issn = {1873-2747},
abstract = {BACKGROUND AND PURPOSE: Primarily by targeting the gray matter (GM), repetitive transcranial magnetic stimulation (rTMS) has shown promise in improving cognitive function in individuals with Alzheimer's disease (AD). However, the impact of rTMS on white matter (WM) remains poorly understood. This study aimed to investigate the functional connectivity (FC) changes in both GM and WM induced by rTMS, and explore their relationship with the clinical manifestation of the disease.

METHODS: Sixteen patients with mild to moderate AD were enrolled and randomly assigned to either the real rTMS group (n = 8) or the sham treatment group (n = 8). Both groups received cognitive training in combination with rTMS. The real rTMS group received 10Hz stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) followed by the left lateral temporal lobe (LTL), with each session lasting 20minutes per day for 4 weeks, while sham with the coil positioned at a 90° angle. Resting-state BOLD signals were averaged to generate mean time series for each of the 82 GM regions and 48 WM bundles, both before and after treatment for each subject. We analyzed the resting-state fMRI data by using a 2 × 2 factorial design with "time" as the within-subjects factor and "group" as the between-subjects factor.

RESULTS: In the analysis of 82 GM regions, when using left LTL as the seed, significant time main effect was observed in right ventral Posterior cingulate cortex (vPCC) (F=9.356, p=0.009, η[2]=0.401) and right inferior temporal gyrus (ITG) (F=11.784, p=0.004, η[2]=0.457). In the analysis of 48 WM bundles, when using left DLPFC as the seed, significant time × group interactions were found in right cingulum (hippocampus part, CGH) (F=12.123, p=0.004, η[2]=0.464). The FC between left DLPFC and right cerebral peduncle (CBRP) demonstrated significant time main effect (F=15.569, p=0.001, η[2]=0.527). Moreover, the FC between left DLPFC and right CGH was significantly correlated with MMSE scores changes (r =-0.610, p=0.027), reflecting cognitive improvements after treatment.

CONCLUSION: The current study suggested that rTMS, when combined with cognitive training, can concurrently modulate functional activities in both GM and WM in patients with mild to moderate AD, which are associated with cognitive improvements. Notably, the limbic system appears to play a pivotal role in facilitating this therapeutic process.},
}

@article {pmid40473011,
year = {2025},
author = {Saeed, TN and Al-Hussainy, AF and Sanghvi, G and Ballal, S and Singh, A and Sabarivani, A and Mishra, S and Rizaev, J and Taher, SG and Alwan, M and Jawad, M and Mushtaq, H},
title = {BDNF biosensors for neurodegenerative disease.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {120412},
doi = {10.1016/j.cca.2025.120412},
pmid = {40473011},
issn = {1873-3492},
abstract = {The brain-derived neurotrophic factor (BDNF) is essential for neuronal health and function. Dysregulated BDNF levels have been correlated with the etiology of several neurological disorders, including Alzheimer's and Parkinson's diseases. Recently, biomarkers of central nervous system (CNS) inflammatory responses have been discovered in a variety of body fluids, including blood, cerebrospinal fluid (CSF), and tears. Personalized medicine and screening programs will become feasible once biosensing technologies advance sufficiently and are widely implemented in communities. This multidisciplinary review provides an overview of the molecular structure and synthesis of BDNF, emphasizing the complexity and intricate regulation of this crucial neurotrophic factor, as well as exploring the potential of BDNF as a biomarker for neurological conditions. It focuses on its role in disease progression and its utility in early disease detection using aptasensors and immunosensors. We also discuss the challenges associated with utilizing BDNF as a biomarker, such as its complex regulation and the need for sensitive and specific detection methods by electrochemical and optical transducers. Furthermore, we highlight the potential of biosensors to overcome these challenges by enabling real-time, non-invasive, and point-of-care (POC) monitoring of BDNF levels.},
}

@article {pmid40472826,
year = {2025},
author = {Saiz Vazquez, O and Ubillos-Landa, S and Puente Martínez, A},
title = {A META ANALYSIS OF THE RELATIONSHIP BETWEEN STROKE AND ALZHEIMER'S DISEASE: THERAPEUTIC AND PROGNOSTIC IMPLICATIONS.},
journal = {Kidney & blood pressure research},
volume = {},
number = {},
pages = {1-31},
doi = {10.1159/000546395},
pmid = {40472826},
issn = {1423-0143},
abstract = {BACKGROUND: Several population-based studies have highlighted the association between stroke and dementia. Alzheimer's disease (AD) related dementia and vascular dementia are the most common causes of dementia, with clearer pathophysiological mechanisms for the latter. Given the ongoing debate surrounding the link between stroke and Alzheimer's disease, to determine their relationship and the possible influence of some moderators (sex, age, and region), a systematic meta-analysis was performed.

METHODS: We searched five databases (ISI Web of Science, Scopus, PubMed, Elsevier Science Direct, and Google Scholar) with no initial publication date restriction, with the last search conducted in 2022. We included longitudinal population-based studies assessing the stroke-AD association, selecting those with reported effect sizes, standardized AD diagnosis, and an AMSTAR score ≥9. Case reports, reviews, animal studies, and non-English publications were excluded. The meta-analysis, conducted using Comprehensive Meta-Analysis 3.1, presented pooled log odds ratios (LogOR) with 95% confidence intervals, heterogeneity analysis (Cochran's Q, I²), and moderator analyses by age, gender, and region.

RESULTS: The meta-analysis included three meta-analyses and twelve primary studies, comprising a total of 14,207 stroke cases and 1,952 AD cases. Our analysis found a significant association between ischemic stroke (IS), hemorrhagic stroke (HS), and microinfarcts (MI) with the risk of AD. Despite some heterogeneity across studies, no significant differences were observed in the stroke-AD association based on age, sex, or region.

CONCLUSION: Our study describes the risk of AD in patients with episodes of stroke (IS, HS and MI), and suggests that the risk of AD may be higher in patients that suffer stroke when compared to matched controls without incidence of stroke. Moreover, moderator analysis supports the robustness of our results. The link between stroke and Alzheimer's suggests that stroke may speed up cognitive decline. This calls for tighter vascular control and points to a worse prognosis in dementia progression.},
}

@article {pmid40472805,
year = {2025},
author = {Sakono, M and Ichida, H and Inobe, T},
title = {The a-type domain of protein disulfide isomerase suppresses amyloid-β aggregation and cytotoxicity.},
journal = {Biochemical and biophysical research communications},
volume = {775},
number = {},
pages = {152141},
doi = {10.1016/j.bbrc.2025.152141},
pmid = {40472805},
issn = {1090-2104},
abstract = {Abnormal aggregation of amyloid-β (Aβ) peptide and associated neurotoxicity are key pathological hallmarks of Alzheimer's disease. Protein disulfide isomerase (PDI) contains four thioredoxin-like domains arranged as a, b, b', and a' from the N-terminus. The a-type domains (a and a') possess catalytic activity essential for redox regulation, while the b-type domains (b and b') are mainly involved in substrate interactions. This study aimed to elucidate the effects of PDI, an enzyme involved in protein redox control and folding, on Aβ aggregation, focusing on its distinct domains. PDI variants containing the a-type domains potently inhibited Aβ aggregation. Furthermore, an aa' variant effectively stabilized Aβ monomers and significantly reduced Aβ-induced cytotoxicity. Conversely, the b-type domains exhibited no clear inhibitory effect on Aβ aggregation. Moreover, in serum-containing medium, the b-type domains potentially hindered the anti-aggregation function of full-length PDI, possibly through interactions with other proteins. These results indicate that PDI's a-type domains play a central role in inhibiting Aβ aggregation and highlight the aa' variant as a potential candidate for novel therapeutic strategies against Alzheimer's disease.},
}

@article {pmid40472637,
year = {2025},
author = {Doulberis, M and Tsilimpotis, D and Polyzos, SA and Vardaka, E and Salahi-Niri, A and Yadegar, A and Kountouras, J},
title = {Unraveling the pathogenetic overlap of Helicobacter pylori and metabolic syndrome-related Porphyromonas gingivalis: Gingipains at the crossroads and as common denominator.},
journal = {Microbiological research},
volume = {299},
number = {},
pages = {128255},
doi = {10.1016/j.micres.2025.128255},
pmid = {40472637},
issn = {1618-0623},
abstract = {Chronic bacterial infections exert profound systemic effects beyond their primary infection sites, influencing a range of inflammatory, metabolic, and neurodegenerative diseases. Helicobacter pylori (Hp) and Porphyromonas gingivalis (Pg) are two highly prevalent pathogens that, despite occupying distinct niches, share remarkable pathogenic similarities. Both bacteria, connected with metabolic syndrome, employ immune evasion strategies, induce chronic inflammation, and contribute to systemic diseases such as metabolic-associated steatotic liver disease, cardiovascular disease, and neurodegeneration, such as Alzheimer's disease. A key unifying factor in their pathogenicity is the role of gingipains-cysteine proteases produced by Pg-which facilitate bacterial invasion, immune modulation, and tissue destruction. Emerging evidence suggests that Hp possesses analogous proteolytic enzymes, further supporting their potential synergistic impact on host health. Moreover, both pathogens have been implicated in metabolic syndrome-related blood-brain barrier disruption, chronic (smoldering) systemic inflammation, and lipid metabolism dysregulation, contributing to progressive neurodegenerative and cardiovascular disorders. The role of galectins, particularly galectin-3, in modulating microglial activation and inflammatory pathways further highlights their involvement in neuroinflammatory diseases. Targeting gingipains presents a promising therapeutic avenue, with bismuth compounds and novel inhibitors showing potential in disrupting these proteases and mitigating their systemic effects. Understanding the interactions between Hp and metabolic syndrome-related Pg is crucial for developing comprehensive treatment strategies, integrating gastroenterology, periodontology, and neurology. Addressing these infections at both local and systemic levels may improve long-term health outcomes and reduce the burden of chronic inflammatory diseases linked to microbial persistence.},
}

@article {pmid40472592,
year = {2025},
author = {Meyer, N and Arroyo, N and Roustan, L and Janot, JM and Perrier, V and Torrent, J and Picaud, F and Balme, S},
title = {Effect of pyrimethanil on aβ42 aggregation mechanisms revealed at single entity level and molecular dynamic simulations.},
journal = {Biophysical chemistry},
volume = {325},
number = {},
pages = {107471},
doi = {10.1016/j.bpc.2025.107471},
pmid = {40472592},
issn = {1873-4200},
abstract = {This study investigated the impact of pyrimethanil, a fungicide, on the aggregation of amyloid-β 42 (aβ42) peptides in vitro. The findings demonstrated that pyrimethanil accelerated aβ42 aggregation kinetics, as evidenced by thioflavin T (ThT) fluorescence assays in both tube and microplate experiments. A combination of single molecule techniques and molecular dynamics simulations is used to elucidate the complex effects of pyrimethanil on aβ42 aggregation mechanism. Nanopore experiments indicated that pyrimethanil promoted the formation of small oligomers (6-13.5 nm) during the lag phase, which were not detected under control conditions. Confocal fluorescence spectroscopy revealed that pyrimethanil induced the formation of larger β-sheet structured aggregates. In the presence of preformed seeds, pyrimethanil exhibited a dual role by fragmenting existing fibrils into smaller species and enhancing aggregation, likely through combined effects with the newly formed smaller seeds. Molecular dynamics simulations confirmed that pyrimethanil has a higher affinity for fibrils than monomers and weakens monomer-fibril interactions. Overall, this study elucidates the complex effects of pyrimethanil on aβ42 aggregation, involving promotion of primary nucleation, fibril fragmentation, and modulation of monomer-fibril interactions. These findings provide important mechanistic insights into how environmental factors like pesticides may influence amyloid aggregation processes relevant to Alzheimer's disease.},
}

@article {pmid40472304,
year = {2025},
author = {Selma-Gonzalez, J and Rubio-Guerra, S and García-Castro, J and Vera-Campuzano, E and Sala, I and Sánchez-Saudinós, MB and Zhu, N and Arranz, J and Arriola-Infante, JE and Rodríguez-Baz, Í and Maure-Blesa, L and Dols-Icardo, O and Videla, L and Valldeneu, S and Barroeta, I and Santos-Santos, M and Carmona-Iragui, M and Vaqué-Alcázar, L and Alvarez-Sanchez, E and Lorente, O and Carreras, M and Belbin, O and Arslan, B and Ashton, NJ and Zetterberg, H and Blennow, K and Montoliu-Gaya, L and Bejanin, A and Lleó, A and Fortea, J and Alcolea, D and Illan-Gala, I},
title = {Association of Plasma Phosphorylated Tau 217 With Clinical Deterioration Across Alzheimer Disease Stages.},
journal = {Neurology},
volume = {105},
number = {1},
pages = {e213769},
doi = {10.1212/WNL.0000000000213769},
pmid = {40472304},
issn = {1526-632X},
mesh = {Humans ; *tau Proteins/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/diagnosis/cerebrospinal fluid/psychology ; Female ; Male ; Aged ; Disease Progression ; Phosphorylation ; Longitudinal Studies ; Retrospective Studies ; Biomarkers/blood/cerebrospinal fluid ; Aged, 80 and over ; Cognitive Dysfunction/blood ; Amyloid beta-Peptides/cerebrospinal fluid ; Prognosis ; Middle Aged ; },
abstract = {BACKGROUND AND OBJECTIVES: Phosphorylated tau at threonine 217 (p-tau217) is a highly sensitive blood-based biomarker for Alzheimer disease (AD) pathology, showing high diagnostic accuracy. However, its prognostic value across different clinical stages of AD remains unclear. The aim of this study was to assess the prognostic utility of plasma p-tau217, measured using a commercially available immunoassay, regarding clinical and functional decline across the clinical stages of AD in a cohort with up to 10 years of follow-up.

METHODS: We conducted a retrospective longitudinal cohort study using data from the Sant Pau Initiative on Neurodegeneration, a research project performed at the Sant Pau Memory Unit between 2011 and 2022. Participants were classified into clinical stages 1-6 based on AD pathology status in CSF, determined by the p-tau181/Aβ1-42 ratio. The primary outcomes were cognitive decline, measured by changes in the Mini-Mental State Examination (MMSE), and progression to dementia. Plasma p-tau217 and CSF p-tau181 levels were assessed, and statistical analysis was performed using linear mixed-effects models for longitudinal changes in MMSE scores and Cox proportional hazard regression was used to examine progression to dementia.

RESULTS: A total of 731 participants (mean age 71.5 ± 10.1 years; 60% female) were included. Plasma p-tau217 levels showed a significant increase across advancing AD stages, with all between-group comparisons remaining significant after false discovery rate adjustment (p < 0.05). Longitudinal analysis showed a significant increase in plasma p-tau217 (β = 7.7, 95% CI 3.0-12.5, p = 0.002) and CSF p-tau181 (β = 3.2, 95% CI 1.4-5.0, p = 0.001). Baseline plasma p-tau217 levels were associated with faster MMSE decline (β = -0.08, 95% CI -0.11 to -0.05, p < 0.001) and progression to dementia (hazard ratio 1.03, 95% CI 1.01-1.05, p < 0.001), independent of clinical stage.

DISCUSSION: Plasma p-tau217 was significantly associated with cognitive and functional decline in AD. These findings support the potential use of plasma p-tau217 as a prognostic marker for monitoring AD progression in clinical practice. Future studies should validate these results across diverse cohorts and explore their utility in early-stage detection and monitoring.},
}

Humans
*tau Proteins/blood/cerebrospinal fluid
*Alzheimer Disease/blood/diagnosis/cerebrospinal fluid/psychology
Female
Male
Aged
Disease Progression
Phosphorylation
Longitudinal Studies
Retrospective Studies
Biomarkers/blood/cerebrospinal fluid
Aged, 80 and over
Cognitive Dysfunction/blood
Amyloid beta-Peptides/cerebrospinal fluid
Prognosis
Middle Aged

@article {pmid40472201,
year = {2025},
author = {Cheishvili, D and Carmo, SD and Caraci, F and Grasso, M and Cuello, AC and Szyf, M},
title = {Correction for: EpiAge: a next-generation sequencing-based ELOVL2 epigenetic clock for biological age assessment in saliva and blood across health and disease.},
journal = {Aging},
volume = {17},
number = {5},
pages = {1368},
doi = {10.18632/aging.206263},
pmid = {40472201},
issn = {1945-4589},
}

@article {pmid40472196,
year = {2025},
author = {Sun, Y and Xie, X and Zou, X and Zhou, F},
title = {Neuroinflammatory chemokine networks in transgenic models of Alzheimer's disease: A comparative multi-compartmental analysis.},
journal = {Human & experimental toxicology},
volume = {44},
number = {},
pages = {9603271251348723},
doi = {10.1177/09603271251348723},
pmid = {40472196},
issn = {1477-0903},
mesh = {Animals ; *Alzheimer Disease/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Chemokines/metabolism/blood ; Mice ; Brain/metabolism ; Microglia/metabolism ; Humans ; Male ; *Neuroinflammatory Diseases/metabolism ; },
abstract = {BackgroundAlzheimer's disease (AD) progression is critically modulated by neuroinflammatory cascades involving chemokine-mediated glial activation.ObjectiveThis study aimed to systematically compare compartment-specific chemokine signatures between two distinct AD mouse models (2×Tg-AD [APPswe/PS1dE9] and 3×Tg-AD [APPswe/PS1M146V/TauP301L]), hypothesizing that differential chemokine expression patterns would emerge in a model- and brain region-specific manner, correlating with glial activation profiles.ResultsUsing a Luminex liquid suspension chip assay, we quantified 22 chemokines in serum and brain tissues from transgenic and non-transgenic controls, complemented by Western blot analysis of microglial and astrocytic markers. Twenty-two chemokines were quantitatively analyzed with three key findings: First, serum analysis revealed elevated levels of (i) CCL11, CCL17, CCL24, CCL27, and CXCL12 in 3×Tg-AD versus non-Tg mice; (ii) CCL22 in 2×Tg-AD versus non-Tg mice; and (iii) CCL5, CCL11, CCL17, CCL24, CCL27, and CXCL12 in 3×Tg-AD versus 2×Tg-AD mice. Second, hippocampal changes showed upregulation of CCL3/CCL12 in 2×Tg-AD and CXCL16 in 3×Tg-AD mice, with cortical alterations demonstrating distinct CCL3/CCL12/CCL4 increases in 2×Tg-AD versus elevated CCL1/CXCL13 in 3×Tg-AD mice. Third, Western blot confirmed enhanced hippocampal microglial activation specifically in 3×Tg-AD mice. ConclusionOur findings establish model-specific chemokine signatures that differentially engage neuroinflammatory pathways, suggesting that 3×Tg-AD mice may better replicate human AD's complex chemokine-glia interactions. This compartmentalized profiling provides a framework for targeting chemokine networks in model-specific therapeutic development and biomarker discovery. Further studies are needed to determine whether elevated chemokine expression directly contributes to microglial activation.},
}

Animals
*Alzheimer Disease/metabolism
Mice, Transgenic
Disease Models, Animal
*Chemokines/metabolism/blood
Mice
Brain/metabolism
Microglia/metabolism
Humans
Male
*Neuroinflammatory Diseases/metabolism

@article {pmid40471990,
year = {2025},
author = {Yang, Y and Lorincz-Comi, N and Li, M and Zhu, X},
title = {A multivariable cis-Mendelian randomization method robust to weak instrument bias and horizontal pleiotropy bias.},
journal = {Briefings in bioinformatics},
volume = {26},
number = {3},
pages = {},
doi = {10.1093/bib/bbaf250},
pmid = {40471990},
issn = {1477-4054},
support = {HG011052/HG/NHGRI NIH HHS/United States ; HG011052-03S1/HG/NHGRI NIH HHS/United States ; },
mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Genetic Pleiotropy ; Bias ; Alzheimer Disease/genetics ; Linkage Disequilibrium ; Polymorphism, Single Nucleotide ; },
abstract = {Multivariable cis-Mendelian randomization (cis-MVMR) has become an effective approach for identifying therapeutic targets that influence disease susceptibility. However, biases from invalid instruments, such as weak instruments and horizontal pleiotropy, remain unsolved. In this paper, we propose a new method called the cis-Mendelian randomization bias correction estimating equation (cis-MRBEE), which mitigates weak instrument bias by leveraging a local sparse genetic architecture: most variants within a genomic region are associated with a trait through linkage disequilibrium with a few causal variants. Cis-MRBEE identifies causal variants or proxies of exposures via fine-mapping, re-estimates genetic associations using the identified variants, and applies a double-penalized minimization to estimate causal exposures and account for horizontal pleiotropic effects. Simulations showed that in the presence of weak instruments and horizontal pleiotropy, directly adapting standard MVMR methods to cis-MVMR was infeasible, and existing cis-MVMR methods failed to control type I errors. In contrast, cis-MRBEE exhibited robustness to these sources of bias. We applied cis-MRBEE to the ANGPTL3 locus and identified a credible set comprising APOA1, APOC1, and PCSK9 as likely causal proteins for LDL-C, HDL-C, and TG. The subsequent analysis revealed a complex protein regulation network that influenced lipid traits. Furthermore, we used cis-MRBEE to discover that the expressions of CR1 in the basal ganglia, hippocampus, and oligodendrocytes were potentially causal for Alzheimer's disease and its biomarkers, A$\beta $42 and pTau, in cerebrospinal fluid.},
}

Humans
*Mendelian Randomization Analysis/methods
*Genetic Pleiotropy
Bias
Alzheimer Disease/genetics
Linkage Disequilibrium
Polymorphism, Single Nucleotide

@article {pmid40471789,
year = {2025},
author = {Lish, AM and Ashour, N and Pearse, RV and Galle, PC and Orme, GA and Heuer, SE and Benoit, CR and Alexander, KD and Grogan, EFL and Terzioglu, G and Scarpa, A and Stern, AM and Seyfried, N and Menon, V and Young-Pearse, TL},
title = {Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures.},
journal = {Cell reports},
volume = {44},
number = {6},
pages = {115777},
doi = {10.1016/j.celrep.2025.115777},
pmid = {40471789},
issn = {2211-1247},
abstract = {Advancements in human induced pluripotent stem cell (hiPSC) technology have enabled co-culture models for disease modeling in physiologically relevant systems. However, co-culturing protocols face challenges in usability and consistency. Here, we introduce a robust, reproducible hiPSC-derived co-culture system integrating astrocytes, neurons, and microglia. This model leverages cryopreserved cells, enabling co-cultures within 20 days post-thaw. Comparing monocultures and tricultures, we demonstrate how cell-cell interactions shape transcriptional and functional states across all three cell types. Neurons in triculture exhibit increased spine density and activity, while astrocytes and microglia show altered responses to proinflammatory stimulation. Surprisingly, the presence of astrocytes induces upregulation of disease-associated microglia (DAM) genes, including TREM2, SPP1, APOE, and GPNMB in microglia. Additionally, while familial Alzheimer's disease neurons induce a prototypical inflammatory response in microglia, the DAM signature is significantly dampened. Collectively, this study establishes a versatile human triculture model as a valuable resource for dissecting neuron-glia interactions and their role in neurodegenerative disease.},
}

@article {pmid40471684,
year = {2025},
author = {Andersen, M and Hirase, H and Kjaerby, C and Nedergaard, M},
title = {Neuroglia's signaling: orchestrating neuronal gamma synchrony?.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
doi = {10.1097/WCO.0000000000001392},
pmid = {40471684},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: Gamma oscillations (30-80 Hz) play a crucial role in sensory processing and cognitive functions, with disruptions in these rhythms linked to neurological disorders such as schizophrenia and Alzheimer's disease. This review highlights the emerging role of astrocytes in regulating gamma oscillations, emphasizing their contribution to the inhibitory tone and extracellular ion homeostasis.

RECENT FINDINGS: Recent studies suggest that astrocytes facilitate gamma synchrony, while dysfunction in astrocytic activity - such as impaired Ca2+ signaling - is associated with deficits in gamma oscillations and increased network hyperexcitability. Thus, astrocytic dysfunction may contribute to the pathophysiology of gamma-related disorders.

SUMMARY: By examining the role of astrocytes in maintaining neuronal network stability, this review highlights new aspects of neuroglia signaling.},
}

@article {pmid40471578,
year = {2025},
author = {Mudrazija, S and Aranda, MP and Gaskin, DJ and Monroe, S and Richard, P},
title = {Economic Burden of Alzheimer Disease and Related Dementias by Race and Ethnicity, 2020 to 2060.},
journal = {JAMA network open},
volume = {8},
number = {6},
pages = {e2513931},
doi = {10.1001/jamanetworkopen.2025.13931},
pmid = {40471578},
issn = {2574-3805},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/economics/ethnology ; *Cost of Illness ; Middle Aged ; Aged ; Cross-Sectional Studies ; United States/epidemiology ; Caregivers/economics/statistics & numerical data ; Black or African American/statistics & numerical data ; *Ethnicity/statistics & numerical data ; *Dementia/economics/ethnology ; White People/statistics & numerical data ; Hispanic or Latino/statistics & numerical data ; Aged, 80 and over ; Health Expenditures/statistics & numerical data ; White ; },
abstract = {IMPORTANCE: Alzheimer disease and related dementias (ADRD) have substantial clinical and public health consequences for individuals, families, employers, and government.

OBJECTIVE: To assess ADRD's economic burden on non-Latino African American, Latino, and non-Latino White adults and their caregivers, employers, and the government between 2020 and 2060.

Population-based cross-sectional study using nationally representative data on African American, Latino, and White adults aged 50 years and older with ADRD and their unpaid caregivers from the 2014 to 2020 Medical Expenditure Panel Survey (MEPS) alongside the 2011 to 2017 National Study of Caregiving (NSOC) and 2013 Panel Study of Income Dynamics. These data were augmented with information from the US Census Bureau, Bureau of Labor Statistics, Internal Revenue Service, and other sources to estimate current and future economic burden. Two-part regression models were used to estimate medical and work-related costs for older adults, and multivariate-distance matching was used to estimate the value of unpaid care, lost wages and productivity, loss of federal income tax revenue, and financial transfers for caregivers. Data were analyzed from March 2023 to February 2025.

EXPOSURE: Older adults with ADRD and their family caregivers.

MAIN OUTCOMES AND MEASURES: Projected medical costs and work-related losses for persons with ADRD, and unpaid care value, forgone earnings, and lost federal income tax payments and labor productivity for caregivers.

RESULTS: Of 31 028 older adults in MEPS, 5184 (10%) were African American; 146 (<1%) American Indian or Alaska Native; 1043 (3%) Asian (Indian, Chinese, or Filipino); 5346 (10%) Latino; 690 (2%) Other Asian, Native Hawaiian, and Pacific Islander; and 18 617 (75%) were White. In the NSOC sample of 1929 older adults, there were 644 (33%) African American, 169 (9%) Latino, and 1116 (58%) White adults. The total estimated economic burden of ADRD was close to $344 billion in 2020 and was projected to increase to over $3 trillion in 2060. African American and Latino adults bore one-third ($113 billion) of it in 2020, with projections rising to $1.7 trillion by 2060, surpassing the economic burden for White adults, which was projected to grow from $231 billion to $1.4 trillion.

CONCLUSIONS AND RELEVANCE: The findings of this study suggest that African American and Latino older adults with ADRD and their families are likely to face disproportionately high burdens, primarily associated with unpaid caregiving. Understanding ADRD prevalence, comorbidity, inadequate care, and support policies may attenuate economic burdens for all US residents.},
}

Humans
Female
Male
*Alzheimer Disease/economics/ethnology
*Cost of Illness
Middle Aged
Aged
Cross-Sectional Studies
United States/epidemiology
Caregivers/economics/statistics & numerical data
Black or African American/statistics & numerical data
*Ethnicity/statistics & numerical data
*Dementia/economics/ethnology
White People/statistics & numerical data
Hispanic or Latino/statistics & numerical data
Aged, 80 and over
Health Expenditures/statistics & numerical data
White

@article {pmid40471493,
year = {2025},
author = {Kärkkäinen, V and Saari, T and Rusanen, M and Uusitalo, H and Leinonen, V and Thiede, B and Kaarniranta, K and Koivisto, AM and Utheim, TP},
title = {Neuroinflammation Markers in Tear Fluid of Mild Alzheimer's Disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {2},
pages = {73},
pmid = {40471493},
issn = {1559-1166},
mesh = {Humans ; *Alzheimer Disease/metabolism ; Aged ; Female ; *Tears/metabolism/chemistry ; Male ; Biomarkers/metabolism ; *Eye Proteins/metabolism/genetics ; Aged, 80 and over ; },
abstract = {The protein composition of tear fluid (TF) reflects the severity and progression of many age-related diseases. Here, we evaluated TF proteins from patients with mild Alzheimer's disease (AD) and cognitively healthy controls (CO) to explore potential new biomarker molecules. The aim of this study was to explore potential new biomarker molecules by examining the expression of TF proteins whose function is related to neuroinflammation. We examined 53 participants (34 COs, mean age 71 years, Mini-Mental State Examination (MMSE) score 28.9 ± 1.4; 19 with AD, Clinical Dementia Rating 0.5-1, mean age 72 years, MMSE 23.8 ± 2.8). All participants underwent neurological status examination, cognitive testing, and ophthalmological examination. TF was collected using Schirmer strips, and TF protein content was evaluated using mass spectrometry-based proteomics and label-free quantification. We report 14 TF proteins that showed altered protein expression in the AD group compared to the CO group. Twelve proteins were significantly upregulated (SERPINA3, FGA, SIAS, ORM1, ANXA3, G6PI/NLK, CH3L2, MSLN, CPPED1, JCHAIN, IGHV5-51, SPARCL1) and two were downregulated (PIP, SCGB2A1) (p ≤ 0.05). Observed altered expression of TF proteins in the AD group may have potential in AD pathology. Since inflammation is one of the earliest signs of neurodegeneration in AD, these proteins are putative new biomarker candidates of early AD.},
}

Humans
*Alzheimer Disease/metabolism
Aged
Female
*Tears/metabolism/chemistry
Male
Biomarkers/metabolism
*Eye Proteins/metabolism/genetics
Aged, 80 and over

@article {pmid40471318,
year = {2025},
author = {Galli, A and Inglese, M and Presotto, L and Malito, R and Di, X and Toschi, N and Pilotto, A and Padovani, A and Tassorelli, C and Perani, D and Sala, A and Caminiti, SP},
title = {Glucose metabolism in hyper-connected regions predicts neurodegeneration and speed of conversion in Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {40471318},
issn = {1619-7089},
support = {1553 11.10.2022//Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP)/ ; },
abstract = {PURPOSE: Here, we combined a longitudinal design to assess whole-brain hyper- and hypo-connectivity in the different clinical phases of Alzheimer's disease (AD) with a multimodal approach to understand how such connectivity changes were related to glucose hypometabolism.

METHODS: We selected a longitudinal cohort of N = 66 subjects with clinical, cerebrospinal fluid and FDG-PET assessments, from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. N = 31 AD individuals were assessed at three stages: mild cognitive impairment (AD-MCI, T0), early phase of dementia (mild-AD, T1) and dementia (AD-D, T2). We included N = 35 age/sex-matched healthy controls. We assessed longitudinal metabolic connectivity using Pearson's correlation, clustering analysis and graph theory metrics.

RESULTS: In the MCI-AD stages, hypo- and hyper-connectivity coexisted. Data-driven, longitudinal clustering analysis identified specific pathological clusters: a default mode network cluster, with prevalent hypo-connectivity and severe, persistent hypometabolism; a limbic cluster showing hyper-connectivity and steeper metabolic decline. Metabolism in hyper-connected limbic regions showed a mediation effect on worsening of AD-like parieto-temporal hypometabolism and predicted faster conversion to dementia.

CONCLUSION: Hypo- and hyper-connectivity, especially in early stages, may have different roles in AD neurodegenerative processes, with metabolism in hyper-connected regions acting as a mediator on the neurodegeneration of core regions of AD pathology.},
}

@article {pmid40470974,
year = {2025},
author = {Li, Z and Ma, JL and Yang, J and Sun, T and Xiao, B and Han, M and Ma, H and Wang, ZZ and Su, Y and Song, J and Li, X and Wang, P and Zhang, Z},
title = {Discovery of Atractylenolide Derivatives as Novel LSD1 Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c02433},
pmid = {40470974},
issn = {1520-5118},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline and memory impairment. Current treatments offer only symptomatic relief, underscoring the urgent need for novel therapeutic strategies. Lysine-specific demethylase 1 (LSD1) plays a crucial role in gene transcription regulation and has emerged as a potential therapeutic target for AD. Building on our previous research on Atractylodes macrocephala, a traditional medicinal plant, this study reported chemical modifications on the sesquiterpene scaffold in Atractylodes. The compounds were evaluated for their LSD1 inhibitory activity and anti-AD properties in both in vitro and in vivo studies. Notably, compound A1 exhibited potent LSD1 inhibition, with an IC50 value of 0.8 μM. In vitro assays demonstrated that A1 significantly inhibits Aβ aggregation and enhances Aβ-induced neuronal cell viability. Molecular dynamics results revealed stable binding interactions of A1 with LSD1 and Aβ. Furthermore, in vivo studies using APP/PS1 transgenic mice showed that A1 treatment improved cognitive function and learning abilities, reduced neuroinflammation by inhibiting the activation of microglia and astrocytes, and decreased Aβ deposition in the hippocampus of AD mice. These findings suggest that compound A1 is a promising candidate for the development of an effective therapy for AD, underscoring the therapeutic potential of novel LSD1 inhibitors.},
}

@article {pmid40470723,
year = {2025},
author = {Jayakody, O and Blumen, HM and Grabanski, M and Ceïde, M and George, C},
title = {Readiness and Barriers to Participate in Alzheimer's and Dementia Research Among Older Adults.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.19568},
pmid = {40470723},
issn = {1532-5415},
support = {//Department of Medicine/Geriatrics, Albert Einstein College of Medicine/ ; },
}

@article {pmid40470403,
year = {2025},
author = {Abbas Raja, A and Amjad, A and Choudhary, A and Atta, A and Atta, M and Hussain, S and Khan, M},
title = {Comparative Effectiveness of Rivastigmine and Donepezil in Patients With Alzheimer's Disease: A Retrospective Cohort Study.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e83498},
pmid = {40470403},
issn = {2168-8184},
abstract = {This is a retrospective cohort study comparing the effectiveness of rivastigmine and donepezil in Alzheimer's disease (AD) patients. Of the 250 subjects, 127 (50.8%) were men, while 123 (49.2%) were women. Baseline cognitive function was assessed using the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). The results showed that 83 (33.2%) patients improved, 84 (33.6%) remained stable, and 83 (33.2%) experienced cognitive decline. The difference between the two groups was not significant with respect to cognitive outcomes (Chi-square = 0.08, df = 2, N = 250, p = 0.96). However, rivastigmine was associated with a higher rate of side effects (65, or 52%), which could hinder adherence. Both groups had an average of 1.48 hospitalization episodes per patient. Biomarker analysis suggested that 144 (57.6%) of patients tested positive for amyloid on positron emission tomography (PET) scans. Cerebrospinal fluid (CSF) analysis data, illustrated through mean values, showed amyloid beta at 546.38 pg/mL and tau at 219.85 pg/mL - both linked to cognitive decline. Higher levels of tau were significantly correlated with greater cognitive decline. Statistically, there were significant differences between the treatment groups in terms of MMSE scores and CSF biomarkers (p < 0.05). Although there was no statistically significant difference in cognitive outcomes between the drugs, subgroup analysis revealed significant differences in baseline MMSE scores and CSF biomarker levels (p < 0.05), suggesting heterogeneity in disease severity. Therefore, personalized strategies for managing patients with AD should be constructed based on the drug's side effect profile, comorbidities, and biomarker status. Future studies should focus on biomarker-directed and combination therapies to improve treatment efficacy.},
}

@article {pmid40470298,
year = {2025},
author = {Sha, D and Zhang, J and Fang, X and Wang, X and He, X and Shu, X},
title = {Expression and potential regulatory mechanism of cellular senescence-related genes in Alzheimer's disease based on single-cell and bulk RNA datasets.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1595847},
pmid = {40470298},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. However, the particular cause of AD development has not been fully elucidated. Currently, cellular senescence is recognized as a contributing factor to the aging process and age-related diseases.

METHODS: The present study aimed to identify the hinge of regulatory factors in dysfunctional cellular senescence genes in AD via integrating multiple omics analysis, including single-cell RNA sequencing and bulk sequencing data. In addition, UMAP scatter diagrams were constructed, while active cell subtypes and pathways involved in cellular senescence were identified via performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, respectively.

RESULTS: The results indicated that a total of seven clusters were detected by known marker genes, including excitatory neurons, inhibitory neurons, astrocytes, microglial cells, oligodendrocytes, oligodendrocyte progenitor cells and pericytes/endothelial cells. CDK18 was specifically expressed in oligodendrocytes, RUNX1 in microglia, SORBS2 and KSR2 in neurons, PDZD2 in oligodendrocyte progenitors, YAP1 in astrocytes and NOTCH3 in pericytes/endothelial cells. Astrocytes, microglia, and pericytes/endothelial cells were found to be the most active cell subtypes. AD-associated cellular senescence genes in the Astrocytes subgroup (SOX5, AR, HMGB1, NR2E1, ID4, TP53, MXD4, FOS, BHLHE40, PIVEP1), microglia subgroup (BCL6, ETS2, CEBPB, MXD4, FOS, NFE2L2, FOXO3, IRF3, PBRM1, RUNX1, IRF5, ZNF148) and pericyte/endothelial cell subgroup (SOX5, BCL6, ETS2, CEBPB, FOS, TP63, TBX2, ETS1, BHLHE40, ID1) were identified. Furthermore, potential therapeutic targets and drugs for AD were identified via analyzing the molecular mechanisms and pathways involved in cellular senescence.

CONCLUSION: The above findings demonstrated that cellular senescence could play a crucial role in the pathogenesis of AD and highlighted the significance of understanding the role of cellular senescence in the pathogenesis of AD. The results of the current study could provide novel insights into the development of potential therapeutic targets and pave the way for the development of novel therapeutic strategies for AD.},
}

@article {pmid40470240,
year = {2025},
author = {Cruchaga, C and Timsina, J and Jiang, C and McCartney, D and Tao, F and Dalmasso, MC and Najar, J and Anastasi, F and Ohlei, O and Puerta, R and Bradley, J and Western, D and Ali, M and Wang, C and Yang, C and Wu, Y and Liu, M and Budde, J and Williams, J and Mahoney, R and Castillo, A and Hohman, T and Dumitrescu, L and Wang, TC and Tesi, N and Kern, S and Waern, M and Skoog, I and van Harten, A and van der Flier, W and Sánchez-Juan, P and Rodriguez-Rodriguez, E and Kleineidam, L and Peters, O and Schneider, A and Küçükali, F and Bellenguez, C and Grenier-Boley, B and Heikkinen, S and de Rojas, I and Rujescu, D and Scherbaum, N and Hausner, L and Duzel, E and Grimmer, T and Wiltfang, J and Vandenberghe, R and Engelborghs, S and Heilmann-Heimbach, S and Schmid, M and Tegos, T and Scarmeas, N and Dols-Icardo, O and Moreno, F and Pérez-Tur, J and Bullido, MJ and Sanchez-Valle, R and Álvarez, V and Garcia-Gonzalez, P and Mir, P and Real, L and Piñol-Ripoll, G and García-Alberca, JM and Seelaar, H and Ramakers, I and Papma, J and Hulsman, M and Laske, C and Teipel, S and Priller, J and Perneczky, R and Buerger, K and Nöthen, M and Lewczuk, P and Kornhuber, J and Maier, W and Hampel, H and Giegling, I and Goldhardt, O and Diehl-Schmid, J and Andrade, V and Heneka, M and Froelich, L and Vogelgsang, J and Graff, C and Thonberg, H and Ullgren, A and Papenberg, G and Boland, A and Deleuze, JF and Wagner, M and Jessen, F and Holstege, H and van Duijn, C and Lebouvier, T and Hanon, O and Leinonen, V and Soininen, H and Herukka, SK and Giedraitis, V and Löwenmark, M and Kilander, L and Genius, P and Rodríguez, B and Luckett, E and Navarro, A and Cano, A and Marquié, M and Blennow, K and Zetterberg, H and Lleo, A and Boada, M and Laza, AR and Lee, V and Deerlin, VV and Deming, Y and Johnson, S and Engelman, C and Pastor, P and Alvarez, I and Peskind, E and Heslegrave, A and Saykin, A and Nho, K and Schindler, S and Morris, J and Holtzman, D and McDade, E and Renton, A and Goate, A and Ibanez, L and Riemenschneider, M and Albert, M and Laws, S and Porter, T and O'Brien, E and Shaw, L and Tijms, B and Ingelsson, M and Visser, PJ and Hiltunen, M and Sleegers, K and Ritchie, C and Sims, R and Lambert, JC and Vilor-Tejedor, N and Fernández, M and Li, Q and Nagle, M and Marioni, R and Ramirez, A and Bertram, L and van der Lee, S},
title = {GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6597595/v1},
pmid = {40470240},
issn = {2693-5015},
abstract = {Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation.},
}

@article {pmid40470227,
year = {2025},
author = {Kim, J and Lipford, ME and Barcus, RA and Frye, BM and Yuan, H and Lyu, Q and Hudson, JP and Lockhart, SN and Sutphen, CL and Register, TC and Mielke, MM and Craft, S and Shively, CA and Whitlow, CT},
title = {Effects of Diminished Cerebrospinal Fluid Flow in the Spinal Canal on Amyloid Pathophysiology in Vervet Monkeys.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6551242/v1},
pmid = {40470227},
issn = {2693-5015},
abstract = {Background Translational models using nonhuman primates provide valuable insights into the pathological changes associated with human brain aging. This study investigates the vervet monkey (Chlorocebus aethiops sabaeus) as a model for age-related Alzheimer's disease (AD)-like amyloid clearance impairment. The cerebrospinal fluid (CSF) plays a crucial role as a transport medium for waste clearance from the brain's interstitial space to lymphatic vessels. Methods To test the hypothesis that diminished CSF perfusion in the central nervous system contributes to AD pathophysiology, we quantified CSF flow dynamics (i.e. stroke volume, amplitude and peak flow) in the spinal canal via phase-contrast MRI and examined its association with age and AD fluid biomarkers in 16 female vervet monkeys aged from 10 to 27 years. Results Strong negative correlations were observed between CSF flow metrics across the cardiac cycle and age (ρ = -0.68 to -0.83), and positive correlations were found between CSF flow metrics and CSF Aβ42/40 ratio (ρ = 0.67 to 0.84), while plasma biomarkers showed no correlation with CSF flow metrics. Age-adjusted analyses demonstrated moderate correlations between CSF flow and CSF Aβ42/40 ratio (ρ = 0.45 to 0.75). Conclusion These findings suggest that diminished CSF flow dynamics in the central nervous system could serve as a valuable imaging marker for impaired amyloid clearance, reflecting early-stage AD-like pathology.},
}

@article {pmid40469932,
year = {2025},
author = {Porché, M and Dumurgier, J and Hourrègue, C and Paquet, C},
title = {Late onset epilepsy and dementia with Lewy bodies: Underestimated association?.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251328613},
pmid = {40469932},
issn = {2542-4823},
abstract = {Relationship between Alzheimer's disease (AD) and late onset epilepsy (LOE) has been widely described leading to an expansion of the clinical spectrum of AD. Dementia with Lewy bodies (DLB) has scarce data detailing its association with epilepsy. We report 4 patients presenting DLB and LOE. Most of them developed LOE before the first symptoms of DLB, they all presented Parkinsonism and cognitive fluctuations, half of them presented status epilepticus and none had co-amyloid pathology, sv2a inhibitors were poorly tolerated and routine EEG were often inefficient to diagnose epileptiform abnormalities.},
}

@article {pmid40469853,
year = {2025},
author = {Buracchio, T and Campbell, M and Krudys, K},
title = {Assessing clinical meaningfulness in clinical trials for Alzheimer's disease: A U.S. regulatory perspective.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70113},
pmid = {40469853},
issn = {2352-8737},
abstract = {UNLABELLED: In the context of recent approvals of amyloid-directed monoclonal antibodies for the treatment of Alzheimer's disease (AD) by the United States (U.S.) Food and Drug administration (FDA), there has been much public discussion regarding the meaningfulness of the treatment effects demonstrated with these drugs in clinical trials. There are a variety of regulatory approaches to evaluate how results on a clinical endpoint reflect a meaningful effect of an intervention, including qualitative and quantitative methodologies. This article will discuss regulatory considerations for clinical benefit across the stages of AD, approaches to the assessment of clinical meaningfulness in clinical trials, and FDA's assessment of clinical benefit in the recent traditional approvals of amyloid-directed monoclonal antibodies for the treatment of AD.

HIGHLIGHTS: Assessment of clinical benefit will depend on the stage of Alzheimer's disease (AD) being studied, the clinical symptoms or findings that occur at that stage of disease, and the mechanism of the drug and its anticipated effects.It is critical to obtain input from patients and caregivers with lived experience to understand their perspectives on clinical benefit.The Food and Drug Administration (FDA) encourages the use of clinically meaningful within-patient change, which captures the assessment of improvement or decline based on the perspective of the individual patient, to assess meaningful score differences.},
}

@article {pmid40469843,
year = {2025},
author = {Kang, J and Liu, M and Yang, Q and Dang, X and Li, Q and Wang, T and Qiu, B and Zhang, Y and Guo, X and Li, X and Liu, Y},
title = {Exercise training exerts beneficial effects on Alzheimer's disease through multiple signaling pathways.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1558078},
pmid = {40469843},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive dysfunction that affects millions of people worldwide, placing a massive burden on families and economies. Exercise training can effectively reduce the prevalence of AD and alleviate its symptoms through the modulation of multiple signaling pathways involved in the pathophysiological process of AD, including the PI3K/Akt, Wnt/β-catenin, AMPK-related, MAPK, NF-κB, PINK1-PARKIN, JAK/STAT, and TREM2 signaling pathways. Different signaling pathways also crosstalk with each other through different targets to inhibit the formation of Amyloid β (Aβ) plaques, reduce the level of hyperphosphorylated tau protein, reduce apoptosis, relieve neuroinflammation, reduce autophagy dysfunction, and ultimately improve cognitive impairment in AD patients. This review summarizes the pathophysiological processes of AD affected by exercise training through different signaling pathways. We further provide a reference for the future development of new effective AD prevention and treatment targets to develop promising personalized, combined intervention strategies.},
}

@article {pmid40469807,
year = {2025},
author = {Bux, T and Pillay, K and Daya, R and Bayat, Z and Greenstein, LS},
title = {An uncommon variant of Alzheimer's disease: Posterior cortical atrophy.},
journal = {The South African journal of psychiatry : SAJP : the journal of the Society of Psychiatrists of South Africa},
volume = {31},
number = {},
pages = {2420},
pmid = {40469807},
issn = {1608-9685},
abstract = {INTRODUCTION: This case report highlights one of the less common variants of major neurocognitive disorder because of Alzheimer's disease, posterior cortical atrophy. There is a paucity of data about this condition in sub-Saharan Africa.

PATIENT PRESENTATION: A 54-year-old female presented to the geriatric clinic following a 2-year history of poor memory and inability to fulfil her work obligations. The most prominent symptom was visual disturbance, with a normal ophthalmic examination.

MANAGEMENT AND OUTCOME: Workup done to reveal reversible causes of dementia did not yield any positive results. After a full history, physical and cognitive examination and radiological investigations, a diagnosis of posterior cortical atrophy variant of major neurocognitive disorder because of Alzheimer's disease as the most likely aetiology was established.

CONCLUSION: Posterior cortical atrophy is a rare variant of Alzheimer's disease, and no case reports from South Africa are available in the literature.

CONTRIBUTION: This case reminds us that unusual presentations of cognitive impairment require a broad differential diagnosis.},
}

@article {pmid40469696,
year = {2025},
author = {Wang, C and Song, X and Zhang, X and Li, P and Wei, W and Sun, S and Chen, Y},
title = {Multifunctional natural chlorogenic acid based nanocarrier for Alzheimer's disease treatment.},
journal = {Materials today. Bio},
volume = {32},
number = {},
pages = {101841},
pmid = {40469696},
issn = {2590-0064},
abstract = {Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of chlorogenic acid (CHA), a multifunctional natural active compound, in AD therapy by developing a trifunctional nanocarrier (MC-H/R/si). CHA was effectively conjugated with iron-based metal-organic frameworks (MIL/Fe-100) through chelation interaction. The resulting nanocomplex (MC) not only enhances the bioavailability of CHA but also facilitates a synergistic antioxidant effect between CHA and MIL/Fe-100. Importantly, CHA can chelate Zn[2+] from β-amyloid/Zn[2+] (Aβ/Zn[2+]) polymers, inhibiting Aβ aggregation. Furthermore, small interfering RNA targeting BACE1 was covalently linked to MC to downregulate BACE1 expression. Both in vitro and in vivo experiments revealed that MC-H/R/si effectively scavenges ROS, reduces inflammation and Aβ plaque, and improves the learning and cognitive abilities of APP/PS1 mice. These findings confirm that the trifunctional nanocarrier MC-H/R/si has great potential for AD treatment.},
}

@article {pmid40469623,
year = {2025},
author = {Mir, FA and Lark, ARS and Nehs, CJ},
title = {Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity.},
journal = {Frontiers in aging},
volume = {6},
number = {},
pages = {1605070},
pmid = {40469623},
issn = {2673-6217},
abstract = {The relationship between sleep and metabolism has emerged as a critical factor in aging and age-related diseases, including Alzheimer's disease and dementia. Mitochondrial oxidative phosphorylation, essential for neuronal energy production, also generates reactive oxygen species (ROS), which increase with age and contribute to oxidative stress. Sleep plays a vital role in modulating redox balance, facilitating the clearance of free radicals, and supporting mitochondrial function. Disruptions in sleep are closely linked to redox imbalances, and emerging evidence suggests that pharmacological interventions, such as dual orexin receptor antagonists and antioxidant-based therapies, may help restore redox homeostasis. Furthermore, antioxidant-rich diets and supplements have shown promise in improving both sleep quality and metabolic health in aging populations. Neurons, with their high energy demands, are particularly vulnerable to oxidative damage, making redox regulation crucial in maintaining brain integrity. This review explores the bidirectional relationship between sleep and redox metabolism through five key areas: (1) sleep's role in free radical regulation, (2) ROS as mediators of age-related sleep disturbances, (3) feedback loops between impaired sleep and brain metabolism, (4) sleep, redox, and aging in peripheral systems, and (5) therapeutic strategies to restore redox balance and improve aging outcomes. Understanding these mechanisms may provide new targets for interventions aimed at mitigating age-associated diseases.},
}

@article {pmid40469616,
year = {2025},
author = {Zegarra-Valdivia, J and Pérez-Fernández, L and Casimiro-Arana, M and Arana-Nombera, H and Gallegos-Manayay, VN and Del Rosario Oliva-Piscoya, M and Alamo-Medina, R and Abanto-Saldaña, E and Vásquez-Zuñe, N and Pérez, LD and Gutierrez-Flores, D and Tantarico, LL and Hernández, N and Cruz-Ordinola, MC and Paredes-Manrique, C and Chino-Vilca, B and Espinoza, G and Cabrejo, J and Castro-Suarez, S and Custodio, N},
title = {Prevalence and risk factors of mild cognitive impairment and dementia in northern Peru.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1567073},
pmid = {40469616},
issn = {2296-2565},
mesh = {Humans ; *Cognitive Dysfunction/epidemiology ; Male ; Female ; Risk Factors ; Aged ; Middle Aged ; Cross-Sectional Studies ; Prevalence ; *Dementia/epidemiology ; Peru/epidemiology ; Aged, 80 and over ; Adult ; Surveys and Questionnaires ; Educational Status ; },
abstract = {BACKGROUND: Global dementia prevalence estimates indicate a growing burden, particularly in Low- and Middle-Income Countries (LMICs). Factors such as education, socioeconomic status, and limited public health interventions contribute to the development of Alzheimer's disease and other dementias. This study aimed to determine the prevalence of Mild Cognitive Impairment (MCI) and dementia in middle-aged and older adults from northern Peru, as well as identify possible associated risk factors.

METHODS: A cross-sectional study was conducted with 385 participants aged 40 to 85 years from Chiclayo, Peru. Cognitive impairment was assessed using the Rowland Universal Dementia Assessment Scale (RUDAS) and INECO Frontal Screening (IFS). Functional activity and depression were evaluated with the Pfeffer Functional Activities Questionnaire (PFAQ) and Patient Health Questionnaire-9 (PHQ-9). Participants were classified as controls, MCI, or dementia based on education-adjusted cutoff scores of those scales through cognitive system classification tools.

RESULTS: According to the results, 31.4% of the sample consisted of subjects without cognitive impairment, 40.5% were identified as possible cases of MCI, and 24.9% as possible cases of dementia. However, the percentages by age group are high. A lower educational level is associated with older age and correlates with lower cognitive scores and functional impairment. Age, hypertension, and hearing loss were significant risk factors for MCI and dementia.

CONCLUSION: The prevalence of possible MCI and dementia in a city in north Peru is high, with a predominance of MCI and dementia in older adults. Age, low education, hypertension, and hearing loss are potential risk factors for cognitive impairment.},
}

Humans
*Cognitive Dysfunction/epidemiology
Male
Female
Risk Factors
Aged
Middle Aged
Cross-Sectional Studies
Prevalence
*Dementia/epidemiology
Peru/epidemiology
Aged, 80 and over
Adult
Surveys and Questionnaires
Educational Status

@article {pmid40469282,
year = {2025},
author = {Qiao, S and Yuan, J and Zhang, SC and Lu, YY and Zhou, P and Xin, T},
title = {Neutrophil extracellular traps in central nervous system disorders: mechanisms, implications, and emerging perspective.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1602336},
pmid = {40469282},
issn = {1664-3224},
mesh = {Humans ; *Extracellular Traps/immunology/metabolism ; *Central Nervous System Diseases/immunology/metabolism/etiology/diagnosis ; *Neutrophils/immunology/metabolism ; Animals ; Blood-Brain Barrier/immunology ; Biomarkers ; },
abstract = {Neutrophil Extracellular Traps (NETs), as a crucial defense mechanism of neutrophils, have garnered increasing attention in recent years for their roles in central nervous system (CNS) disorders. This review comprehensively summarizes the fundamental characteristics and formation mechanisms of NETs, while highlighting the latest research advances regarding their involvement in various CNS diseases. Specific mechanistic insights are discussed, including how NETs exacerbate ischemic stroke through immunothrombosis, promote blood-brain barrier disruption in multiple sclerosis, and contribute to neuroinflammation in Alzheimer's disease. The paper systematically explores the potential mechanistic contributions of NETs to disease pathogenesis and progression, as well as their prospects as diagnostic biomarkers and therapeutic targets. Through an in-depth analysis of the multifaceted roles of NETs in CNS pathologies, this review aims to provide novel insights and references for advancing the understanding, clinical diagnosis, and therapeutic management of central nervous system disorders.},
}

Humans
*Extracellular Traps/immunology/metabolism
*Central Nervous System Diseases/immunology/metabolism/etiology/diagnosis
*Neutrophils/immunology/metabolism
Animals
Blood-Brain Barrier/immunology
Biomarkers

@article {pmid40469246,
year = {2025},
author = {Sobral, M and Oliveira, S},
title = {Economic evaluation of non-pharmacological interventions in Alzheimer's disease.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {},
pages = {e20240219},
pmid = {40469246},
issn = {1980-5764},
abstract = {UNLABELLED: Alzheimer's disease (AD) has significant physical, psychological, and socioeconomic impacts, shortens life expectancy, and reduces quality of life. Non-pharmacological interventions (NPIs) in dementia provide health gains.

OBJECTIVE: The aim of this study was to conduct a cost-utility study of NPIs in AD, assessing both the costs and health gains associated with cognitive stimulation interventions in AD patients.

METHODS: A sample of 40 patients undergoing NPIs and another 40 individuals (control group) were included. Data collected included sociodemographic, clinical, cognitive, and functional information, as well as health status, quality of life, and outpatient costs.

RESULTS: The NPI, considering the discounted cost value of €21,621.31 and the discounted quality-adjusted life year (QALY) gain of 0.81333, resulted in an estimated cost per QALY of €26,583.76. This cost per QALY is within the threshold generally considered acceptable by regulatory authorities in Portugal and in several European countries.

CONCLUSION: This study supports the recommendation that interventions adjusted to the needs of patients with AD should be implemented, which may include NPIs providing both health gains and economic value.},
}

@article {pmid40469245,
year = {2025},
author = {de Brito, MH and Coutinho, AM and Ono, CR and Trés, ES and Brucki, SMD},
title = {Visual field defect as the first manifestation of Alzheimer's disease.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {},
pages = {e20250292},
pmid = {40469245},
issn = {1980-5764},
}

@article {pmid40469059,
year = {2025},
author = {Adegboye, HA and Patterson, KL and Libby, J and Sun, Y and Zhang, P and Liu, D and Robb, WH and Peterson, AJ and Cole, KR and Arul, AB and Oliver, NC and Whitaker, MD and Pechman, KR and Dumitrescu, L and Bolton, CJ and Blennow, K and Zetterberg, H and Hohman, TJ and Robinson, RAS and Jefferson, AL},
title = {LC-MS/MS proteomics identifies plasma proteins related to cognition over 9-year follow-up.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70276},
doi = {10.1002/alz.70276},
pmid = {40469059},
issn = {1552-5279},
support = {IIRG-08-88733/ALZ/Alzheimer's Association/United States ; 2023-00356//Swedish Research Council supported by grants from the Swedish Research Council/ ; 2022-01018//Swedish Research Council supported by grants from the Swedish Research Council/ ; 2019-02397//Swedish Research Council supported by grants from the Swedish Research Council/ ; 2017-00915//Swedish Research Council supported by grants from the Swedish Research Council/ ; 2022-00732//Swedish Research Council supported by grants from the Swedish Research Council/ ; 101053962//European Union's Horizon Europe Research and Innovation Programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF)/ ; ADSF-21-831376-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831381-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831377-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; 22HLT07//European Partnership on Metrology, co-financed from the European Union's Horizon Europe Research and Innovation Programme/ ; FO2022-0270//Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden/ ; 860197//Marie Skłodowska-Curie/ ; PND2021-00694//European Union Joint Programme-Neurodegenerative Disease Research/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; AF-930351//Swedish Alzheimer Foundation/ ; AF-939721//Swedish Alzheimer Foundation/ ; AF-968270//Swedish Alzheimer Foundation/ ; AF-994551//Swedish Alzheimer Foundation/ ; ALZ2022-0006//Hjärnfonden, Sweden/ ; FO2024-0048-TK-130//Hjärnfonden, Sweden/ ; FO2024-0048-HK-24//Hjärnfonden, Sweden/ ; ALFGBG-965240//Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement/ ; ALFGBG-1006418//Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Alzheimer's Association 2021 Zenith/ ; SG-23-1038904//Alzheimer's Association 2022-2025/ ; AF-994551//Alzheimerfonden/ ; JPND2019-466-236//UK Dementia Research Institute/ ; 860197//HORIZON EUROPE Marie Sklodowska-Curie Actions/ ; FO2024-0048-HK-24//Hjärnfonden/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation/ ; 22HLT07//HORIZON EUROPE European Research Council/ ; ALFGBG-1006418//Vetenskapsrådet/ ; S10-OD023680//NIH Office of the Director/ ; UL1-TR002243/TR/NCATS NIH HHS/United States ; UL1-TR000445/TR/NCATS NIH HHS/United States ; T32-GM007347/GM/NIGMS NIH HHS/United States ; P20-AG068082/AG/NIA NIH HHS/United States ; R01-AG034962/AG/NIA NIH HHS/United States ; R01-AG056534/AG/NIA NIH HHS/United States ; K24-AG046373/AG/NIA NIH HHS/United States ; R01-AG064950/AG/NIA NIH HHS/United States ; F30-AG085905/AG/NIA NIH HHS/United States ; T32-AG058524/AG/NIA NIH HHS/United States ; F31-AG079640/AG/NIA NIH HHS/United States ; //Vanderbilt University/ ; },
mesh = {Humans ; Male ; *Proteomics/methods ; Female ; Aged ; *Blood Proteins/metabolism/analysis ; Tandem Mass Spectrometry ; Follow-Up Studies ; *Cognitive Dysfunction/blood ; Neuropsychological Tests/statistics & numerical data ; Chromatography, Liquid ; *Cognition/physiology ; Biomarkers/blood ; Longitudinal Studies ; Liquid Chromatography-Mass Spectrometry ; },
abstract = {INTRODUCTION: This project identified plasma proteins predictive of cognitive decline across a robust neuropsychological protocol over a 9-year period.

METHODS: Vanderbilt Memory and Aging Project participants (n = 336, 73 ± 7 years, 59% male, 87% non-Hispanic White, 10% Black/African American) underwent blood draw for baseline plasma protein abundance using mass spectrometry analysis of tandem mass tag (TMT)-labeled peptides and serial neuropsychological assessment (follow-up = 6.1 ± 2.3 years). Linear mixed-effects regressions related protein levels to neuropsychological outcomes in fully adjusted models. False discovery rate correction was applied.

RESULTS: Initial proteomics analyses yielded 3764 unique protein identifications across 23 16-plex TMT batches, and 686 proteins passed quality control. Proteins were identified predicting longitudinal decline in language (EGFR, RTN4RL2), information processing speed (EGFR, NOMO2, CLEC3B), executive function (A1BG), and visuospatial skills (RTN4RL2, GALNT1, SERPINA4, SERPINA5, C8A, ALDOB), but not episodic memory.

DISCUSSION: Large-scale proteomics analyses identified 10 plasma proteins that predicted subsequent cognitive decline over a 9-year follow-up in multiple cognitive domains.

HIGHLIGHTS: There were 3764 unique protein identifications across 23 16-plex TMT batches. Rigorous quality control yielded 686 proteins used as predictors in analyses. Identified proteins related to all domains assessed, except for episodic memory. Many proteins identified were differentially expressed in MCI.},
}

Humans
Male
*Proteomics/methods
Female
Aged
*Blood Proteins/metabolism/analysis
Tandem Mass Spectrometry
Follow-Up Studies
*Cognitive Dysfunction/blood
Neuropsychological Tests/statistics & numerical data
Chromatography, Liquid
*Cognition/physiology
Biomarkers/blood
Longitudinal Studies
Liquid Chromatography-Mass Spectrometry

@article {pmid40469052,
year = {2025},
author = {Lane-Donovan, C and Smith, AW and Saloner, R and Miller, BL and Casaletto, KB and Kao, AW},
title = {Tau phosphorylation at Alzheimer's disease biomarker sites impairs its cleavage by lysosomal proteases.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70320},
doi = {10.1002/alz.70320},
pmid = {40469052},
issn = {1552-5279},
support = {//Creative Minds Care, Weill Neurosciences Institute, Drew and Ellen Bradley, Bluefield Project to Cure FTD/ ; //Paul G. Allen Frontiers Group/ ; //Rainwater Charitable Foundation/ ; //Association for Frontotemporal Degeneration/ ; //American Brain Foundation/ ; AARG-20-683875/ALZ/Alzheimer's Association/United States ; R01AG072475/NS/NINDS NIH HHS/United States ; R01AG057234/NS/NINDS NIH HHS/United States ; R01AG057342/NS/NINDS NIH HHS/United States ; K23AG058752/NS/NINDS NIH HHS/United States ; K08AG083050/NS/NINDS NIH HHS/United States ; R25NS070680/NS/NINDS NIH HHS/United States ; R01NS095257/NS/NINDS NIH HHS/United States ; RF1NS127414/NS/NINDS NIH HHS/United States ; U54NS123985/NS/NINDS NIH HHS/United States ; /AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/metabolism/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/metabolism ; Phosphorylation ; *Lysosomes/metabolism/enzymology ; Biomarkers/cerebrospinal fluid ; Female ; *Peptide Hydrolases/metabolism ; Male ; Aged ; Proteolysis ; Hydrogen-Ion Concentration ; },
abstract = {INTRODUCTION: Phospho-tau peptides from the proline-rich domain (PRD) of tau are sensitive biomarkers for Alzheimer's disease (AD). The PRD is known to be relatively resistant to lysosomal proteolytic cleavage, but the effects of phosphorylation on cleavage are unknown.

METHODS: Using in silico modeling and in vitro protease assays, we quantified the effects of phosphorylation on lysosomal proteolysis of tau. We further assessed levels of lysosomal proteases in patient-derived cerebrospinal fluid (CSF) relative to phosphorylated tau-181 (p-tau181).

RESULTS: Phosphorylation renders the PRD significantly resistant to cleavage by the lysosome, especially at less acidic pH setpoints. In Alzheimer's disease subjects, CSF levels of lysosomal proteases correlate with p-tau181, suggesting that p-tau peptides are released with lysosomal contents.

DISCUSSION: Loss of lysosomal acidity may contribute to the release of phospho-tau biomarkers. This study shows that phosphorylation of tau impairs its cleavage by proteases in a pH-dependent manner and provides a novel molecular basis for p-tau biomarker accumulation in AD.

HIGHLIGHTS: Phosphorylated tau-181 (p-tau181) and p-tau217 originate from tau regions that are poorly cleaved by lysosomal proteases. Phosphorylation further impairs the proteolytic cleavage of AD biomarker peptides. Impaired proteolytic cleavage of phosphorylated tau is pH dependent. Levels of p-tau181 are correlated with lysosomal proteases in Alzheimer's disease (AD) cerebrospinal fluid samples. AD-associated lysosomal dysfunction may contribute to presence of disease biomarkers.},
}

Humans
*tau Proteins/metabolism/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/metabolism
Phosphorylation
*Lysosomes/metabolism/enzymology
Biomarkers/cerebrospinal fluid
Female
*Peptide Hydrolases/metabolism
Male
Aged
Proteolysis
Hydrogen-Ion Concentration

@article {pmid40469048,
year = {2025},
author = {Maure-Blesa, L and Carmona-Iragui, M and Lott, I and Head, E and Wisniewski, T and Rafii, MS and Espinosa, J and Flórez, J and Mobley, WC and Holland, A and Strydom, A and Zaman, S and Fortea, J},
title = {The history of Down syndrome-associated Alzheimer's disease; past, present, and future.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70158},
doi = {10.1002/alz.70158},
pmid = {40469048},
issn = {1552-5279},
support = {CM23/00291//European Union/ ; //AC Immune/ ; //Adamed/ ; //Biogen/ ; //Eisai/ ; //Esteve/ ; //Fujirebio/ ; //Ionis/ ; //Laboratorios Carnot/ ; //Life Molecular Imaging/ ; //Lundbeck/ ; //Perha/ ; //Roche/ ; //Eisai (AHEAD Study)/ ; //Eli Lilly/ ; //Alzheon/ ; //Aptah Bio/ ; //Embic/ ; //Prescient Imaging/ ; //Positrigo/ ; //Elli Lily/ ; //Biohaven/ ; //Perha Pharmaceuticals/ ; //Global Down Syndrome Foundation/ ; P30AG066512/GF/NIH HHS/United States ; P01AG060882/GF/NIH HHS/United States ; R01AG087280/GF/NIH HHS/United States ; P30AG066512//Foundation for the National Institutes of Health/ ; P01AG060882//Foundation for the National Institutes of Health/ ; and R01AG087280//Foundation for the National Institutes of Health/ ; CM23/00291//Instituto de Salud Carlos III/ ; },
mesh = {*Down Syndrome/history/complications ; *Alzheimer Disease/history/etiology/genetics ; Humans ; History, 20th Century ; History, 21st Century ; },
abstract = {The landscape of Down syndrome-associated Alzheimer's disease (DSAD) research reflects decades of scientific endeavor and collaborative effort, charting a remarkable journey from initial observations to the elucidation of complex genetic and molecular mechanisms. This perspective article chronicles key milestones and breakthroughs, paying homage to the pioneering scientists and advancements that have shaped the field. A thorough review of historical and contemporary literature offers a comprehensive narrative, highlighting the evolution of knowledge surrounding DSAD, from early recognition to the characterization of clinical presentation and natural history. The unique challenges and ethical considerations associated with DSAD populations are also examined, underscoring the importance of tailoring research and clinical approaches. By reflecting on the field's trajectory, this work celebrates past achievements while emphasizing the critical need for sustained research efforts. As part of a special issue, this article provides a foundation for appreciating the challenges and opportunities that lie ahead in advancing DSAD understanding and care. HIGHLIGHTS: This article provides a comprehensive overview of Down syndrome-associated Alzheimer's disease (DSAD) history, from early descriptions to its recognition as a genetic form of AD. It reflects on historical challenges faced by individuals with intellectual disabilities in achieving inclusion in scientific research. This historical perspective highlights the critical contributions of individuals with DS in advancing understanding of AD natural history. It explores pivotal milestones and efforts that have driven progress in DSAD research. Finally, it provides context to understand challenges and opportunities in DSAD research and its future directions.},
}

*Down Syndrome/history/complications
*Alzheimer Disease/history/etiology/genetics
Humans
History, 20th Century
History, 21st Century

@article {pmid40469030,
year = {2025},
author = {Lau, V and VanderZwaag, J and Murray, CJ and Tremblay, MÈ},
title = {Exploring Iron Deposition Patterns Using Light and Electron Microscopy in the Mouse Brain Across Aging and Alzheimer's Disease Pathology Conditions.},
journal = {Journal of neurochemistry},
volume = {169},
number = {6},
pages = {e70086},
doi = {10.1111/jnc.70086},
pmid = {40469030},
issn = {1471-4159},
support = {39965//Innovation John R. Evans Leaders Fund/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism ; Male ; *Aging/metabolism/pathology ; Mice ; *Iron/metabolism ; *Brain/metabolism/pathology/ultrastructure ; Mice, Transgenic ; Plaque, Amyloid/pathology/metabolism ; Microscopy, Electron ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD) involves cognitive decline, possibly via multiple concurrent pathologies associated with iron accumulation. To investigate if iron accumulation in AD is more likely due to pathological iron-rich compartments, or a compensatory response of iron within oligodendrocytes to disease progression, we sought to quantify iron-rich staining (via Perl's diaminobenzidine; DAB). Healthy wild-type (WT) and APP[Swe]-PS1Δe9 (APP-PS1; amyloid-beta overexpressing) male mice were examined during middle age, at 14 months. The frontal cortex, a brain region affected over the course of dementia progression, was investigated. Iron-rich compartments were found across genotypes, including oligodendrocytes and immune cells at the blood-brain barrier, and exclusively amyloid plaques in the APP-PS1 genotype. A semi-automated approach was employed to quantify the staining intensity of iron-rich compartments with light microscopy. Mouse frontal cortex of each genotype was also assessed qualitatively and ultrastructurally with scanning electron microscopy, to novelly discern and confirm iron-rich staining (via Perl's DAB). We found parenchymal iron staining corresponding to oligodendrocytes, pericytes, astrocytes, microglia and/or infiltrating macrophages, and amyloid plaques; increased iron deposition and clustering were detected in middle-aged male APP-PS1 versus WT frontal cortex, supporting that AD pathology may involve greater brain iron levels and local clustering. Unexpectedly, iron-rich cells were enriched at the central nervous system (CNS) interface and perivascular space in control and APP-PS1 mouse models, with ultrastructural examination revealing examples of these cells loaded with many secretory granules containing iron. Together, our results provide novel exploration and confirmation of iron-rich cells/compartments in scanning electron microscopy and reinforce literature that iron deposition is relatively increased in AD over healthy cognitive aging and involves greater local clusters of iron burden. Increased iron burden along the aging trajectory, regardless of cognitive status, may also be attributed to novelly discovered iron-rich cells secreting granules along the CNS border.},
}

Animals
*Alzheimer Disease/pathology/metabolism
Male
*Aging/metabolism/pathology
Mice
*Iron/metabolism
*Brain/metabolism/pathology/ultrastructure
Mice, Transgenic
Plaque, Amyloid/pathology/metabolism
Microscopy, Electron
Mice, Inbred C57BL

@article {pmid40469001,
year = {2025},
author = {Tao, Y and Ge, S},
title = {A Mapper Algorithm with Implicit Intervals and Its Optimization.},
journal = {Journal of computational biology : a journal of computational molecular cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1089/cmb.2024.0919},
pmid = {40469001},
issn = {1557-8666},
abstract = {The Mapper algorithm is an essential tool for visualizing complex, high-dimensional data in topological data analysis and has been widely used in biomedical research. It outputs a combinatorial graph whose structure encodes the shape of the data. However, the need for manual parameter tuning and fixed (implicit) intervals, along with fixed overlapping ratios, may impede the performance of the standard Mapper algorithm. Variants of the standard Mapper algorithms have been developed to address these limitations, yet most of them still require manual tuning of parameters. Additionally, many of these variants, including the standard version found in the literature, were built within a deterministic framework and overlooked the uncertainty inherent in the data. To relax these limitations, in this work, we introduce a novel framework that implicitly represents intervals through a hidden assignment matrix, enabling automatic parameter optimization via stochastic gradient descent (SGD). In this work, we develop a soft Mapper framework based on a Gaussian mixture model for flexible and implicit interval construction. We further illustrate the robustness of the soft Mapper algorithm by introducing the Mapper graph mode as a point estimation for the output graph. Moreover, a SGD algorithm with a specific topological loss function is proposed for optimizing parameters in the model. Both simulation and application studies demonstrate its effectiveness in capturing the underlying topological structures. In addition, the application to an RNA expression dataset obtained from the Mount Sinai/JJ Peters VA Medical Center Brain Bank successfully identifies a distinct subgroup of Alzheimer's Disease. The implementation of our method is available at https://github.com/FarmerTao/Implicit-interval-Mapper.git.},
}

@article {pmid40468981,
year = {2025},
author = {Cai, X and Cao, J and Yan, X and Zhao, P},
title = {High-Dimensional Multiresponse Partially Functional Linear Regression.},
journal = {Statistics in medicine},
volume = {44},
number = {13-14},
pages = {e70140},
doi = {10.1002/sim.70140},
pmid = {40468981},
issn = {1097-0258},
support = {12201306//National Natural Science Foundation of China/ ; 12101270//National Natural Science Foundation of China/ ; 12325109//National Natural Science Foundation of China/ ; 12371267//National Natural Science Foundation of China/ ; RGPIN-2023-04057//Natural Sciences and Engineering Research Council of Canada/ ; 2024YFA1012200//National Key R&D Program of China/ ; },
mesh = {Humans ; Linear Models ; Alzheimer Disease/diagnostic imaging ; Computer Simulation ; Principal Component Analysis ; Least-Squares Analysis ; Likelihood Functions ; Neuroimaging/statistics & numerical data ; },
abstract = {We propose a new class of high-dimensional multiresponse partially functional linear regressions (MR-PFLRs) to investigate the relationship between scalar responses and a set of explanatory variables, which include both functional and scalar types. In this framework, both the dimensionality of the responses and the number of scalar covariates can diverge to infinity. To account for within-subject correlation, we develop a functional principal component analysis (FPCA)-based penalized weighted least squares estimation procedure. In this approach, the precision matrix is estimated using penalized likelihoods, and the regression coefficients are then estimated through the penalized weighted least squares method, with the precision matrix serving as the weight. This method allows for the simultaneous estimation of both functional and scalar regression coefficients, as well as the precision matrix, while identifying significant features. Under mild conditions, we establish the consistency, rates of convergence, and oracle properties of the proposed estimators. Simulation studies demonstrate the finite-sample performance of our estimation method. Additionally, the practical utility of the MR-PFLR model is showcased through an application to Alzheimer's disease neuroimaging initiative (ADNI) data.},
}

Humans
Linear Models
Alzheimer Disease/diagnostic imaging
Computer Simulation
Principal Component Analysis
Least-Squares Analysis
Likelihood Functions
Neuroimaging/statistics & numerical data

@article {pmid40468848,
year = {2025},
author = {Gaster, B and Zigman Suchsland, M and Liao, JM and McKiddy, S and Fitzpatrick, AL and Belza, B and Hsu, AP and Raetz, J},
title = {A Large Health System Quality Improvement Intervention Providing Training and Tools to Improve Detection of Cognitive Impairment in Primary Care.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.19565},
pmid = {40468848},
issn = {1532-5415},
support = {FA215973/A180843/CC/CDC HHS/United States ; //Davos Alzheimer's Collaborative/ ; },
abstract = {BACKGROUND: Primary care providers (PCPs) are at the forefront of evaluating cognitive concerns and detecting Alzheimer's disease and related dementias (ADRD), but they generally lack the training and tools to do so.

METHODS: We performed a 2-year pragmatic intervention across a large health system of 14 community-based primary care clinics (94 PCPs). The intervention consisted of an education series integrated with workup tools in the exam room to assist PCPs in evaluating cognition. Electronic health record (EHR) data was extracted for 9 months before and 9 months after the intervention. Outcome measures were the number of cognitive assessments that PCPs recorded as discrete results in the EHR and the number of patients who PCPs newly diagnosed with an ADRD-related diagnosis.

RESULTS: Comparing EHR data from the 9 months before the intervention to the 9 months after the intervention, the number of cognitive assessments documented in the EHR increased from 2.8 per month to 19.8 per month (p < 0.001), and the number of new ADRD-related diagnoses made by PCPs increased from 6.2 per month to 14.6 per month (p = 0.012).

CONCLUSIONS: An intervention integrating tools for PCPs to use in the exam room, together with concise continuing education, increased the number of cognitive evaluations and the number of ADRD-related diagnoses in a large primary care health system. Such interventions are essential for building age-friendly ambulatory health systems and connecting patients to improved and innovative models of ADRD care.},
}

@article {pmid40468843,
year = {2025},
author = {Nan, N and Tian, L},
title = {Assessing accuracy for multi-class classification when subclasses are involved.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802251343600},
doi = {10.1177/09622802251343600},
pmid = {40468843},
issn = {1477-0334},
abstract = {Classifications that involve subclasses are common in many applied fields. "Compound multi-class classification" refers to the settings which involve three or more main classes and at least one of the main classes has multiple subclasses. In this paper, we propose an accuracy metric proper for "compound M-class classification," namely "hypervolume under compound ROC manifold (HUMC,M)." The proposed HUMC,M evaluates the overall accuracy of a biomarker measured on continuous scale correctly identifying M main classes without requiring specification of an ordering in terms of marker values for subclasses relative to each other within each main class. The probabilistic interpretation of HUMC,M is analytically derived. A network-based computing algorithm which enables efficient computation of the empirical estimate of HUMC,M is developed. Non-parametric bootstrap percentile confidence intervals of HUMC,M are assessed through extensive simulation studies. Lastly, a real data example is included to illustrate the usage of our proposed method.},
}

@article {pmid40468810,
year = {2025},
author = {Zhang, Y and Steingrimsson, JA and Ambekar, A and Oh, H and Eloyan, A and , },
title = {Radiomics of PET Using Neural Networks for Prediction of Alzheimer's Disease Diagnosis.},
journal = {Statistics in medicine},
volume = {44},
number = {13-14},
pages = {e70128},
doi = {10.1002/sim.70128},
pmid = {40468810},
issn = {1097-0258},
support = {R01 AG075511/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis ; *Positron-Emission Tomography/methods/statistics & numerical data ; *Neural Networks, Computer ; Aged ; Cognitive Dysfunction/diagnostic imaging ; Male ; Deep Learning ; Female ; Neuroimaging/methods ; Longitudinal Studies ; Radiomics ; },
abstract = {Positron emission tomography (PET) imaging technology is widely used for diagnosing Alzheimer's disease (AD) in people with dementia. Although various computational methods have been proposed for diagnosis of AD using PET images, prediction of disease diagnosis by leveraging longitudinal PET imaging data has not been widely studied. In this paper, we propose novel implementations of deep learning models graph neural network (GNN) and transformer encoder (TE), to leverage longitudinal sequences of PET images in addition to cognitive scores for prediction of AD diagnosis and prediction of conversion from cognitively unimpaired or mild cognitive impairment to AD using data collected in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. In addition, we compare the performance of these two approaches with other methods including simple feed-forward networks (FFN) that only utilize PET images from a single time point and recurrent neural networks (RNN) that model longitudinal images by considering them as sequences, while failing to take into account between visit time variability. We show that GNN and TE have higher predictive performance than FFN and RNN in predicting disease diagnosis, where predictive performance is measured by accuracy, area under receiver operating characteristic (AUC) curve, and the Brier score. Furthermore, we illustrate the potential of PET images in predicting conversion from mild cognitive impairment or cognitively normal to AD.},
}

Humans
*Alzheimer Disease/diagnostic imaging/diagnosis
*Positron-Emission Tomography/methods/statistics & numerical data
*Neural Networks, Computer
Aged
Cognitive Dysfunction/diagnostic imaging
Male
Deep Learning
Female
Neuroimaging/methods
Longitudinal Studies
Radiomics

@article {pmid40468463,
year = {2025},
author = {Lei, L and Cheng, Y and Yin, A and Han, JM and Wu, G and Yang, F and Wang, Q and Wang, JZ and Liu, R and Li, HL and Wang, X},
title = {Aging-dependent YAP1 reduction contributes to AD pathology by upregulating the Nr4a1-AKT/GSK-3β axis.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {29},
pmid = {40468463},
issn = {2047-9158},
support = {82330041//National Natural Science Foundation of China/ ; 82071440//National Natural Science Foundation of China/ ; },
mesh = {Animals ; YAP-Signaling Proteins ; Mice, Inbred C57BL ; *Alzheimer Disease/metabolism/pathology/genetics ; Mice ; *Aging/metabolism/pathology ; Signal Transduction/physiology ; *Proto-Oncogene Proteins c-akt/metabolism ; Hippocampus/metabolism/pathology ; Male ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Adaptor Proteins, Signal Transducing/metabolism ; Up-Regulation/physiology ; Rats ; Humans ; Cell Cycle Proteins/metabolism ; Neurons/metabolism ; },
abstract = {BACKGROUND: Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for > 95% of all Alzheimer's disease (AD) cases. Yes-associated protein 1 (YAP1), an aging-dependent protein, is a key element in the classical Hippo-YAP1 pathway mediated by a kinase cascade. Research showed that YAP1 was markedly reduced in the brains of individuals with AD. However, the mechanisms underlying the susceptibility of the Hippo-YAP1 signaling pathway in the context of LOAD remain unclear.

METHODS: AAV9-YAP1-RNAi was injected into the hippocampi of C57BL/6J mice to establish a YAP1 knockdown model. Overexpression of full-length YAP1 was achieved by injecting AAV9-YAP1 into the hippocampi of SAMP8 mice. To establish the model of knockdown of nuclear receptor subfamily 4 group A member 1 (Nr4a1), AAV9-Nr4a1-RNAi was injected into the hippocampi of SAMP8 mice. In the C57BL/6J mice with YAP1 knockdown, Nr4a1 expression was either knocked down or inhibited with DIM-C to examine the impact of Nr4a1 on tau phosphorylation and cognitive deficits. Primary hippocampal neurons from Sprague-Dawley (SD) rats were infected with lentivirus (LV)-YAP1 to create a YAP1 overexpression model, and Aβ treatment was used to induce neuronal senescence. Protein levels were assessed using immunofluorescence, Western blotting, and ELISA. Animal behavior was evaluated using the Morris water maze test, novel object recognition test, and open field test.

RESULTS: YAP1 was reduced in the hippocampus of both aged C57BL/6J mice and SAMP8 AD model mice through Hippo pathway activation, as well as in Aβ-induced senescent neurons. Overexpression of YAP1 in primary neurons significantly mitigated the Aβ-induced neuronal senescence by downregulating several senescence-related genes, including p16 and p53. The levels of phosphorylated AKT/GSK-3β in neurons were increased with overexpression of YAP1 both in vivo and in vitro. Knockdown of YAP1 induced AD-like symptoms and exacerbated cognitive decline in 2-month-old C57BL/6J mice. Injection of AAV9-YAP1 in the brains of SAMP8 mice partially alleviated neuronal senescence and enhanced cognitive function. Notably, genetic knockdown and chemical inhibition of Nr4a1 significantly ameliorated cognitive deficits as well as AD-like pathology in these subjects.

CONCLUSIONS: These findings reveal an etiopathogenic relationship between aging and AD, which is associated with the YAP1-Nr4a1-AKT/GSK-3β signaling pathway. Our findings provide insight into the therapeutic strategies aimed at delaying brain aging and combating neurodegenerative diseases such as AD.},
}

Animals
YAP-Signaling Proteins
Mice, Inbred C57BL
*Alzheimer Disease/metabolism/pathology/genetics
Mice
*Aging/metabolism/pathology
Signal Transduction/physiology
*Proto-Oncogene Proteins c-akt/metabolism
Hippocampus/metabolism/pathology
Male
*Glycogen Synthase Kinase 3 beta/metabolism
*Adaptor Proteins, Signal Transducing/metabolism
Up-Regulation/physiology
Rats
Humans
Cell Cycle Proteins/metabolism
Neurons/metabolism

@article {pmid40468412,
year = {2025},
author = {Karunakaran, DKP and Ley, M and Guo, J and Khatri, A and Sadleir, K and Popovic, J and Upadhyay, AK and Savas, J and Procissi, D and Atwal, J and Vassar, R},
title = {The UNC5C T835M mutation associated with Alzheimer's disease leads to neurodegeneration involving oxidative stress and hippocampal atrophy in aged mice.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {65},
pmid = {40468412},
issn = {1750-1326},
support = {AG0577277/AG/NIA NIH HHS/United States ; AARF-16-443173/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; *Alzheimer Disease/genetics/pathology/metabolism ; *Oxidative Stress/genetics/physiology ; *Hippocampus/pathology/metabolism ; Mice ; *Netrin Receptors/genetics ; Atrophy/genetics/pathology ; Mutation ; Neurons/metabolism/pathology ; Disease Models, Animal ; Mice, Transgenic ; Aging/pathology ; *Nerve Degeneration/genetics/pathology ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and synaptic and neuronal loss. Recently, a rare autosomal dominant coding mutation, T835M, in the Un-coordinated 5c (UNC5C) netrin receptor gene was segregated with late-onset AD (LOAD). Overexpression of T835M in primary hippocampal neurons increased cell death in response to neurotoxic stimuli including beta-amyloid (Aβ) suggesting a mechanism by which T835M may confer increased risk of LOAD. However, the molecular mechanism of T835M-mediated cell death remained under explored. Toward this end, we generated a mouse T835M knock-in (Unc5c[KI/KI]) model and employed biochemical and histological analyses to understand the molecular mechanism of T835M-mediated pathogenesis in late onset Alzheimer's disease. We show that homozygous KI mice have significantly reduced hippocampal volume, increased ventricular volume, dendritic disorganization (CA1 region) and reduced UNC5C protein level by 12-18 months of age. Further, we show that the neuronal cell death is observed in the Unc5c[KI/KI] mice by 12 months of age by TUNEL analysis and activated Caspase 3/7 assay. Proteomic analysis of hippocampal samples showed upregulation of oxidative stress and downregulation of chaperone proteins at 18 months corroborating the biochemical and histological results showing increased c-Jun N-terminal Kinase (JNK) phosphorylation, NADPH oxidase, and decreased Netrin1 levels. Moreover, Unc5c[KI/KI] mice also show morphological changes in the astrocytes with increased number of branched processes, reduced GFAP levels, and significantly increased activation of microglia. Overall, these results suggest that T835M mutation causes neurodegeneration by creating an oxidative stress environment leading to synaptic degeneration and weakened astrocytes, thereby leading to neuronal cell death via apoptosis. Furthermore, to assess the effects of amyloid pathology on the mutation, we crossed Unc5c[KI/KI] mice with App[NL-G-F/NL-G-F] mice and observed an exacerbation of mutation-associated changes along with increased levels of Aβ42, suggesting that the T835M mutation increases the susceptibility of neurons to cell death and elevated Aβ42 levels, thus promoting AD pathogenesis. Understanding the molecular mechanism of cell death in regions susceptible to neurodegeneration such as the hippocampus could shed light on the players and pathways involved in cell death in AD pathogenesis and therefore could inform therapeutic approaches for AD.},
}

Animals
*Alzheimer Disease/genetics/pathology/metabolism
*Oxidative Stress/genetics/physiology
*Hippocampus/pathology/metabolism
Mice
*Netrin Receptors/genetics
Atrophy/genetics/pathology
Mutation
Neurons/metabolism/pathology
Disease Models, Animal
Mice, Transgenic
Aging/pathology
*Nerve Degeneration/genetics/pathology

@article {pmid40468388,
year = {2025},
author = {Tahiroğlu, V and Gören, K and Bağlan, M},
title = {In Silico drug evaluation by molecular docking, ADME studies and DFT calculations of 2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N, N-dipropylacetamide.},
journal = {BMC pharmacology & toxicology},
volume = {26},
number = {1},
pages = {116},
pmid = {40468388},
issn = {2050-6511},
mesh = {Molecular Docking Simulation ; Density Functional Theory ; Humans ; *Imidazoles/pharmacokinetics/chemistry ; *Acetamides/pharmacokinetics/chemistry ; *Pyridines/pharmacokinetics/chemistry ; *Anti-Anxiety Agents/pharmacokinetics/chemistry/pharmacology ; Computer Simulation ; Animals ; },
abstract = {In this study, the structural, electronic, pharmacokinetic, and biological properties of molecule 2-(6-kloro-2-(4-klorofenil)imidazo[1,2-a]piridin-3-il)-N, N-dipropilasetamid (Alpidem), an imidazopyridine derivative anxiolytic known for its high BZ1 (benzodiazepine-1) receptor affinity and low adverse effect profile, were comprehensively investigated by density functional theory (DFT) and in-silico methods. The alpidem molecule was optimized using the 6-311G(d, p) basis set with the B3LYP and B3PW91 methods; information on the stability and chemical reactivity of the structure was obtained via the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), molecular electrostatic potential (MEP) maps, natural bonding orbital (NBO) analysis, non-linear optical (NLO) properties, and Mulliken charge distributions. Comparative analysis of two different methods has shown that the results are consistent with each other and provide reliable data. In addition, the drug similarity, bioavailability score, bioactivity values, absorption, distribution, metabolism, and excretion (ADME) profiles of the Alpidem molecule were calculated, and it was determined that the Alpidem molecule has pharmacologically favorable properties. Within the scope of molecular docking analyses, its interactions with two different enzymes (PDB ID: 2Z5X and 4BDT) associated with Alzheimer's disease were evaluated. The binding energy values obtained were - 8.00 kcal/mol (2Z5X) and - 9.60 kcal/mol (4BDT), respectively, and the strong binding affinity, especially with the 4BDT protein, suggests that Alpidem may be a potential inhibitor candidate in Alzheimer's disease. This multi-level theoretical study demonstrates that Alpidem is a drug repurposing molecule not only as an anxiolytic but also in neurodegenerative diseases and provides important data that will shed light on experimental studies. The results of this multi-level theoretical study show that Alpidem is a drug repurposing molecule not only as an anxiolytic but also in neurodegenerative diseases and provides important data that will shed light on experimental studies.},
}

Molecular Docking Simulation
Density Functional Theory
Humans
*Imidazoles/pharmacokinetics/chemistry
*Acetamides/pharmacokinetics/chemistry
*Pyridines/pharmacokinetics/chemistry
*Anti-Anxiety Agents/pharmacokinetics/chemistry/pharmacology
Computer Simulation
Animals

@article {pmid40468377,
year = {2025},
author = {Wang, Z and Zhang, L and Qin, C},
title = {Alzheimer's disease pathogenesis: standing at the crossroad of lipid metabolism and immune response.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {67},
pmid = {40468377},
issn = {1750-1326},
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/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/pathology ; *Lipid Metabolism/physiology/immunology ; Animals ; Brain/metabolism/immunology/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by macroscopic features such as cortical atrophy, narrowing of the gyri, widening of the sulci, and enlargement of the ventricles. At the cellular level, the pathological characteristics include the extracellular aggregation of β-amyloid (Aβ) forming senile plaques, and the intracellular accumulation of hyperphosphorylated tau proteins forming neurofibrillary tangles. AD leads to the progressive decline of cognitive, behavioral, and social abilities, with no effective treatment available currently. The pathophysiology of AD is complex, involving mechanisms such as immune dysregulation and lipid metabolism alterations. Immune cells, such as microglia, can identify and clear pathological aggregates like Aβ early in the disease. However, prolonged or excessive activation of immune cells may trigger chronic neuroinflammation, thereby accelerating neuronal damage and the progression of AD. Lipid metabolism plays a critical role in maintaining cell membrane structure and function, regulating the production and clearance of Aβ, and supplying energy to the brain. Disruptions in these processes are closely linked to the pathological progression of AD. The interaction between lipid metabolism and the immune system further exacerbates the disease progression of AD. In this review, we discuss the lipid metabolism and immune response in AD, summarize their intricate interactions, and highlight the complexity of the multifactorial pathogenic cascade, offering insights into new interventions targeting the immune-metabolic axis in AD.},
}

Humans
*Alzheimer Disease/immunology/metabolism/pathology
*Lipid Metabolism/physiology/immunology
Animals
Brain/metabolism/immunology/pathology
Amyloid beta-Peptides/metabolism

@article {pmid40468360,
year = {2025},
author = {Yan, T and Clarkson, BD and Lou, Z and Springer, W and Fiesel, FC},
title = {The many connections of UFMylation with Alzheimer's disease: a comprehensive review.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {66},
pmid = {40468360},
issn = {1750-1326},
support = {AARF-22-974258/ALZ/Alzheimer's Association/United States ; RF1 NS085070/NS/NINDS NIH HHS/United States ; R56 AG062556/AG/NIA NIH HHS/United States ; W81XWH-17-1-0248//U.S. Department of Defense/ ; 22A07//Florida Department of Health/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Protein Processing, Post-Translational/physiology ; Animals ; tau Proteins/metabolism ; Brain/metabolism ; *Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that is characterized by the accumulation of pathologic tau and beta-amyloid proteins. UFMylation is an emerging ubiquitin-like post-translational modification that is crucial for healthy brain development. The UFM1 cascade was recently identified as a major modifier of tau aggregation in vitro and in vivo. Moreover, post-mortem AD brain shows pronounced alterations of UFMylation that are significantly associated with pathological tau, suggesting UFM1 might indeed be a modifier of human disease. However, the link between AD and UFMylation is yet to be fully explored. Interestingly, the UFMylation cascade is known to play important roles for several pathways that are known to be altered in AD, such as the DNA damage response, ER homeostasis, autophagy and the immune response. This review discusses the many connections between UFMylation with AD pathogenesis, emphasizing the role of UFMylation in these pathways and their abnormalities in AD. Understanding these connections is important to elucidate molecular mechanisms how UFM1 may impact AD and to uncover novel therapeutic strategies targeting UFMylation pathways for disease modification.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Protein Processing, Post-Translational/physiology
Animals
tau Proteins/metabolism
Brain/metabolism
*Proteins/metabolism

@article {pmid40468230,
year = {2025},
author = {Wang, X and Wu, S and Deng, Z and Yan, M and Wang, D and Yang, M and Zhong, F and Song, J and Chen, L and Chen, Y and Tian, Q and Yu, W and Lü, Y},
title = {GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer's disease.},
journal = {Molecular medicine (Cambridge, Mass.)},
volume = {31},
number = {1},
pages = {219},
pmid = {40468230},
issn = {1528-3658},
support = {cstc2022ycjh- bgzxm0184//Chongqing Talent Plan/ ; KJZD-K202200405//Key Project of Science and Technology Research Program of Chongqing Municipal Education Commission/ ; },
}

@article {pmid40467940,
year = {2025},
author = {Devyatov, A and Kozlov, I and Das, V},
title = {Differentiation of SH-SY5Y Cells into Cortical Neuron-like Cells for Tauopathy Modeling and Seeding Assays.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40467940},
issn = {1559-1182},
support = {IGA_LF_2024_038//Palacky University in Olomouc/ ; IGA_LF_2024_038//Palacky University in Olomouc/ ; 23-06301J//Grantová Agentura České Republiky/ ; LX22NPO5107//Ministry of Education, Youth and Sports of the Czech Republic/ ; TN02000109//Technology Agency of the Czech Republic/ ; },
abstract = {SH-SY5Y cells are widely used as an in vitro neuronal model, yet reliable differentiation protocols tailored for tauopathy research remain limited. Effective differentiation is essential for studying tau aggregation, propagation, and neurodegenerative mechanisms. Here, we present an optimized two-step differentiation protocol for TauP301L-expressing SH-SY5Y cells that enhances neuronal maturation and tauopathy modeling, providing a physiologically relevant system for investigating tau seeding. SH-SY5Y cells expressing TauP301L-EGFP under an inducible system were differentiated using a two-step protocol consisting of retinoic acid (RA) for 72 h, followed by brain-derived neurotrophic factor (BDNF) and RA for 72 h. Differentiated neurons were then exposed to exogenous P301L tau peptide fibrils to assess their susceptibility to tau seeding and aggregation. Differentiation resulted in increased neurite outgrowth, cholinergic marker expression (ChAT upregulation, TH downregulation), and upregulation of the mature 2N4R tau isoform. Western blot analysis showed increased T22 and pSer262 tau immunoreactivity in seeded cells, consistent with tau conformational changes and pathological phosphorylation. These findings may reflect early stages of tau misfolding but do not confirm oligomer formation. Seeding also induced neurite remodeling, varicosity formation, and reduced neurite diameter-features consistent with tau-mediated pathology involving cytoskeletal changes, organelle accumulation, or axonal transport defects. This optimized differentiation protocol provides an experimentally tractable tauopathy model for investigating tau propagation and neuronal dysfunctions in a controlled human cell context. Compared to existing SH-SY5Y differentiation methods, our system provides faster neuronal maturation, controlled TauP301L induction, and enhanced tau isoform expression, making it a valuable platform for studying early tau misfolding events and therapeutic interventions in tauopathies.},
}

@article {pmid40467939,
year = {2025},
author = {Verma, H and Dhureja, M and Yadav, A and Yadav, B and Rao, R and Dhiman, M and Kumar, P and Mantha, AK},
title = {An In Vivo C57BL/6 Mouse Study Demonstrating Fine-Tuning of Serum and Brain-Derived Exosomes Reveal Therapeutic Potential of Phytochemical Ferulic Acid Against Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40467939},
issn = {1559-1182},
support = {CRG/2021/002524//SERB/ ; CRG/2021/002524//SERB/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by memory loss, synaptic impairment, and biochemical changes. The study aimed to investigate the neuroprotective role of ferulic acid (FA) in an AD mouse C57BL/6 model induced by the Aβ(25-35) peptide. Cognitive deficits, which include memory and spatial learning deficits caused by Aβ, were evaluated using a set of behavioural tests. Transmission electron microscopy (TEM), dynamic light scattering (DLS), and Western blot analysis were used to characterize the exosomes from the brain and the serum. The activity of acetylcholinesterase (AChE) in exosomes was also evaluated, and the proteomic analysis of the serum-derived exosomes was conducted through LC-MS Triple ToF and bioinformatics to identify the altered pathways associated with identified proteins. The results obtained showed that there were significant alterations in the exosomal proteome profile after Aβ treatment. The levels of some of the proteins that are involved in energy metabolism, amyloid clearance, cytoskeleton, oxidative stress, and neuroinflammation were particularly affected. Treatment with the phytochemical FA modulated the exosomal proteome profile alterations and the activity of AChE in exosomes, which are some of the hallmarks of cholinergic dysfunction in the case of AD. However, the analysis of the proteome of the AD condition revealed that there were distinct alterations in the content of serum-derived exosomes, which could be used as candidates for non-invasive biomarkers of AD progression. This work also highlights the possibility of using the phytochemical FA to prevent and treat the neurotoxicity and neurodegenerative cascade induced by Aβ and to correct the protein content of exosomes in AD.},
}

@article {pmid40467855,
year = {2025},
author = {Lei, Y and Nougaisse, J and Malek, M and Mishu, MM and Bai, Y and Denney, K and Du, Q and Stranahan, AM and Garza, JC and Lu, XY},
title = {Chronic social isolation-unpredictable stress induces early-onset cognitive deficits and exacerbates Aβ accumulation in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {40467855},
issn = {1476-5578},
support = {AG083841//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG062166//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG064895//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG076235//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Aging and genetic predisposition are the primary risk factors for Alzheimer's disease (AD), while chronic stress represents a modifiable risk factor that can accelerate aging and drive AD progression. However, the complex interplay between aging, chronic stress and genetic underpinnings in AD pathogenesis remains poorly understood. Notably, cognitive phenotyping in AD mouse models has yielded inconsistent results. In this study, we characterized the age-dependent trajectory of phenotypes in 5xFAD mice on a congenic C57BL/6 J background. These mice harbor five familial AD (FAD)-related mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes. Aβ plaque deposition was detected in specific brain regions by 4 months of age, but cognitive performance remained intact at this stage. However, by 8-9 months, these mice developed impairments in spatial working memory, novel object recognition memory, and social recognition memory. By 11 months, they also showed metabolic alterations, including lower body weight, higher energy expenditure and increased locomotor activity. Furthermore, after 10 days of chronic social isolation-unpredictable stress, 4-month-old 5xFAD mice exhibited cognitive deficits, accompanied by increased Aβ accumulation in the medial prefrontal cortex, hippocampus, and entorhinal cortex. In contrast, age- and sex-matched wild-type littermate controls subjected to the same stress paradigm showed no significant cognitive changes. These observations suggest that Aβ deposition increases stress vulnerability in 5xFAD mice. We conclude that the phenotypic expression of AD-related gene mutations, including pathological changes and cognitive decline, progresses with age and can be induced by chronic psychological stress, underscoring the interactive effects of stress, aging, and genetic vulnerability on disease onset and severity.},
}

@article {pmid40467596,
year = {2025},
author = {Mekky, RH and Thabet, MM and El-Gindi, O and Said, MA and Ahmed, SA and Abdelhameed, RFA},
title = {Comparative phytochemical and biological evaluation of Egyptian Swinglea glutinosa stems and leaves.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {19543},
pmid = {40467596},
issn = {2045-2322},
mesh = {*Plant Leaves/chemistry ; *Plant Stems/chemistry ; *Plant Extracts/chemistry/pharmacology ; *Phytochemicals/pharmacology/chemistry ; Molecular Docking Simulation ; alpha-Amylases/antagonists & inhibitors/chemistry ; Glycoside Hydrolase Inhibitors/pharmacology/chemistry ; alpha-Glucosidases/metabolism/chemistry ; Egypt ; *Verbenaceae/chemistry ; Tandem Mass Spectrometry ; },
abstract = {The hydroalcoholic extracts of both stems and leaves of Egyptian Swinglea glutinosa have been evaluated for their biological activities and phytochemical profiling. LC-MS/MS assists in identifying 80 phytoconstituent compounds that alternate between the stem and leaves, the majority of which are new to the genus. Biological investigation results revealed the superiority of stem extract in inhibiting α-amylase and α-glucosidase enzymes scoring IC50 (15.32 ± 0.76) and (0.656 ± 0.03) over the leaves extract, which gives IC50 (112.1 ± 5.55) and (2.721 ± 0.13) respectively at (P < 0.05) and when compared to the antidiabetic standard acarbose it shows better result than it in inhibiting α-amylase and to close to it in inhibiting α-glucosidase enzymes which later score IC50 (27.2 ± 1.35)and (0.375 ± 0.02) at (P < 0.05). Stem extract also shows good inhibitory activity on acetylcholinesterase enzymes compared to standard donepezil, and that was supported by results of intermolecular docking for six compounds (2-Deoxy-2,3-dehydro-N-acetyl-neuraminic acid (DANA), ascorbic acid, glucuronic acid, protocatechuic acid, galacturonic acid, gallic acid) which only identified in stem extract. All of them show high fitting scores and strong binding interactions. Moreover, among tested compounds, DANA, ascorbic acid, and glucuronic acid have the highest-ranking scores against all target enzymes. Highly fitting and binding scores by DANA were remarkably noticed, and the molecular dynamic simulation study proved the effect of DANA against the α-amylase enzyme via decreasing the fluctuations of the enzyme's amino acid residues due to the stabilization of enzyme-ligand complex.},
}

*Plant Leaves/chemistry
*Plant Stems/chemistry
*Plant Extracts/chemistry/pharmacology
*Phytochemicals/pharmacology/chemistry
Molecular Docking Simulation
alpha-Amylases/antagonists & inhibitors/chemistry
Glycoside Hydrolase Inhibitors/pharmacology/chemistry
alpha-Glucosidases/metabolism/chemistry
Egypt
*Verbenaceae/chemistry
Tandem Mass Spectrometry

@article {pmid40467577,
year = {2025},
author = {Che, P and Cai, L and Liu, F and Wang, Y and Zhang, Y and Wang, Y and Lu, Q and Piao, Z and Zhang, X and Qin, W and Zhang, N},
title = {Cerebral perfusion is correlated with cerebral metabolism and amyloid deposition in Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {189},
pmid = {40467577},
issn = {2158-3188},
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging/physiopathology ; Male ; Female ; Positron-Emission Tomography ; Aged ; *Cerebrovascular Circulation/physiology ; Fluorodeoxyglucose F18 ; *Brain/metabolism/diagnostic imaging ; Aniline Compounds ; Middle Aged ; Thiazoles ; *Amyloid beta-Peptides/metabolism ; Radiopharmaceuticals ; Aged, 80 and over ; Case-Control Studies ; },
abstract = {Cerebral blood flow (CBF) changes play a pivotal role in the pathogenesis and progression of Alzheimer's disease (AD), but their effects on other pathological processes, such as neurodegeneration and amyloid-β deposition, are unclear. We investigated the correlations between cerebral perfusion measured with arterial spinal labeling (ASL) and cerebral metabolism and amyloid deposition on positron emission tomography (PET) scans in AD. Sixty-four AD patients and 56 cognitively unimpaired controls were included. Cerebral perfusion was indicated by the expression of AD-related perfusion pattern (ADRP), global CBF and the relative value of regional CBF. The standardized uptake value ratio (SUVR) of regions of interest (ROIs) was calculated for [18]F-fluorodeoxyglucose (FDG)-PET and [11]C-Pittsburgh Compound B (PiB)-PET images in AD patients. The subject expression score of ADRP showed strong negative correlations with FDG SUVR in all ROIs and a positive correlation with PiB SUVR in temporal. FDG SUVR in some ROIs were also positively correlated with global CBF and relatively regional CBF in the temporoparietal cortex, precuneus and posterior cingulate, and negatively correlated with relatively regional CBF in the thalamus and pre- and postcentral regions. The PiB SUVR of the ROIs were negatively correlated with the relatively regional CBF in the left inferior parietal region and were positively correlated with the relatively regional CBF in the right thalamus and left precentral regions. CBF was significantly correlated with hypometabolism and amyloid deposition in AD.},
}

Humans
*Alzheimer Disease/metabolism/diagnostic imaging/physiopathology
Male
Female
Positron-Emission Tomography
Aged
*Cerebrovascular Circulation/physiology
Fluorodeoxyglucose F18
*Brain/metabolism/diagnostic imaging
Aniline Compounds
Middle Aged
Thiazoles
*Amyloid beta-Peptides/metabolism
Radiopharmaceuticals
Aged, 80 and over
Case-Control Studies

@article {pmid40467562,
year = {2025},
author = {Wang, Y and Song, P and Zhou, H and Wang, P and Li, Y and Shao, Z and Wang, L and You, Y and Lei, Z and Yu, J and Li, C},
title = {An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5179},
pmid = {40467562},
issn = {2041-1723},
support = {92159304, 82394433, 82227806,82025019//National Natural Science Foundation of China (National Science Foundation of China)/ ; 22174023, 22378072//National Natural Science Foundation of China (National Science Foundation of China)/ ; 22ZR1414700//Natural Science Foundation of Shanghai (Natural Science Foundation of Shanghai Municipality)/ ; },
mesh = {*Mitophagy/drug effects ; Humans ; *Mitochondria/metabolism/drug effects ; Microscopy, Fluorescence/methods ; Animals ; Alzheimer Disease/metabolism/pathology/drug therapy ; Autophagosomes/metabolism/drug effects ; Mice ; *Artificial Intelligence ; Amyloid beta-Peptides/metabolism ; Lysosomes/metabolism/drug effects ; HeLa Cells ; },
abstract = {Mitophagy, the selective autophagic elimination of mitochondria, is essential for maintaining mitochondrial quality and cell homeostasis. Impairment of mitophagy flux, a process involving multiple sequential intermediates, is implicated in the onset of numerous neurodegenerative diseases. Screening mitophagy inducers, particularly understanding their impact on mitophagic intermediates, is crucial for neurodegenerative disease treatment. However, existing techniques do not allow simultaneous visualization of distinct mitophagic intermediates in live cells. Here, we introduce an artificial intelligence-assisted fluorescence microscopic system (AI-FM) that enables the uninterrupted recognition and quantification of key mitophagic intermediates by extracting mitochondrial pH and morphological features. Using AI-FM, we identify a potential mitophagy modulator, Y040-7904, which enhances mitophagy by promoting mitochondria transport to autophagosomes and the fusion of autophagosomes with autolysosomes. Y040-7904 also reduces amyloid-β pathologies in both in vitro and in vivo models of Alzheimer's disease. This work offers an approach for visualizing the entire mitophagy flux, advancing the understanding of mitophagy-related mechanisms and enabling the discovery of mitophagy inducers for neurodegenerative diseases.},
}

*Mitophagy/drug effects
Humans
*Mitochondria/metabolism/drug effects
Microscopy, Fluorescence/methods
Animals
Alzheimer Disease/metabolism/pathology/drug therapy
Autophagosomes/metabolism/drug effects
Mice
*Artificial Intelligence
Amyloid beta-Peptides/metabolism
Lysosomes/metabolism/drug effects
HeLa Cells

@article {pmid40467545,
year = {2025},
author = {Caramello, A and Fancy, N and Tournerie, C and Eklund, M and Chau, V and Adair, E and Papageorgopoulou, M and Willumsen, N and Jackson, JS and Hardy, J and Matthews, PM},
title = {Intracellular accumulation of amyloid-ß is a marker of selective neuronal vulnerability in Alzheimer's disease.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5189},
pmid = {40467545},
issn = {2041-1723},
mesh = {*Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Humans ; *Neurons/metabolism/pathology ; Male ; Female ; Aged ; Biomarkers/metabolism ; Aged, 80 and over ; Microglia/metabolism/pathology ; tau Proteins/metabolism ; Temporal Lobe/pathology/metabolism ; Forkhead Transcription Factors/metabolism ; Neocortex/pathology/metabolism ; Middle Aged ; },
abstract = {Defining how amyloid-β and pTau together lead to neurodegeneration is fundamental to understanding Alzheimer's disease (AD). We used imaging mass cytometry to identify neocortical neuronal subtypes lost with AD in post-mortem brain middle temporal gyri from non-diseased and AD donors. Here we showed that L5,6 RORB[+]FOXP2[+] and L3,5,6 GAD1[+]FOXP2[+] neurons, which accumulate amyloid-β intracellularly from early Braak stages, are selectively vulnerable to degeneration in AD, while L3 RORB[+]GPC5[+] neurons, which accumulate pTau but not amyloid-β, are not lost even at late Braak stages. We discovered spatial associations between activated microglia and these vulnerable neurons and found that vulnerable RORB[+]FOXP2[+] neuronal transcriptomes are enriched selectively for pathways involved in inflammation and glycosylation and, with progression to AD, also protein degradation. Our results suggest that the accumulation of intraneuronal amyloid-β, which is associated with glial inflammatory pathology, may contribute to the initiation of degeneration of these vulnerable neurons.},
}

*Alzheimer Disease/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Humans
*Neurons/metabolism/pathology
Male
Female
Aged
Biomarkers/metabolism
Aged, 80 and over
Microglia/metabolism/pathology
tau Proteins/metabolism
Temporal Lobe/pathology/metabolism
Forkhead Transcription Factors/metabolism
Neocortex/pathology/metabolism
Middle Aged

@article {pmid40467024,
year = {2025},
author = {Hu, X and Morihara, R and Fukui, Y and Bian, Y and Sun, H and Ota-Elliott, RS and Ishiura, H and Abe, K and Yamashita, T},
title = {Spearmint extract Neumentix downregulates amyloid-β accumulation by promoting phagocytosis in APP23 mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {149752},
doi = {10.1016/j.brainres.2025.149752},
pmid = {40467024},
issn = {1872-6240},
abstract = {In recent years, many researchers have focused on natural compounds that can effectively delay symptoms of Alzheimer's disease (AD). The spearmint extract Neumentix, which is rich in phenolic compounds, has been shown to reduce inflammatory responses and oxidative stress in mice. However, the effect of Neumentix on AD has not been thoroughly studied. In this study, APP23 transgenic female and male mice were administered Neumentix orally from 4 to 18 months of age at a dosage of 2.65 g/kg/day (containing 0.41 g/kg/day of rosmarinic acid). The impact was evaluated by behavioral tests and histological analyses and compared with APP23 mice to which Neumentix was not administered. The results showed that Neumentix administration increased the survival rate of APP23 mice and effectively reduced Aβ accumulation by enhancing its phagocytosis by microglial cells. These findings suggest that Neumentix is a potential natural nutritional treatment for improving the progression of AD.},
}

@article {pmid40466990,
year = {2025},
author = {Chen, G and Zhang, J and Dong, A and Xiao, L and Huang, P and Huang, T and Ye, Q and Huang, E},
title = {AXL-mediate GEF-H1 phosphorylation was involved in microglia synapse phagocytosis in 5xFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115327},
doi = {10.1016/j.expneurol.2025.115327},
pmid = {40466990},
issn = {1090-2430},
abstract = {Studies indicated that microglial synapse phagocytosis played a critical role in synapse loss and pathogenesis in Alzheimer's disease. AXL was one of key phagocytic receptors and was upgraded in disease associated microglia. This study aimed to investigate the role of AXL-mediated microglial synapse phagocytosis in AD mice model. Our data indicated that AXL was increased in microglia in 5xFAD mouse AD model. The lentivirus PLV-CXC3CR1-shAXl was applied to especially knockdown the AXL expression in microglia and the shAXL treatment ameliorated the cognitive impairment in 5xFAD mice. AXL knockdown decreased the 6E10 positive amyloid plaques, the diffusion index of amyloid plaques and the level of phosphorylated Tau. shAXL treatment increased microglial complexity and reduced the microglial synapse phagocytosis. This study further demonstrated that GEF-H1 was identified as a substrate of AXL and mainly phosphorylated at Y470 by AXL. The AXL-mediated GEF-H1-Y470 phosphorylation enhanced the phagocytic capacity of BV2. It seems paradoxical that amyloid plaque load and microglial phagocytosis were both decreased at the same time when the AXL was knockdown, but these indicated that microglia phagocytosis related synapse loss played a more critical role in cognitive impairment and AD pathogenesis than amyloid plaque load. Our study demonstrated that the activated AXL in microglia in 5xFAD enhanced synapse phagocytosis via phosphorylating GEF-H1 at Y470, which led to synapse loss and cognitive impairment. The application of AXL blockage would be a potential therapeutic strategy for AD treatment.},
}

@article {pmid40466904,
year = {2025},
author = {Sathian, B and Iqbal, J and Hamad, HA},
title = {Reevaluating Leucine's effects on Alzheimer's disease: evidence of potential benefits overlooked.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.05.309},
pmid = {40466904},
issn = {1873-7544},
}

@article {pmid40466786,
year = {2025},
author = {Stack-Sanchez, P and Beaulieu, C and Gross, DW},
title = {Rapid 1 mm isotropic diffusion tensor imaging with denoising and improved parameter estimation for detecting focal hippocampal lesions in temporal lobe epilepsy.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110443},
doi = {10.1016/j.mri.2025.110443},
pmid = {40466786},
issn = {1873-5894},
abstract = {While high resolution diffusion tensor imaging (DTI) at 1 mm isotropic can detect focal lesions of the hippocampus in temporal lobe epilepsy (TLE), faster acquisition times would facilitate potential clinical implementation. The purpose here is to assess different published denoising algorithms to overcome the low signal-to-noise ratio and accelerate 1 mm isotropic DTI of the human hippocampus at 3 T while maintaining diffusivity metric accuracy and image quality for focal lesion detection in TLE. The previously published 5.5 min protocol of 110 diffusion images per slice (10 directions × 10 averages and 10 b = 0 s/mm[2]) was assessed for subsets of 1-10 averages (same 10 directions) that were denoised using four algorithms that have been applied to other diffusion MRI datasets. In healthy controls, the variance-stabilizing transformation and optimal singular-value manipulation (VST) and Non-Local Spatial and Angular Matching (NLSAM) denoising greatly improved image quality while minimizing voxels with spurious extremes of fractional anisotropy (FA) or mean diffusivity (MD) down to 4 averages (i.e. 40 diffusion images and 4 b = 0 s/mm[2]) in healthy controls. The identification of focal lesions indicated by elevated MD and alterations of internal micro-architecture with only 4 averages were comparable to the full data set of 10 averages. Therefore, denoising of 1 mm isotropic DTI of the hippocampus enables a clinically feasible scan time of 2.2 min at 3 T that can be used for the detection of focal hippocampal lesions in TLE, as well as other neurological disorders such as multiple sclerosis, dementia and Alzheimer's disease.},
}

@article {pmid40466775,
year = {2025},
author = {Zhang, Z and Guo, S and Li, M and Shao, K and Xiao, B and Jin, Q},
title = {Blocking the NR2B in the hippocampal dentate gyrus reduced the spatial memory deficits and apoptosis through the PERK-CHOP pathway in a rat model of sporadic Alzheimer's disease.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115685},
doi = {10.1016/j.bbr.2025.115685},
pmid = {40466775},
issn = {1872-7549},
abstract = {The hippocampal dentate gyrus (DG) integrates multiple sensory inputs and encodes spatial memory. DG-dependent spatial memory deficits have been observed in early Alzheimer's disease (AD). Our previous study demonstrated that glutamate (Glu)-mediated excitotoxicity contributes to spatial learning and memory impairment in AD. It has been reported that the N-methyl-D-aspartic acid receptor (NMDAR) 2B subunit (NR2B) is predominantly localized to extrasynaptic sites, where it is associated with Ca[2+] neurotoxicity and neuronal loss. However, the specific contribution of NR2B-mediated excitotoxicity to DG neuronal apoptosis and memory impairment in sporadic AD (sAD) remains unclear. In this study, we established a sAD rat model through a single intraventricular injection of streptozotocin combined with intraperitoneal injection of D-galactose. We investigated the role of NR2B in DG apoptosis and spatial learning and memory by microinjecting ifenprodil, an NR2B antagonist, into the hippocampal DG. Behavioral tests showed increased escape latency, reduced swimming distance in the target quadrant and platform crossings, and the significantly increased expression of cleaved caspase-3, PARP, and p-PERK, p-eIF2α, and CHOP in the sAD rats. Microinjection of ifenprodil into the DG markedly inhibited the levels of p-PERK, p-eIF2α, CHOP, cleaved caspase-3, PARP, and neuronal apoptosis in the DG, while also ameliorating the spatial learning and memory impairments in sAD rats. These results suggest that NR2B in the hippocampal DG is associated with neuronal apoptosis via the PERK-CHOP pathway and contributes to the spatial learning and memory deficits observed in sAD rats.},
}

@article {pmid40466640,
year = {2025},
author = {Liu, J and Liu, Y and Yin, D and Tian, Y},
title = {Electrochemical sensor toolkit for simultaneous glutamate detection at edge of cleft and peri-soma.},
journal = {Cell chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.chembiol.2025.05.002},
pmid = {40466640},
issn = {2451-9448},
abstract = {Simultaneously monitoring glutamate (Glu) dynamic at edge of synaptic cleft and peri-soma is crucial for understanding Glu-related pathology. Here, we created an electrochemical Glu sensors toolkit with spatial resolution of ∼60 nm, combining biologically engineered Glu binding protein for specifically capturing Glu together with chemically designed ferrocene groups for signal labeling. Modulation conjugation approach between GluR and ferrocene significantly improved sensitivity up to 32-folds. More importantly, protein engineering of residue mutation and linker peptides flexibility expanded linear range from 10 μM to 6 mM, accelerated on/off times down to 35/40 ms. This toolkit realized real-time quantifying of Glu both at edge of cleft and peri-soma, we discovered that Glu was almost released through SLC7A11 channels in calyx of held synapse upon oxygen-glucose-deprivation, while Glu was mainly released through hemichannels upon β-amyloid42 stimulation. Our work provided a methodology for investigating Glu release and reuptake and offered insights for Glu related pathology.},
}

@article {pmid40466273,
year = {2025},
author = {Behar, AE and Maayan, G},
title = {Structure-function relationship within helical peptoids for Cu[2+] chelation in the context of Alzheimer's disease.},
journal = {Journal of inorganic biochemistry},
volume = {271},
number = {},
pages = {112961},
doi = {10.1016/j.jinorgbio.2025.112961},
pmid = {40466273},
issn = {1873-3344},
abstract = {Peptoids (N-substituted glycine oligomers) represent an excellent platform for drug development, such as selective chelators for Cu[2+] ions towards chelation therapy, due to their efficient synthesis, high stability and good bioavailability. We previously showed that peptoids helicity is essential for selective Cu[2+] binding and identified a unique peptoid hexamer, having 2,2':6',2″-terpyridine, and 8-hydroxyquinoline as metal-binding sidechains facing the same side of the helix, which exhibits high selectivity to Cu[2+] ions. However, maintaining a stable helix required the incorporation of bulky chiral sidechains, resulting in a hydrophobic peptoid, insoluble in aqueous solutions, and limited in its use as a drug candidate. Our attempts to solubilize this peptoid led to the discovery of a water-soluble sequence able to selectively extract Cu[2+] from Cu-amyloid complex, and by this stop the formation of reactive oxygen species (ROS) in the context of Alzheimer's disease (AD). This peptoid, however, had limited solubility in buffer solutions (that mimic biological environment), thus its potential for further development as a therapeutic for AD was limited. In this current study, we explore the structure-function relationship within a newly synthesized set of helical and water-soluble peptoids. By extensive spectroscopic analysis we test the effect of helix stability as well as the type and number of the solubilizing group(s) and their position along the sequence, on the solubility of these peptoids in buffer, and on their selectivity for Cu and ability to inhibit ROS production. The results provide insights about the relationships between the structure of the peptoids/Cu-peptoids and ROS production inhibition.},
}

@article {pmid40466093,
year = {2025},
author = {Levinson, AJ and Ayers, S and Clark, S and Woodburn, R and Markle-Reid, M and McKenna, B and Oliver, D and Papaioannou, A and Siu, H and Sztramko, R},
title = {Web-Based Education Program for Care Partners of People Living With Dementia (iGeriCare): Protocol for a Pilot Randomized Controlled Trial.},
journal = {JMIR research protocols},
volume = {14},
number = {},
pages = {e67048},
doi = {10.2196/67048},
pmid = {40466093},
issn = {1929-0748},
mesh = {Humans ; *Dementia/psychology/therapy ; Pilot Projects ; *Caregivers/education/psychology ; Canada ; Female ; Male ; Internet ; *Internet-Based Intervention ; Feasibility Studies ; Randomized Controlled Trials as Topic ; Aged ; Adult ; Self Efficacy ; Middle Aged ; },
abstract = {BACKGROUND: The prevalence of dementia is increasing in Canada and in many countries internationally. People living with dementia are highly dependent on family and friend care partners, who may have little knowledge of the disorder. Web-based interventions in dementia have been shown to improve care partner mental health and reduce burden, but few have been widely implemented or rigorously studied. We developed a web- and email-based dementia education platform for care partners, iGeriCare, which includes 12 asynchronous, multimedia, e-learning lessons and email-based content to reinforce the learning.

OBJECTIVE: The primary objective of this pilot study is to evaluate the feasibility and care partner acceptance of the intervention, including study methods. Secondary objectives will examine the effectiveness of the educational resources on family care partners' knowledge, self-efficacy, and sense of burden.

METHODS: This study is a 2-arm, pilot, feasibility, randomized controlled trial. A total of 125 family or friend care partners for a person living with dementia-who are residing in Canada, aged 16+ years, and comfortable using the internet and email-will be recruited using coinvestigator networks and Facebook digital marketing advertisements. Participants will be randomly assigned to either the intervention group (receiving the dementia web- and email-based educational intervention) or the control group (receiving an alternate topic e-learning lesson and emails) and will have 8 weeks to complete baseline surveys and the assigned e-learning. After 8 weeks, participants will have 2 weeks to complete poststudy surveys. This protocol will be repeated with a second cohort of 100 care partners recruited from a paid panel service based on learnings from initial feasibility results.

RESULTS: Initial recruitment began on September 6, 2022, and concluded on October 2, 2022. A total of 125 participants were randomly assigned to the intervention (n=61) or control (n=64) group. Data collection concluded in January 2023. Preliminary feasibility results showed a substantial number of participants who did not engage with the protocol as intended. A decision was made to recruit a second cohort of participants to address these protocol deviations. Secondary recruitment began on June 12, 2023, and concluded on June 27, 2023. A total of 100 participants were randomly assigned to the intervention (n=53) or control (n=47) group. Data collection concluded in September 2023. Further results will be published in peer-reviewed journals and presented at conferences.

CONCLUSIONS: This study is investigating the feasibility, acceptability, and effectiveness of a web- and email-based dementia care partner educational intervention. The results of this study will contribute to the planning of a larger randomized controlled trial in the future, as well as the evaluation of innovative, cost-effective, and efficient dementia care partner resources that can complement traditional approaches.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05114187; https://clinicaltrials.gov/study/NCT05114187.

DERR1-10.2196/67048.},
}

Humans
*Dementia/psychology/therapy
Pilot Projects
*Caregivers/education/psychology
Canada
Female
Male
Internet
*Internet-Based Intervention
Feasibility Studies
Randomized Controlled Trials as Topic
Aged
Adult
Self Efficacy
Middle Aged

@article {pmid40466018,
year = {2025},
author = {Agosta, F and Cecchetti, G and Spinelli, EG and Ghirelli, A and Rugarli, G and Filippi, M},
title = {MRI protocols and sequences for amyloid-related imaging abnormalities monitoring in Alzheimer's disease patients treated with monoclonal antibodies.},
journal = {Current opinion in neurology},
volume = {},
number = {},
pages = {},
doi = {10.1097/WCO.0000000000001388},
pmid = {40466018},
issn = {1473-6551},
abstract = {PURPOSE OF REVIEW: This review provides an updated overview of amyloid-related imaging abnormalities (ARIA) associated with antiamyloid monoclonal antibodies (mAbs) in Alzheimer's disease (AD). Following regulatory approvals for both lecanemab and donanemab in the United States, and pending decisions in Europe, standardized understanding of ARIA definitions, risk factors, and optimal MRI surveillance is increasingly important to guide treatment and ensure safety.

RECENT FINDINGS: ARIA, including vasogenic edema (ARIA-E) and microhemorrhages/siderosis (ARIA-H), are a frequent adverse event in patients receiving antiamyloid mAbs, particularly among APOE ε4 homozygotes. Incidence varies by agent and trial design. While often asymptomatic and self-limiting, ARIA can occasionally present with symptoms or recur. MRI, especially FLAIR and susceptibility-sensitive imaging, is essential for baseline risk stratification and monitoring. Key imaging biomarkers include microbleeds and superficial siderosis. Recent guidelines support genotyping and risk-adapted MRI protocols before and during therapy.

SUMMARY: ARIA reflect vascular vulnerability during amyloid clearance in AD. Their management requires close collaboration between neurologists and neuroradiologists, with harmonized MRI protocols and risk mitigation strategies critical for safe and effective use of disease-modifying therapies.},
}

@article {pmid40465828,
year = {2025},
author = {Yu, L and Du, L and Wang, T and Barnes, LL and Dage, JL and Russ, KA and Foroud, T and Bennett, DA and Schneider, JA and Boyle, PA},
title = {Neuropathologic correlates of distinct plasma biomarker profiles in community-living older adults.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf211},
pmid = {40465828},
issn = {1460-2156},
abstract = {There has been a rapid growth in research on peripheral fluid biomarkers for Alzheimer's Disease and Alzheimer's Disease related dementias (AD/ADRD) because they are non-invasive, relatively inexpensive, and easily accessible. The most commonly used plasma biomarkers include β-amyloid (Aβ), phosphorylated tau (p-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). The extent to which distinct profiles of multiple plasma biomarkers correlate with common neuropathologies is unclear. Using clinicopathologic data from 405 community-dwelling older adults, we applied latent profile analysis on 4 plasma biomarkers, i.e., Aβ42/40 ratio, p-tau217, NfL and GFAP, and examined the correlates of the latent profiles with 4 degeneration measures of AD, Lewy bodies, limbic-predominant age-related TDP-43 encephalopathy (LATE), hippocampal sclerosis, and 5 vascular measures including chronic macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis and arteriosclerosis. On average, participants died at the age of 89 and blood samples for plasma biomarkers were measured 3.9 years before death. Over 75% were female and 24% were non-Latino Black. We observed 3 distinct biomarker profiles. Profile #1, characterized by low p-tau217, low GFAP, low NfL and high Aβ42/40, represents most participants (55.6%) with better than average biomarker levels. Both Profile #2 and Profile #3 showed worse than average biomarker levels. Profile #2, representing 34.8% of the participants, was high in p-tau217 and GFAP. By contrast, Profile #3, representing 9.6% of the participants, was high in NfL and GFAP. Examination of neuropathologic correlates of these plasma biomarker profiles revealed that Profile #2 exemplifies older adults with a high burden of neurodegeneration; almost all participants (92.9%) in Profile #2 had a diagnosis of pathologic AD, and the group also had the highest percentage of participants with Lewy bodies (41.1%). In comparison, Profile #3 exemplifies older adults with more severe vascular conditions; participants in this group had the highest percentage of macroscopic infarcts (31.6%) and moderate or severe atherosclerosis (42.1%). Together, these findings suggest that common plasma biomarkers may exhibit profiles reflective of distinct pathophysiologic processes.},
}

@article {pmid40465757,
year = {2025},
author = {Ventura-Antunes, L and Nackenoff, A and Romero-Fernandez, W and Wang, Y and Bosworth, AM and Prusky, A and Wang, E and Carvajal-Tapia, C and Shostak, A and Harmsen, H and Mobley, B and Maldonado, J and Womble, N and Solopova, E and Snider, JC and Merryman, WD and Lippmann, ES and Schrag, M},
title = {Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to Aβ deposition and lysyl oxidase.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70254},
doi = {10.1002/alz.70254},
pmid = {40465757},
issn = {1552-5279},
support = {R03NS111486-01/GF/NIH HHS/United States ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Protein-Lysine 6-Oxidase/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; Aged ; Arterioles/pathology ; Microscopy, Atomic Force ; Aged, 80 and over ; *Vascular Stiffness/physiology ; Middle Aged ; *Brain/pathology/blood supply ; Muscle, Smooth, Vascular/pathology ; },
abstract = {INTRODUCTION: The morphological and molecular changes associated with the degeneration of arterioles in cerebral amyloid angiopathy (CAA) are incompletely understood.

METHODS: Post mortem brains from 26 patients with CAA or neurological controls were analyzed using light-sheet microscopy, and morphological features of microvascular degeneration were quantified using surface volume rendering. Vascular stiffness was analyzed using atomic force microscopy.

RESULT: Vascular smooth muscle cells (VSMCs) volume was reduced by ≈ 55% in CAA. This loss of VSMC volume correlated with increased arteriolar diameter, variability in diameter, and the volume of amyloid beta (Aβ) deposition in the vessel. Vessels with CAA were > 300% stiffer than controls. The volume of extracellular matrix cross-linking enzyme lysyl oxidase (LOX) correlated closely with vascular degenerative features.

DISCUSSION: Our findings provide valuable insights into the connections among LOX, Aβ deposition, and vascular stiffness in CAA. Restoration of physiologic extracellular matrix properties in penetrating arteries may yield a novel therapeutic strategy for CAA.

HIGHLIGHTS: We conducted 3D microscopy on human brains with cerebral amyloid angiopathy. We quantified features of vascular degeneration, β-amyloid, and lysyl oxidase in CAA Vascular degeneration correlated with Aβ, loss of VSMCs , and increased LOX. Arterioles with CAA were stiffer than controls in data from atomic force microscopy. Vascular extracellular matrix properties may be a therapeutic target for CAA.},
}

Humans
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Protein-Lysine 6-Oxidase/metabolism
*Amyloid beta-Peptides/metabolism
Male
Female
Aged
Arterioles/pathology
Microscopy, Atomic Force
Aged, 80 and over
*Vascular Stiffness/physiology
Middle Aged
*Brain/pathology/blood supply
Muscle, Smooth, Vascular/pathology

@article {pmid40465699,
year = {2025},
author = {Kremen, WS and Ericsson, M and Gatz, M and Karlsson, IK and Nygaard, M and Pedersen, NL and Panizzon, MS},
title = {A lifespan perspective on cognitive reserve and risk for dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70176},
doi = {10.1002/alz.70176},
pmid = {40465699},
issn = {1552-5279},
support = {R01AG060470/NH/NIH HHS/United States ; R01AG081248/NH/NIH HHS/United States ; R01AG050595/NH/NIH HHS/United States ; R01AG076838/NH/NIH HHS/United States ; 2021-00180//Vetenskapsrådet/ ; R01 AG081248/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cognitive Reserve/physiology ; *Dementia/epidemiology ; Male ; Educational Status ; Sweden/epidemiology ; Middle Aged ; Risk Factors ; Adult ; Registries ; Young Adult ; Survival Analysis ; },
abstract = {INTRODUCTION: We addressed whether higher education plays a causal role in reducing dementia risk by comparing two indices of cognitive reserve: education and young adult general cognitive ability (GCA).

METHODS: We conducted a 52-year survival analysis to examine associations of GCA and education with dementia in 16,619 male conscripts identified in Swedish national health registries born between 1936 and 1958 and with available data for models including midlife occupational complexity, physical activity, and socioeconomic status (SES).

RESULTS: Higher GCA was associated with lower dementia risk (hazard ratio = 0.865, 95% confidence interval = 0.756 to 0.990). After accounting for GCA, no other measure contributed significantly to dementia risk.

DISCUSSION: Putative reserve effects of education or occupational complexity likely reflect largely downstream effects of prior GCA. From a lifespan perspective on reducing dementia risk, the results may suggest favoring interventions aimed at enhancing cognitive development during childhood when there is substantial brain development as opposed to later-life cognitive training.

HIGHLIGHTS: Education and GCA serve as indices of cognitive reserve. Education is a modifiable risk factor that is associated with dementia risk. The effect of higher education on reduced dementia risk is not directly causal. Education is largely a downstream effect of prior level of GCA. Increasing GCA during childhood may be more effective than later cognitive training.},
}

Humans
*Cognitive Reserve/physiology
*Dementia/epidemiology
Male
Educational Status
Sweden/epidemiology
Middle Aged
Risk Factors
Adult
Registries
Young Adult
Survival Analysis

@article {pmid40465679,
year = {2025},
author = {Wang, P and Song, YE and Lynn, A and Miskimen, K and Gulyayev, A and Prough, MB and Dorfsman, DA and Laux, RA and Fuzzell, SL and Hochstetler, SD and Zaman, AF and Adams, LD and Caywood, LJ and Clouse, JE and Herington, SD and Whitehead, P and Liu, Y and Moore, N and Ogrocki, P and Lerner, AJ and Griswold, AJ and Vance, JM and Cuccaro, ML and Scott, WK and Pericak-Vance, MA and Haines, JL},
title = {Alzheimer's disease plasma biomarkers in the Midwestern Amish.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70328},
doi = {10.1002/alz.70328},
pmid = {40465679},
issn = {1552-5279},
support = {AG019085/AG/NIA NIH HHS/United States ; AG019726/AG/NIA NIH HHS/United States ; AG058066/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/blood/genetics/ethnology ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; Male ; Female ; Biomarkers/blood ; Aged ; *Peptide Fragments/blood ; Aged, 80 and over ; Apolipoprotein E4/genetics ; Phosphorylation ; Midwestern United States ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) plasma biomarkers are non-invasive measures of the key amyloid beta (Aβ) and tau pathologies. Validation and generalization studies are needed to fully understand their potential for AD prediction and diagnosis in the elderly population.

METHODS: In 1067 Amish individuals aged ≥ 65, we measured plasma Aβ and tau to assess their relationships with AD-related outcomes.

RESULTS: Among Amish individuals with AD, plasma phosphorylated tau protein at epitope 181 (p-tau181) was significantly higher (p = 0.04), and plasma Aβ42/p-tau181 ratio was significantly lower (p = 0.01) than cognitively normal individuals. The association of AD with elevated p-tau181 was driven by apolipoprotein E (APOE) ε4 carriers (odds ratio = 6.02, p < 0.001). Cluster analysis identified two subgroups defined by differing Aβ and tau levels, with the high-risk cluster having more APOE ε4 carriers (p < 0.001).

DISCUSSION: Plasma biomarkers, particularly p-tau181, Aβ42/Aβ40, and Aβ42/p-tau181 ratio, are promising surrogate biomarkers for AD-related pathology and clinical outcomes in the Amish.},
}

Humans
*Alzheimer Disease/blood/genetics/ethnology
*tau Proteins/blood
*Amyloid beta-Peptides/blood
Male
Female
Biomarkers/blood
Aged
*Peptide Fragments/blood
Aged, 80 and over
Apolipoprotein E4/genetics
Phosphorylation
Midwestern United States

@article {pmid40465637,
year = {2025},
author = {Gholampour, M and Basu, MK and Swerdlow, RH and Zhuo, X and Haeri, M},
title = {Cell-specific protein expression in Alzheimer's disease prefrontal cortex.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70339},
doi = {10.1002/alz.70339},
pmid = {40465637},
issn = {1552-5279},
support = {P30 AG072973/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Prefrontal Cortex/metabolism/pathology ; *Microglia/metabolism ; Neprilysin/metabolism ; Male ; *Neurons/metabolism ; Aged ; Female ; Astrocytes/metabolism ; *Proteome/metabolism ; Aged, 80 and over ; Lysosomal-Associated Membrane Protein 2/metabolism ; },
abstract = {INTRODUCTION: Analyzing the proteomes of different brain cell types is fundamental for understanding the pathophysiology of Alzheimer's disease (AD). However, spatial analysis of these diverse and limited cell populations poses significant challenges.

METHODS: The GeoMx Digital Spatial Profiler (DSP) platform was used to analyze protein level in the prefrontal cortex of AD and non-AD brains. The platform interrogated 76 proteins and used immunofluorescence to distinguish between three cell types.

RESULTS: Neprilysin (NEP), which promotes amyloid beta degradation, was significantly higher in AD neurons and microglia. Lysosome-associated membrane protein 2A (LAMP2A) level was higher in neurons of individuals with AD compared to a control group. In addition, markers of neuroinflammation, such as CD11c, CD11b, and CD163, were also elevated in AD neurons.

DISCUSSION: Our findings indicate the DSP platform effectively facilitates cell-specific snapshots of the AD brain proteome.

HIGHLIGHTS: The expression of 76 proteins was studied in neurons, astrocytes, and microglia. We identified 18 differentially expressed proteins in AD neurons. Neprilysin was upregulated in neurons and microglia.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Prefrontal Cortex/metabolism/pathology
*Microglia/metabolism
Neprilysin/metabolism
Male
*Neurons/metabolism
Aged
Female
Astrocytes/metabolism
*Proteome/metabolism
Aged, 80 and over
Lysosomal-Associated Membrane Protein 2/metabolism

@article {pmid40465636,
year = {2025},
author = {DiFilippo, AH and Jonaitis, EM and Ennis, GE and McVea, AK and McLachlan, M and Bettcher, B and Schulz, N and Pasquesi, ME and Davenport-Sis, NJ and Thor, Y and Grover, E and Chin, N and Barnhart, TE and Asthana, S and Betthauser, TJ and Engle, JW and Johnson, SC and Bendlin, BB and Christian, BT},
title = {Examining the association between synaptic density and neurofibrillary tau among cognitively impaired and unimpaired older adults with and without Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70321},
doi = {10.1002/alz.70321},
pmid = {40465636},
issn = {1552-5279},
support = {R01 AG062285/AG/NIA NIH HHS/United States ; P30AG062715/AG/NIA NIH HHS/United States ; R01AG027161/AG/NIA NIH HHS/United States ; U54 HD090256/HD/NICHD NIH HHS/United States ; S10 OD025245/CD/ODCDC CDC HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Male ; Female ; Positron-Emission Tomography ; *Neurofibrillary Tangles/pathology/metabolism ; Aged ; *Cognitive Dysfunction/pathology/diagnostic imaging/metabolism ; *Synapses/pathology ; *tau Proteins/metabolism ; Aged, 80 and over ; Plaque, Amyloid/pathology/diagnostic imaging ; Hippocampus/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: Synapse loss is a key driver of cognitive decline in Alzheimer's disease (AD), yet its direct relationship with neurofibrillary tau tangle (NFT) burden remains unclear. This study leveraged positron emission tomography (PET) imaging to investigate the link between NFT accumulation and synaptic density in older adults with and without AD pathology.

METHODS: Older adults (N = 94) underwent PET imaging to quantify synaptic density ([[11]C]UCB-J distribution volume ratio [DVR]), Aβ plaque burden ([[11]C]PiB DVR), and NFT burden ([[18]F]MK-6240 standardized uptake value ratio). Analyses focused on NFT-synaptic density correlations in the hippocampus (Hp) and entorhinal cortex (ERC), with additional subgroup analyses based on cognitive and Aβ status.

RESULTS: Hp NFT burden strongly correlated with synaptic density, while the ERC showed weaker effects. Subgroup analyses found robust Hp associations in unimpaired AD participants.

CONCLUSION: Hippocampal synaptic density is highly vulnerable to early NFT accumulation. SV2A PET imaging enables early detection of synaptic loss and may also identify resilience to AD pathology.

HIGHLIGHTS: Hippocampal synaptic density is similar in controls and unimpaired biologic AD. Hp synaptic density particularly vulnerable to Hp, ERC NFT burden. NFT-synaptic density relationship may vary between unimpaired and impaired biologic AD.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Male
Female
Positron-Emission Tomography
*Neurofibrillary Tangles/pathology/metabolism
Aged
*Cognitive Dysfunction/pathology/diagnostic imaging/metabolism
*Synapses/pathology
*tau Proteins/metabolism
Aged, 80 and over
Plaque, Amyloid/pathology/diagnostic imaging
Hippocampus/pathology/diagnostic imaging

@article {pmid40465608,
year = {2025},
author = {Liu, L and Li, Y and Yang, K},
title = {Dynamically weighted graph neural network for detection of early mild cognitive impairment.},
journal = {PloS one},
volume = {20},
number = {6},
pages = {e0323894},
doi = {10.1371/journal.pone.0323894},
pmid = {40465608},
issn = {1932-6203},
mesh = {*Cognitive Dysfunction/diagnosis/physiopathology ; Humans ; *Neural Networks, Computer ; Aged ; Early Diagnosis ; Alzheimer Disease/diagnosis/physiopathology ; Male ; Female ; Brain/physiopathology ; Magnetic Resonance Imaging ; Algorithms ; *Nerve Net/physiopathology ; Graph Neural Networks ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disease that primarily affects the elderly population. The early detection of mild cognitive impairment (MCI) holds significant clinical importance for prompt intervention and treatment of AD. Currently, functional connectivity (FC) networks-based diagnostic methods for early MCI (eMCI) detection are widely employed. FC considers the interaction patterns between brain regions as a topological structure. Recently, graph neural network (GNN) approaches have been utilized for disease diagnosis using FC networks, leveraging their ability to extract features from topological structures. However, existing methods typically treat FC features as GNN node attributes, disregarding the fact that FC features represent the weights of connection edges in FC networks with topological characteristics. In this paper, we propose a dynamically weighted GNN-based approach for early eMCI detection. Our method takes into account the topological structure and dynamic properties of FC networks by utilizing temporal FC features as the weighted adjacency matrix for dynamic GNNs. Moreover, the weighted graph local clustering coefficient of brain regions is employed as the node feature for GNNs. We extensively evaluated our approach using the ADNI database and achieved accuracies of 91.67% and 78.33% on low- and high-order FC networks, respectively. These results demonstrate the effectiveness and superiority of our proposed method compared to existing approaches.},
}

*Cognitive Dysfunction/diagnosis/physiopathology
Humans
*Neural Networks, Computer
Aged
Early Diagnosis
Alzheimer Disease/diagnosis/physiopathology
Male
Female
Brain/physiopathology
Magnetic Resonance Imaging
Algorithms
*Nerve Net/physiopathology
Graph Neural Networks

@article {pmid40465535,
year = {2025},
author = {Zetterberg, H},
title = {Biofluid-based biomarker panels toward personalized medicine in dementia diagnostics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70178},
doi = {10.1002/alz.70178},
pmid = {40465535},
issn = {1552-5279},
support = {#2023-00356//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; #2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer Drug Discovery Foundation (ADDF), USA/ ; //AD Strategic Fund/ ; #ADSF-21-831376-C #ADSF-21-831381-C #ADSF-21-831377-C/ALZ/Alzheimer's Association/United States ; #ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; //European Partnership on Metrology/ ; #22HLT07//NEuroBioStand/ ; #FO2022-0270//Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden/ ; 860197//Marie Skłodowska-Curie/ ; JPND2021-00694//Neurodegenerative Disease Research/ ; UKDRI-1003//National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the UK Dementia Research Institute at UCL/ ; },
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Precision Medicine/methods ; *Dementia/diagnosis ; *Alzheimer Disease/diagnosis ; },
abstract = {Alzheimer's & Dementia publishes a set of papers exploring the diagnostic and prognostic capabilities of a novel cutting-edge multiplexed biomarker measurement technology across neurodegenerative dementias.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Precision Medicine/methods
*Dementia/diagnosis
*Alzheimer Disease/diagnosis

@article {pmid40465519,
year = {2025},
author = {Thangavel, P and Park, D and Lee, YC},
title = {Neurotoxic Effects of Airborne Particulate Matter: Mechanisms and Health Implications.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {6},
pages = {e70322},
doi = {10.1002/jbt.70322},
pmid = {40465519},
issn = {1099-0461},
support = {//This study was supported by the Basic Science Research Capacity Enhancement Project through a Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education (2019R1A6C1010016), and the Gachon University Research Fund of 2021 (GCU-202106620001)./ ; },
mesh = {Humans ; *Particulate Matter/toxicity/adverse effects ; Animals ; Oxidative Stress/drug effects ; Blood-Brain Barrier/drug effects/pathology/metabolism ; *Air Pollutants/toxicity ; *Neurotoxicity Syndromes/etiology ; *Neurodegenerative Diseases/chemically induced/metabolism/pathology ; },
abstract = {Exposure to particulate matter (PM) impacts various aspects of health. PM exposure has been increasingly associated with adverse neurological effects, including both neurodevelopmental disorders and neurodegenerative diseases. This review examines the pathways through which PM affects the central nervous system (CNS), including inhalation, systemic circulation, and direct olfactory translocation, leading to neuroinflammation, oxidative stress, and disruption of the blood-brain barrier (BBB). Epidemiological and experimental studies suggest a strong correlation between PM exposure and cognitive impairments, Alzheimer's disease (AD), Multiple sclerosis, and Parkinson's disease (PD). Investigating the PM-neurodegenerative disease relationship is a pressing public health priority, offering opportunities to protect vulnerable populations from the effects of neurodegenerative diseases. The potential of PM for long-term accumulation and neurotoxicity is further demonstrated by its toxicokinetics, which include its absorption, distribution, metabolism, and excretion. Understanding these pathways is essential for developing solutions to reduce PM-induced neurological hazards.},
}

Humans
*Particulate Matter/toxicity/adverse effects
Animals
Oxidative Stress/drug effects
Blood-Brain Barrier/drug effects/pathology/metabolism
*Air Pollutants/toxicity
*Neurotoxicity Syndromes/etiology
*Neurodegenerative Diseases/chemically induced/metabolism/pathology

@article {pmid40465455,
year = {2025},
author = {Valle, ML and Getaneh, B and Loveland, J and Erdjument-Bromage, H and William, C and Neubert, TA and Rostagno, A and Ghiso, J},
title = {Protocol for culture, purification, and target validation of a hybridoma-generated monoclonal antibody targeting Aβ truncated species.},
journal = {STAR protocols},
volume = {6},
number = {2},
pages = {103864},
doi = {10.1016/j.xpro.2025.103864},
pmid = {40465455},
issn = {2666-1667},
abstract = {Alzheimer's disease (AD) is characterized by the deposition of full-length and truncated amyloid beta (Aβ) species within brain parenchyma and cerebral vessels. However, Aβ truncated species remain understudied. Here, we present a protocol for culture and characterization of a mouse monoclonal antibody targeting N-terminally truncated proteoforms starting at position 4. We describe a detailed procedure for hybridoma culture, antibody collection, and isolation via affinity chromatography. We then describe steps for target validation via dot blot, as well as potential applications. For complete details on the use and execution of this protocol, please refer to Cabrera et al. and Rostagno et al.[1][,][2].},
}

@article {pmid40465350,
year = {2025},
author = {Amirahmadi, A and Etminani, F and Björk, J and Melander, O and Ohlsson, M},
title = {Trajectory-Ordered Objectives for Self-Supervised Representation Learning of Temporal Healthcare Data Using Transformers: Model Development and Evaluation Study.},
journal = {JMIR medical informatics},
volume = {13},
number = {},
pages = {e68138},
doi = {10.2196/68138},
pmid = {40465350},
issn = {2291-9694},
mesh = {Humans ; *Electronic Health Records ; *Supervised Machine Learning ; *Deep Learning ; },
abstract = {BACKGROUND: The growing availability of electronic health records (EHRs) presents an opportunity to enhance patient care by uncovering hidden health risks and improving informed decisions through advanced deep learning methods. However, modeling EHR sequential data, that is, patient trajectories, is challenging due to the evolving relationships between diagnoses and treatments over time. Significant progress has been achieved using transformers and self-supervised learning. While BERT-inspired models using masked language modeling (MLM) capture EHR context, they often struggle with the complex temporal dynamics of disease progression and interventions.

OBJECTIVE: This study aims to improve the modeling of EHR sequences by addressing the limitations of traditional transformer-based approaches in capturing complex temporal dependencies.

METHODS: We introduce Trajectory Order Objective BERT (Bidirectional Encoder Representations from Transformers; TOO-BERT), a transformer-based model that advances the MLM pretraining approach by integrating a novel TOO to better learn the complex sequential dependencies between medical events. TOO-Bert enhanced the learned context by MLM by pretraining the model to distinguish ordered sequences of medical codes from permuted ones in a patient trajectory. The TOO is enhanced by a conditional selection process that focus on medical codes or visits that frequently occur together, to further improve contextual understanding and strengthen temporal awareness. We evaluate TOO-BERT on 2 extensive EHR datasets, MIMIC-IV hospitalization records and the Malmo Diet and Cancer Cohort (MDC)-comprising approximately 10 and 8 million medical codes, respectively. TOO-BERT is compared against conventional machine learning methods, a transformer trained from scratch, and a transformer pretrained on MLM in predicting heart failure (HF), Alzheimer disease (AD), and prolonged length of stay (PLS).

RESULTS: TOO-BERT outperformed conventional machine learning methods and transformer-based approaches in HF, AD, and PLS prediction across both datasets. In the MDC dataset, TOO-BERT improved HF and AD prediction, increasing area under the receiver operating characteristic curve (AUC) scores from 67.7 and 69.5 with the MLM-pretrained Transformer to 73.9 and 71.9, respectively. In the MIMIC-IV dataset, TOO-BERT enhanced HF and PLS prediction, raising AUC scores from 86.2 and 60.2 with the MLM-pretrained Transformer to 89.8 and 60.4, respectively. Notably, TOO-BERT demonstrated strong performance in HF prediction even with limited fine-tuning data, achieving AUC scores of 0.877 and 0.823, compared to 0.839 and 0.799 for the MLM-pretrained Transformer, when fine-tuned on only 50% (442/884) and 20% (176/884) of the training data, respectively.

CONCLUSIONS: These findings demonstrate the effectiveness of integrating temporal ordering objectives into MLM-pretrained models, enabling deeper insights into the complex temporal relationships inherent in EHR data. Attention analysis further highlights TOO-BERT's capability to capture and represent sophisticated structural patterns within patient trajectories, offering a more nuanced understanding of disease progression.},
}

Humans
*Electronic Health Records
*Supervised Machine Learning
*Deep Learning

@article {pmid40464863,
year = {2025},
author = {Ren, Z and Chen, H and Wu, H and Ma, LY and Gan, J and Liu, S and Zhou, F and Zhang, G and Ji, Y},
title = {Serum ferritin levels linked to cognitive decline and biomarker profiles in dementia with lewy bodies.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {40464863},
issn = {2240-2993},
support = {82171182//the National Natural Science Foundation of China/ ; 82171182//the National Natural Science Foundation of China/ ; },
abstract = {OBJECTIVE: Elevated serum ferritin levels have been associated with neurodegenerative diseases, yet their specific role in dementia with Lewy bodies (DLB) remains insufficiently explored.

METHOD: A total of 434 participants were enrolled, including 217 controls, 217 Alzheimer's disease (AD) patients, and 89 DLB patients. Demographic and clinical characteristics, cognitive performance, and neurobehavioral symptoms were evaluated. Serum ferritin levels were stratified into quartiles, and logistic regression models were used to examine the association between ferritin levels and the risk of DLB. Additionally, biomarker profiles of Aβ42, Aβ40, t-tau, and p-tau were analyzed across ferritin quartiles in DLB patients.

RESULTS: DLB patients exhibited the most severe neurobehavioral symptoms (NPI: 11.09 ± 1.24) and significant cognitive impairment (MMSE: 14.16 ± 6.81; MoCA: 9.77 ± 6.20) compared to controls. Higher serum ferritin levels were significantly associated with increased DLB risk, with the highest quartile showing an adjusted odds ratio of 7.58 (95% CI: 2.52-22.81). In DLB patients, ferritin levels were significantly associated with Aβ42 (p < 0.001), with Aβ42 concentrations following a U-shaped distribution across quartiles, suggesting a complex interplay between ferritin and amyloid pathology. Aβ40, t-tau, and p-tau showed weaker or non-significant associations.

CONCLUSION: Elevated serum ferritin levels are strongly associated with an increased risk of DLB and may modulate amyloid pathology, particularly Aβ42. These findings underscore the relevance of iron metabolism in the pathophysiology of DLB and suggest ferritin as a potential biomarker for diagnosis and disease monitoring.},
}

@article {pmid40464817,
year = {2025},
author = {Tawhid, MNA and Siuly, S and Kabir, E and Li, Y},
title = {Advancing Alzheimer's disease detection: a novel convolutional neural network based framework leveraging EEG data and segment length analysis.},
journal = {Brain informatics},
volume = {12},
number = {1},
pages = {13},
pmid = {40464817},
issn = {2198-4018},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects memory, thinking, and behavior, leading to dementia, a severe cognitive decline. While no cure currently exists, recent advancements in preventive drug trials and therapeutic management have increased interest in developing clinical algorithms for early detection and biomarker identification. Electroencephalography (EEG) is noninvasive, cost-effective, and has high temporal resolution, making it a promising tool for automated AD detection. However, conventional machine learning approaches often fall short in accurately detecting AD due to their limited architectures. We also need to investigate the impact of EEG signal segment length on classification accuracy. To address these issues, a deep learning-based framework is proposed to detect AD using EEG data, focusing on determining the optimal segment length for classification. This framework contains EEG data collection, pre-processing for noise removal, temporal segmentation, convolutional neural network (CNN) model training and classification, and finally, evaluation. We have tested different segment lengths to test the impact on AD detection. We have used both 10-fold and leave-one-out cross-validation techniques and obtained accuracy of 97.08% and 96.90%, respectively, on a publicly available dataset from AHEPA General University Hospital of Thessaloniki. We have also tested the generalizability of the proposed model by testing it to detect frontotemporal dementia and obtained better results than existing studies. Furthermore, we have validated our proposed CNN model using several ablation studies and layer-wise extracted feature visualization. This study will establish a pioneering direction for future researchers and technology experts in the field of neurodiseases.},
}

@article {pmid40464816,
year = {2025},
author = {Savran, Z and Baltaci, SB and Aladag, T and Mogulkoc, R and Baltaci, AK},
title = {Vitamin D and Neurodegenerative Diseases Such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Alzheimer's Disease (AD), and Amyotrophic Lateral Sclerosis (ALS): A Review of Current Literature.},
journal = {Current nutrition reports},
volume = {14},
number = {1},
pages = {77},
pmid = {40464816},
issn = {2161-3311},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Vitamin D/metabolism ; Multiple Sclerosis ; Alzheimer Disease ; Parkinson Disease ; Receptors, Calcitriol/metabolism ; Amyotrophic Lateral Sclerosis ; Oxidative Stress/drug effects ; Animals ; Cholecalciferol ; },
abstract = {PURPOSE OF REVIEW: This review explores the role of Vitamin D3 and its derivatives as inhibitors of pathological metabolic modifications in neurodegenerative diseases. The manuscript investigates how Vitamin D3 impacts neuronal calcium regulation, antioxidative pathways, immunomodulation, and neuroprotection during detoxification, beyond its known functions in intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization.

RECENT FINDINGS: Recent studies have highlighted the synthesis of the active metabolite 1,25(OH)2D3 (vitamin D) in glial cells via the hydroxylation process of CY-P24A1, an enzyme in the cytochrome P450 system in the brain. The effects of vitamin D occur through the vitamin D receptor (VDR), a nuclear steroid receptor, which has been identified in various brain regions, including the cerebellum, thalamus, hypothalamus, basal ganglia, hippocampus, olfactory system, temporal, and orbital regions. Neurodegeneration is primarily associated with oxidative stress, protein aggregation, neuroinflammation, mitochondrial dysfunction, apoptosis, and autophagy changes, all of which Vitamin D and VDR are believed to influence. Vitamin D and VDR are recognized as both environmental and genetic factors in the etiopathogenesis of neurodegenerative diseases such as Multiple Sclerosis (MS), Parkinson's Disease (PD), Alzheimer's Disease (AD), and Amyotrophic Lateral Sclerosis (ALS). A deficiency in Vitamin D is postulated to have detrimental effects on the brain and other diseases throughout various stages of life. This review consolidates findings from clinical and experimental studies, as well as past publications, focusing on the implications of Vitamin D deficiency in these neurodegenerative conditions. Current articles published in PubMed were extensively considered for this review.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy
*Vitamin D/metabolism
Multiple Sclerosis
Alzheimer Disease
Parkinson Disease
Receptors, Calcitriol/metabolism
Amyotrophic Lateral Sclerosis
Oxidative Stress/drug effects
Animals
Cholecalciferol

@article {pmid40464737,
year = {2025},
author = {Liu, W and Wu, L and Hu, J and Gao, Z},
title = {Correlations between ghrelin gene polymorphisms, cognitive function, and activities of daily living among elderly patients with Alzheimer's disease.},
journal = {Annals of human biology},
volume = {52},
number = {1},
pages = {2507048},
doi = {10.1080/03014460.2025.2507048},
pmid = {40464737},
issn = {1464-5033},
mesh = {Humans ; *Ghrelin/genetics/metabolism ; *Alzheimer Disease/genetics/psychology ; Aged ; Male ; *Polymorphism, Single Nucleotide ; Female ; *Cognition ; *Activities of Daily Living ; Aged, 80 and over ; Genotype ; },
abstract = {BACKGROUND: Single nucleotide polymorphisms (SNPs) of ghrelin gene are associated with cognitive function while ghrelin is associated with Alzheimer's disease (AD).

AIM: To determine the relationship between ghrelin SNPs, cognitive function, and activities of daily living (ADLs) in elderly AD patients.

SUBJECTS AND METHODS: This study included 100 elderly AD patients as the AD group, and 72 elderly healthy patients as the control group. Pearson's correlation analysis was performed.

RESULTS: The frequency of the A allele at rs55821288 was significantly higher in the AD group than the control group (p < 0.05). Similarly, the frequency of the AA genotype at rs55821288 was higher in the AD group than the control group (p < 0.05). The MMSE, QOL-AD, and ADLs scores were lower in the AD group than the control group (p < 0.05). Pearson's correlation analysis revealed that the A allele at rs55821288 was inversely correlated with the MMSE, QOL-AD, and ADLs scores (p < 0.05). The distribution of the AA genotype at the rs55821288 locus had a negative linear correlation with the MMSE, QOL-AD, and ADLs scores (p < 0.05).

CONCLUSIONS: Ghrelin allele A and genotype AA are closely associated with cognitive function and ADLs among elderly AD patients.},
}

Humans
*Ghrelin/genetics/metabolism
*Alzheimer Disease/genetics/psychology
Aged
Male
*Polymorphism, Single Nucleotide
Female
*Cognition
*Activities of Daily Living
Aged, 80 and over
Genotype

@article {pmid40464669,
year = {2025},
author = {Polishchuk, H and Synowiec, A and Zubrzycka, N and Kantyka, T},
title = {Porphyromonas gingivalis: Multiple Tools of an Inflammatory Damage.},
journal = {Molecular oral microbiology},
volume = {},
number = {},
pages = {},
doi = {10.1111/omi.12496},
pmid = {40464669},
issn = {2041-1014},
support = {2016/22/E/NZ5/00332//National Centre of Science SONATA Bis/ ; 2021/41/N/NZ6/03762//National Centre of Science Preludium/ ; },
abstract = {Periodontitis (periodontal disease [PD]) is a complex inflammatory disease caused by a polymicrobial infection that facilitates the destruction of the connective tissue and bone that support the teeth. PD is highly correlated with cardiovascular disease, low birth weight, preterm osteoporosis, Alzheimer's disease, and rheumatoid arthritis. Porphyromonas gingivalis, a main causative agent of PD, is a non-motile, asaccharolytic, Gram-negative bacterium identified in subgingival, supragingival, and tongue sites in patients. P. gingivalis produces an arsenal of virulence factors, which include fimbriae, lipopolysaccharide (LPS), gingipains and other proteases, P. gingivalis peptidyl arginine deiminase (PPAD), and others. Recently, a number of reports highlighted novel aspects of P. gingivalis virulence. LPS signaling via Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) was elucidated; outer membrane vesicles (OMVs) were implicated as the shuttle for inflammatory induction and neurotoxicity, and gingipains were found to disrupt the integrity of blood-brain barrier (BBB). Further, Tpr protease substrate specificity was described in detail, a novel variant of PPAD was identified and correlated with the aggressive disease, and the role of C-terminal domain as the substrate for the Type IX secretion system (T9SS) transport has been unveiled, together with the identification of the first T9SS inhibitors. The impact of the COVID-19 pandemic prompted the novel research, expanding our understanding of the P. gingivalis correlation with viral infections. These recent findings implicate the need to update the current knowledge of the P. gingivalis virulence factors and provide a comprehensive review of the current trends in P. gingivalis research.},
}

@article {pmid40464663,
year = {2025},
author = {Rashid, M and Thomas, S and Isaac, J and Karkare, SC and Klein, H and Murugan, M},
title = {A ventral hippocampal-lateral septum pathway regulates social novelty preference.},
journal = {eLife},
volume = {13},
number = {},
pages = {},
doi = {10.7554/eLife.97259},
pmid = {40464663},
issn = {2050-084X},
support = {R01MH130755/NH/NIH HHS/United States ; F31MH133373/NH/NIH HHS/United States ; },
mesh = {Animals ; *Hippocampus/physiology ; Mice ; *Social Behavior ; Male ; *Neural Pathways/physiology ; *Septal Nuclei/physiology ; Mice, Inbred C57BL ; Ventral Tegmental Area/physiology ; Optogenetics ; Behavior, Animal ; },
abstract = {The ability to distinguish strangers from familiar individuals is crucial for the survival of most mammalian species. In humans, an inability to recognize kin and familiar individuals and engage in appropriate behaviors is associated with several types of dementia, including Alzheimer's disease. Mice preferentially spend more time investigating a novel individual relative to a familiar individual. Yet, how social novelty-related information drives increased investigation of the novel animal remains poorly understood. Recent evidence has implicated the ventral hippocampus (vHPC) as a key node in encoding information about conspecific identity. Of particular interest are vHPC projections to the lateral septum (LS), a region that has been implicated in driving a wide range of motivated social behaviors. In this study using chemogenetics, optogenetics, and monosynaptic rabies tracing, we identified a novel vHPC-LS-ventral tegmental area (VTA) pathway that is necessary for mice to preferentially investigate novel conspecifics. Using monosynaptic rabies tracing, we established that LS neurons make direct monosynaptic connections onto dopaminergic neurons in the VTA. Thus, we have identified a potential pathway via which conspecific identity could be transformed to drive motivated social behaviors.},
}

Animals
*Hippocampus/physiology
Mice
*Social Behavior
Male
*Neural Pathways/physiology
*Septal Nuclei/physiology
Mice, Inbred C57BL
Ventral Tegmental Area/physiology
Optogenetics
Behavior, Animal

@article {pmid40464500,
year = {2025},
author = {Dedoni, S and Avdoshina, V and Olianas, MC and Onali, P},
title = {Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {5},
pages = {28245},
doi = {10.31083/FBL28245},
pmid = {40464500},
issn = {2768-6698},
mesh = {Humans ; *Lysophospholipids/metabolism ; *Nervous System Diseases/physiopathology/metabolism/drug therapy ; Animals ; Receptors, Lysophosphatidic Acid/metabolism ; Signal Transduction ; },
abstract = {Lysophosphatidic acid (LPA), a bioactive lipid molecule, has been identified as a critical regulator of several cellular processes in the central nervous system, with significant impacts on neuronal function, synaptic plasticity, and neuroinflammatory responses. While Alzheimer's disease, Multiple Sclerosis, and Parkinson's disease have garnered considerable attention due to their incidence and socioeconomic significance, many additional neurological illnesses remain unclear in terms of underlying pathophysiology and prospective treatment targets. This review synthesizes evidence linking LPA's function in neurological diseases such as traumatic brain injury, spinal cord injury, cerebellar ataxia, cerebral ischemia, seizures, Huntington's disease, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, autism, migraine, and human immunodeficiency virus (HIV)-associated complications Despite recent advances, the specific mechanisms underlying LPA's actions in various neurological disorders remain unknown, and further research is needed to understand the distinct roles of LPA across multiple disease conditions, as well as to investigate the therapeutic potential of targeting LPA receptors in these pathologies. The purpose of this review is to highlight the multiple functions of LPA in the aforementioned neurological diseases, which frequently share the same poor prognosis due to a scarcity of truly effective therapies, while also evaluating the role of LPA, its receptors, and signaling as promising actors for the development of alternative therapeutic strategies to those proposed today.},
}

Humans
*Lysophospholipids/metabolism
*Nervous System Diseases/physiopathology/metabolism/drug therapy
Animals
Receptors, Lysophosphatidic Acid/metabolism
Signal Transduction

@article {pmid40464462,
year = {2025},
author = {Yang, Z and Sheng, J and Zhang, Q and Zhao, X and Song, Y and Dong, G and Zhang, R and Zhao, H and Wang, J and Pan, R and Zhu, H},
title = {Multimodal Imaging Markers of Cognitive Resilience and Molecular Mechanisms of Brain Resilience in Alzheimer's Disease.},
journal = {Journal of integrative neuroscience},
volume = {24},
number = {5},
pages = {26584},
doi = {10.31083/JIN26584},
pmid = {40464462},
issn = {0219-6352},
support = {LZ24F010007//Key Project of the Natural Science Foundations of Zhejiang Province (CN)/ ; 62271177//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/genetics/pathology/physiopathology/metabolism ; *Brain/diagnostic imaging/pathology ; *Neuroimaging/methods ; *Multimodal Imaging/methods ; *Cognitive Reserve/physiology ; Biomarkers ; *Cognitive Dysfunction/diagnostic imaging ; },
abstract = {Owing to the intricacy of the dementia course and the selection of clinical trial populations, research on distinct populations, comorbid conditions, and disease heterogeneity is currently a topic of great interest. For instance, more than 30% of individuals enlisted for natural history and clinical trial studies may exhibit pathology extending beyond Alzheimer's disease (AD). Additionally, recent autopsy studies have evinced significant heterogeneity in the neuropathology of individuals who succumb to dementia, with approximately 10%-30% of those clinically diagnosed with AD revealing no neurological lesions at autopsy. Nevertheless, 30%-40% of cognitively intact elderly individuals exhibit neurological lesions at autopsy. This indicates that the brain can withstand accumulated aging and neurological lesions while retaining brain integrity (brain resilience) or cognitive function (cognitive resilience). Presently, there is a lack of consensus on how to precisely define and measure the resilience of the brain and cognitive decline. This article encapsulates the research on constructing multimodal neuroimaging biomarkers for cognitive resilience, summarizes existing methods, and proposes some improvements. Furthermore, research findings on the biological mechanisms and genetic traits of brain resilience were collated, and the mechanisms for the formation of resilience and the genetic loci governing it were elucidated. Potential future research directions are also discussed.},
}

Humans
*Alzheimer Disease/diagnostic imaging/genetics/pathology/physiopathology/metabolism
*Brain/diagnostic imaging/pathology
*Neuroimaging/methods
*Multimodal Imaging/methods
*Cognitive Reserve/physiology
Biomarkers
*Cognitive Dysfunction/diagnostic imaging

@article {pmid40464460,
year = {2025},
author = {Ruggeri, F and Fumi, D and Bassis, L and Pippo, MD and Abdolrahimzadeh, S},
title = {The Role of the Ganglion Cell Layer as an OCT Biomarker in Neurodegenerative Diseases.},
journal = {Journal of integrative neuroscience},
volume = {24},
number = {5},
pages = {26039},
doi = {10.31083/JIN26039},
pmid = {40464460},
issn = {0219-6352},
mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Retinal Ganglion Cells/pathology ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; Biomarkers ; *Alzheimer Disease/diagnostic imaging/pathology ; *Multiple Sclerosis/diagnostic imaging/pathology ; *Parkinson Disease/diagnostic imaging/pathology ; },
abstract = {Optical coherence tomography (OCT) is a non-invasive imaging technique in the field of ophthalmology that has been increasingly recognized for its capability to identify potential biomarkers in neurodegenerative processes. While the retinal nerve fiber layer (RNFL) has been vastly explored, this review focuses on the ganglion cell layer (GCL), highlighting its relevance and potential advantages in the diagnostic approach and monitoring of neurodegenerative conditions. In the present review we explore the role of GCL changes detected by OCT in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We focus on these conditions due to their prevalence and substantial social impact among neurodegenerative diseases. We summarize key findings on the changes in the GCL and their correlations with disease progression and severity. Moreover, we highlight GCL measurements in the context of a multidisciplinary diagnostic approach, and their potential in adapting tailored therapeutic strategies in neurodegenerative disease management. Challenges such as methodological variability in OCT measurements, automatic instrumental output parameters, the limitations of GCL as a standalone diagnostic tool, and the impact of systemic and ocular factors are discussed. Finally, we propose that forthcoming advancements in OCT technology, integration with other biomarkers, and longitudinal studies will likely further enhance the understanding of GCL changes over time.},
}

Humans
*Tomography, Optical Coherence/methods
*Retinal Ganglion Cells/pathology
*Neurodegenerative Diseases/diagnostic imaging/pathology
Biomarkers
*Alzheimer Disease/diagnostic imaging/pathology
*Multiple Sclerosis/diagnostic imaging/pathology
*Parkinson Disease/diagnostic imaging/pathology

@article {pmid40464422,
year = {2025},
author = {Eimil-Ortiz, M and Alcántara-Miranda, P and Martínez-Morante, S},
title = {[Alzheimer's and Its Diagnosis: Are We Prepared to Accompany Our Patients? Shared Care Planning as a Relational Framework].},
journal = {Revista de neurologia},
volume = {80},
number = {4},
pages = {42462},
doi = {10.31083/RN42462},
pmid = {40464422},
issn = {1576-6578},
}

@article {pmid40464420,
year = {2025},
author = {Martínez Campos, E and Tellechea Aramburo, P and Sánchez Ruiz de Gordoa, J and Larumbe Ilundain, R},
title = {[Cerebrospinal Fluid Biomarker Profile in Atypical Alzheimer's Disease].},
journal = {Revista de neurologia},
volume = {80},
number = {4},
pages = {36399},
doi = {10.31083/RN36399},
pmid = {40464420},
issn = {1576-6578},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Female ; Aged ; Male ; Biomarkers/cerebrospinal fluid ; *tau Proteins/cerebrospinal fluid ; Retrospective Studies ; *Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Aged, 80 and over ; *Peptide Fragments/cerebrospinal fluid ; Phenotype ; },
abstract = {INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are essential for the early identification of non-amnestic phenotypes. Increased levels of total tau (t-tau) and phosphorylated tau (p-tau) have been reported in atypical AD cases, although the specific pattern remains a subject of debate. This study aimed to evaluate CSF biomarker profiles in relation to clinical phenotype.

MATERIALS AND METHODS: A retrospective review was performed, analyzing demographic data, time to diagnosis, clinical phenotype, and core AD biomarkers (beta-amyloid peptide 1-42 (Aβ1-42), t-tau, p-tau) in CSF from patients evaluated at University Hospital in Navarra between 2019 and 2022.

RESULTS: The study included 57 patients (54% female, mean age 67 years), of whom 41 met AD diagnostic criteria. Among these, 10 patients (25%) presented with atypical phenotypes (50% aphasic, 30% frontal, 20% mixed non-amnestic). Compared with the amnestic phenotype, the atypical group exhibited significantly higher t-tau (562.9 pg/mL vs 320.3 pg/mL, p = 0.021) and p-tau (81.5 pg/mL vs 37.7 pg/mL, p = 0.016) levels, independent of age, sex, and time to diagnosis.

CONCLUSIONS: Atypical cases demonstrated increased tau levels, suggesting earlier and more extensive cortical damage than the amnestic phenotype. These findings underscore the significance of CSF biomarkers in phenotypic differentiation, disease course prediction, and individualized treatment strategies for AD.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Female
Aged
Male
Biomarkers/cerebrospinal fluid
*tau Proteins/cerebrospinal fluid
Retrospective Studies
*Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Aged, 80 and over
*Peptide Fragments/cerebrospinal fluid
Phenotype

@article {pmid40464332,
year = {2025},
author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Islam, A},
title = {The Role of Kinases in Neurodegenerative Diseases: From Pathogenesis to Treatment.},
journal = {The European journal of neuroscience},
volume = {61},
number = {11},
pages = {e70156},
doi = {10.1111/ejn.70156},
pmid = {40464332},
issn = {1460-9568},
mesh = {Humans ; *Neurodegenerative Diseases/enzymology/drug therapy/metabolism ; Animals ; *Protein Kinases/metabolism ; Protein Kinase Inhibitors/therapeutic use ; },
abstract = {Neurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid-β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α-synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood-brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/enzymology/drug therapy/metabolism
Animals
*Protein Kinases/metabolism
Protein Kinase Inhibitors/therapeutic use

@article {pmid40464180,
year = {2025},
author = {Khabibov, M and Garifullin, A and Sadreeva, A and Fernandez, MF and Kashaev, M and Topchu, I and Kharin, L and Boumber, Y},
title = {Functional and Clinical Relevance of the Crosstalk between the Glymphatic System and the Lymphatic System.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X359861250224051857},
pmid = {40464180},
issn = {1875-6190},
abstract = {In this review, we describe the concept of the glymphatic system as a glial-dependent clearance pathway in the brain. The hypothesis of the glymphatic system function suggests that dural lymphatic vessels absorb the cerebrospinal fluid and brain interstitial fluid via the glymphatic system and transport fluid into deep cervical lymph nodes. We present the accumulated data of various studies confirming the possible interconnection among the brain interstitial fluid, cerebrospinal fluid, and the glymphatic system. Anatomical features are discussed here together with a possible variety of glymphatic system functions, including the removal of waste products, transport of substances, and immune function. The glymphatic system is hypothesized to be involved in pathogenesis of many diseases, including Alzheimer's disease, stroke, and Parkinson's disease. We also discuss the role of the glymphatic system in pathophysiology and the complications of brain tumors. Meningeal lymphatics is thoroughly analyzed as well. Finally, we propose new treatment approaches to brain tumors, Parkinson's disease, and stroke using cervical lymph nodes and backward fluid flow in the meningeal lymphatic vessels.},
}

@article {pmid40464173,
year = {2025},
author = {Günaydın, T and Varlı, S},
title = {Computer-Aided Decision Support Systems of Alzheimer's Disease Diagnosis - A Systematic Review.},
journal = {Current medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734056359358250516101749},
pmid = {40464173},
issn = {1573-4056},
abstract = {BACKGROUND AND OBJECTIVE: The incidence of Alzheimer's disease is rising with the increasing elderly population worldwide. While no cure exists, early diagnosis can significantly slow disease progression. Computer-aided diagnostic systems are becoming critical tools for assisting in the early detection of Alzheimer's disease. In this systematic review, we aim to evaluate recent advancements in computer-aided decision support systems for Alzheimer's disease diagnosis, focusing on data modalities, machine learning methods, and performance metrics.

METHODS: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies published between 2021 and 2024 were retrieved from PubMed, IEEEXplore and Web of Science, using search terms related to Alzheimer's disease classification, neuroimaging, machine learning, and diagnostic performance. A total of 39 studies met the inclusion criteria, focusing on the use of Magnetic Resonance Imaging, Positron Emission Tomography, and biomarkers for Alzheimer's disease classification using machine learning models.

RESULTS: Multimodal approaches, combining Magnetic Resonance Imaging with Positron Emission Tomography and Cognitive assessments, outperformed single-modality studies in diagnostic accuracy reliability. Convolutional Neural Networks were the most commonly used machine learning models, followed by hybrid models and Random Forest. The highest accuracy reported for binary classification was 100%, while multi-class classification achieved up to 99.98%. Techniques like Synthetic Minority Over-sampling Technique and data augmentation were frequently employed to address data imbalance, improving model generalizability.

DISCUSSION: Our review highlights the advantages of using multimodal data in computer-aided decision support systems for more accurate Alzheimer's disease diagnosis. However, we also identified several limitations, including data imbalance, small sample sizes, and the lack of external validation in most studies. Future research should utilize larger, more diverse datasets, incorporate longitudinal data, and validate models in real-world clinical trials. Additionally, there is a growing need for explainability in machine learning models to ensure they are interpretable and trusted in clinical settings.

CONCLUSION: While computer-aided decision support systems show great promise in improving the early diagnosis of Alzheimer's disease, further work is needed to enhance their robustness, generalizability, and clinical applicability. By addressing these challenges, computer-aided decision support systems could play a pivotal role in the early detection and management of Alzheimer's disease, potentially improving patient outcomes and reducing healthcare costs.},
}

@article {pmid40463938,
year = {2025},
author = {Sheng, L and Zheng, X and Ding, Z and Liu, J and Song, W},
title = {Neurovascular coupling dysfunction in encephalopathy: pathophysiological advances and clinical implications.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1522485},
pmid = {40463938},
issn = {1664-2295},
abstract = {Neurovascular coupling (NVC) is a sophisticated and vital physiological mechanism that ensures the brain's intricate balance and optimal performance. It refers to the precise coordination between the brain's neural activity and the local cerebral blood flow (CBF), which is essential for meeting the metabolic demands of active neurons. This coupling allows for the efficient delivery of oxygen and nutrients to brain regions experiencing increased activity and facilitates the removal of metabolic waste products. In encephalopathy, a collective term for a wide range of conditions that impair brain function, NVC dysfunction has been identified as a key factor contributing to the progression of these disorders and the emergence of clinical symptoms. This comprehensive review aims to explore the complex pathophysiological mechanisms that lead to NVC dysfunction in several encephalopathic conditions. These include but are not limited to Alzheimer's disease (AD), Parkinson's disease (PD), cerebral small vessel disease (CSVD), stroke, migraine, traumatic brain injury (TBI) and epilepsy. Across the spectrum of encephalopathies discussed in this review, a unifying molecular target emerges: endothelin-1 (ET-1) and its receptors. ET-1, a potent vasoconstrictor produced by endothelial cells and astrocytes, is intricately linked to NVC dysfunction in these conditions. A thorough understanding of the role of NVC in encephalopathic disorders can inform the development of diagnostic tools and therapeutic strategies. For instance, identifying early markers of NVC dysfunction could facilitate early intervention and potentially slow disease progression. Moreover, targeting the restoration of NVC could become a novel therapeutic approach to mitigate symptoms and improve patient outcomes. This review also proposes new directions for future research, encouraging the exploration of NVC's complex interactions and its potential as a therapeutic target in the management of encephalopathic conditions.},
}

@article {pmid40463936,
year = {2025},
author = {Cortese, MD and Cernuzio, G and Tonin, P and Priftis, K and Piccione, F},
title = {The assessment of walking skills: Italian version.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1579638},
pmid = {40463936},
issn = {1664-2295},
abstract = {Apraxia is a neuropsychological disorder that impairs voluntary, purposeful movements, with "Gait apraxia" specifically affecting walking. Because of the lack of standardized diagnostic tools, in Italian, we translated and adapted the "Assessment of Walking Skills" (AWS) scale, originally developed for identifying gait apraxia in Alzheimer's patients. The AWS includes 42 items that evaluate trunk and leg movements, useful for comparing the performance between patients and healthy controls. This translation and adaptation represent a critical step toward standardizing the AWS scale for the Italian population.},
}

@article {pmid40463912,
year = {2025},
author = {Liu, T and Sun, W and Guo, S and Yuan, Z and Zhu, M and Lu, J and Chen, T and Qu, Y and Feng, C and Yang, T},
title = {Role of mitochondrial quality control in neurodegenerative disease progression.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1588645},
pmid = {40463912},
issn = {1662-5102},
abstract = {Neurodegenerative diseases are a diverse group of neurological disorders, in which abnormal mitochondrial function is closely associated with their development and progression. This has generated significant research interest in the field. The proper functioning of mitochondria relies on the dynamic regulation of the mitochondrial quality control system. Key processes such as mitochondrial biogenesis, mitophagy, and mitochondrial dynamics (division/fusion) are essential for maintaining this balance. These processes collectively govern mitochondrial function and homeostasis. Therefore, the mitochondrial quality control system plays a critical role in the onset and progression of neurodegenerative diseases. This article provides a concise overview of the molecular mechanisms involved in mitochondrial biogenesis, mitophagy, and mitochondrial dynamics, explores their interactions, and summarizes current research progress in understanding the mitochondrial quality control system in the context of neurodegenerative diseases.},
}

@article {pmid40463724,
year = {2025},
author = {Gills, JL and Jones, MD and Campitelli, A and Paulson, S and Diehl, C and Rodgers, C and Madero, E and Myers, JR and Bryk, K and Bubu, OM and Glenn, JM and Gray, M},
title = {The examination of physical function and cognitive outcomes in middle-to-older high-risk adults: an unsupervised clustering method.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1351658},
pmid = {40463724},
issn = {2296-2565},
mesh = {Humans ; Female ; Male ; Middle Aged ; Aged ; *Cognition/physiology ; Cluster Analysis ; },
abstract = {Alzheimer's disease rates are expected to triple by 2050. Early detection and specific mitigation efforts are warranted to blunt the alarming increase. Physical function index (PFI) declines with age; additionally, higher PFI is associated with better cognitive functioning in middle-to-older age individuals. However, most studies utilize one domain of PFI to examine associations with cognition. Therefore, using clustering methods, the purpose of this investigation was to determine if high-risk individuals with higher PFI have better cognitive outcomes compared to individuals with lower PFI. Participants (n = 215; 73.1% female; 45-75 years) completed a body mass scan, venous blood draw, 7 PFI tasks, and 7 cognitive tests. A k-means cluster analysis was utilized to identify PFI cluster for participants, one-way ANCOVAs were used to assess differences in cognition among clusters. Cluster 1 (C1; n = 29) was characterized as the highest strength/power, faster dual-task walking time, and higher aerobic capacity, Cluster 3 (C3; n = 113) had the lowest values between PFI groups, Cluster 2 (C3; n = 74) was in-between C1 and C3. Individuals in C1 had significantly higher global cognitive, visuospatial scores, digital executive functioning and associative learning compared to individuals in C3 (p < 0.05). Individuals in C1 and C2 had significantly higher values on orientation task and figure recall than individuals in C3 (p < 0.05). The results from this current study demonstrate that individuals with higher combined PFI output have higher global cognitive scores than individuals with lower combined PFI output. Examining PFI variables together may be a valuable tool when assessing cognition among cognitively at-risk individuals.},
}

Humans
Female
Male
Middle Aged
Aged
*Cognition/physiology
Cluster Analysis

@article {pmid40463637,
year = {2025},
author = {Cummings, JL and Zhou, Y and Lee, G and Zhong, K and Fonseca, J and Leisgang-Osse, AM and Cheng, F},
title = {Alzheimer's disease drug development pipeline: 2025.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70098},
pmid = {40463637},
issn = {2352-8737},
abstract = {UNLABELLED: Clinical trials for Alzheimer's disease (AD) must be registered on clinicaltrials.gov. The registry presents a variety of types of information related to the planned clinical trial. We assess clinicaltrials.gov to document and compare aspects of drug development across the AD pipeline. Currently, there are 138 drugs being assessed in 182 clinical trials in the AD pipeline. Biological disease-targeted therapies (DTTs) comprise 30% of the pipeline; small molecule DTTs account for 43% of the pipeline; drugs addressing cognitive enhancement account for 14% of the pipeline; and drugs aiming to ameliorate neuropsychiatric symptoms in participants with AD contribute 11% of the pipeline. Biomarkers are among the primary outcomes of 27% of active trials. Repurposed agents represent 33% of the pipeline agents. The pipeline has more trials and more drugs compared to the 2024 pipeline.

HIGHLIGHTS: The 2025 Alzheimer's disease drug development pipeline hosts 182 trials and 138 novel drugs.The 2025 Alzheimer's disease drug development pipeline is diverse, with agents that address 15 basic disease processes.The 2025 Alzheimer's disease drug development pipeline has more trials and more drugs than the 2024 pipeline.Biomarkers play an important role in current trials to determine trial eligibility and as outcomes of trials.Repurposed agents comprise approximately one-third of the agents and trials in the 2025 Alzheimer's disease drug development pipeline.},
}

@article {pmid40463636,
year = {2025},
author = {Iulita, MF and Streel, E and Harrison, J},
title = {Digital biomarkers: Redefining clinical outcomes and the concept of meaningful change.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70114},
pmid = {40463636},
issn = {2352-8737},
abstract = {UNLABELLED: MCID (minimal clinically important difference) is a patient-centered concept used in clinical research that represents the smallest change that someone living with Alzheimer's disease would identify as important. There are several challenges associated with the universal application of this construct. Alzheimer's disease progresses differently for each individual, complicating the establishment of a universal standard that accounts for individual-level issues. Alzheimer's disease is also a gradual and evolving disorder, and what is perceived as clinically meaningful can vary significantly at early and late disease stages. People living with Alzheimer's disease and caregivers may have differing perspectives on the benefits of treatment outcomes, making it more challenging to establish an appropriate MCID. Moreover, Alzheimer's trials rely on a variety of tests to evaluate cognitive and functional impairments. However, these tests often lack sensitivity to early-stage changes and are affected by variability in rater rankings. Digital biomarkers and advanced health technologies have emerged as a hot topic in modern medicine. They offer a promising approach for detecting real-time, objective clinical differences and improving patient outcomes by enabling continuous monitoring, individualized assessments, and leveraging artificial intelligence learning for complex analytical predictions. However, while these advancements hold great potential, they also raise important considerations around standardization, accuracy, and integration into current clinical frameworks. As new technologies are introduced alongside evolving regulatory frameworks, the primary focus must remain on outcomes that truly matter to people living with Alzheimer's disease and their caregivers, ensuring that the principle of clinical meaningfulness is not lost.

HIGHLIGHTS: Minimal clinically important difference (MCID) represents the smallest change in a patient's condition that would be considered meaningful, but defining this for Alzheimer's disease is challenging due to its heterogeneity.The perception of what is clinically meaningful may differ at the individual level, at different disease stages within the same individual, and between patient and caregiver.Traditional tests used as endpoints in Alzheimer's trials lack the sensitivity to detect subtle changes and are limited by range restrictions, making them less effective for accurately capturing treatment efficacy.Digital biomarkers and artificial intelligence (AI)-driven health technologies may offer the potential to enhance the detection of clinically meaningful changes by providing continuous, objective monitoring and advanced analytics for individualized patient assessments.Both the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) are playing pivotal roles in advancing the use of digital health technologies, facilitating the evolution of regulatory frameworks to ensure these innovations are effectively integrated into clinical research and practice.},
}

@article {pmid40463548,
year = {2025},
author = {Boyle, R and Dehghani, N and Emrani, S and Wadhwani, AR and Matyi, M and Cousins, KAQ and Rhodes, E and Nelson, B and Stites, SD and Xie, SX and Dratch, L and Van Deerlin, VM and Snyder, A and Irwin, D and McMillan, CT and Massimo, L},
title = {Neighborhood deprivation moderates prognosis in behavioral-variant frontotemporal degeneration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.12.25327099},
pmid = {40463548},
abstract = {INTRODUCTION: Neighborhood deprivation has been associated with shorter survival, cognitive impairment and neurodegeneration in aging and Alzheimer's disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown.

METHODS: We examined associations between tertiles of neighborhood deprivation, using the Area Deprivation Index (ADI), and survival in 311 individuals clinically diagnosed with bvFTD from the Penn Frontotemporal Degeneration (FTD) Center. In a subset of participants with complete baseline data across measures of global cognition, executive function, and language (n=163), we examined the association of ADI with longitudinal change.

RESULTS: Higher neighborhood deprivation was associated with shorter survival after symptom onset and faster decline in global cognition, executive and language functions, independent of genetic risk.

DISCUSSION: Living in more deprived neighborhoods (i.e. above the 50 [th] percentile nationally) was associated with an accelerated disease course in bvFTD, highlighting an important socioeconomic disparity in disease prognosis.

N/A.},
}

@article {pmid40463541,
year = {2025},
author = {Vrillon, A and Spina, S and Mejia-Perez, J and Lamore, T and Yballa, C and Soleimani-Meigooni, DN and Blazhenets, G and Boxer, AL and Rojas, JC and Lago, AL and Jagust, WJ and Miller, BL and Rosen, HJ and Seeley, WW and Grinberg, LT and Rabinovici, GD and Vandevrede, L and La Joie, R},
title = {Association of [ [18] F]Flortaucipir-PET and plasma p-tau217 with tau neuropathology in AD and other neurodegenerative disorders.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.14.25326954},
pmid = {40463541},
abstract = {BACKGROUND AND OBJECTIVES: Evaluating tau biomarkers in patients with available autopsy data is critical for validating their sensitivity and specificity to detect Alzheimer's disease neuropathologic changes (ADNC). We examined the association between tau-PET (using [ [18] F]Flortaucipir), plasma ptau-217, and measures of AD neuropathology in a group of clinically-impaired participants from a tertiary dementia center, including patients with AD and FTLD.

METHODS: We analyzed Flortaucipir-PET (80-100 minutes post-injection acquisition, normalized to inferior cerebellar cortex) from 73 patients with a clinical diagnosis of various neurodegenerative diseases who underwent autopsy at the Neurodegenerative Disease Brain Bank (median [IQR] age: 67 [59, 73] years, 60% male, median [IQR] PET-to-autopsy duration: 3.9 years, [2.1, 5.1]). Standardized uptake value ratios (SUVRs) were extracted from the entorhinal cortex (an early tau region) and the temporal meta-ROI (a widely used AD signature region). A semi-quantitative rating of AD NFT burden in cortical areas was available for 56 participants. Plasma p-tau217 was quantified with Simoa (Janssen®) in 56 participants (median [IQR] PET-to-plasma duration: 1.7 months [0.5, 4.1]).

RESULTS: Our cohort included patients with a primary pathological diagnosis of AD (n=39), FTLD (tauopathies n=28, non-tauopathies n=4), and Lewy body dementia (n=2). Flortaucipir SUVRs were elevated in patients with a neuropathological diagnosis of AD compared with non-AD patients. Consistently elevated PET signal was detected in both the entorhinal cortex and temporal meta-ROI of patients with neurofibrillary tangle (NFT) at Braak stage VI and with high ADNC levels. No elevation of Flortaucipir SUVRs was observed at intermediate levels of ADNC. The burden of AD NFTs was correlated with local Flortaucipir SUVRs across cortical brain regions. Plasma p-tau217 concentrations were increased in patients at Braak stage V and VI and strongly correlated with Flortaucipir SUVRs across ROIs (r's≥0.75), driven by Braak V-VI cases. Flortaucipir SUVRs and plasma p-tau217 concentrations identified high Braak stages (V-VI) and high/intermediate ADNC levels with similarly high performance (area under the curve≥ 0.90).

DISCUSSION: Flortaucipir-PET and plasma p-tau217 both displayed strong specificity for primary AD neuropathological diagnosis but lacked sensitivity to detect early AD-related tau co-pathology in patients with a non-AD diagnosis.},
}

@article {pmid40463532,
year = {2025},
author = {Wang, P and Song, YE and Lynn, A and Miskimen, K and Gulyayev, A and Prough, MB and Dorfsman, DA and Laux, RA and Fuzzell, SL and Hochstetler, SD and Zaman, AF and Adams, LD and Caywood, LJ and Clouse, JE and Herington, SD and Whitehead, P and Liu, Y and Moore, N and Ogrocki, P and Lerner, AJ and Griswold, AJ and Vance, JM and Cuccaro, ML and Scott, WK and Pericak-Vance, MA and Haines, JL},
title = {Heritability of Alzheimer-related plasma biomarkers in the Amish population.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.13.25327557},
pmid = {40463532},
abstract = {INTRODUCTION: Plasma biomarkers for Alzheimer disease (AD) hold promise for disease diagnosis and prediction, yet their genetic underpinnings remain underexplored.

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

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

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

@article {pmid40463529,
year = {2025},
author = {Gauron, MC and Prokopenko, D and Lee, S and Wolfe, SA and Hecker, J and Willett, J and Waqas, M and Lordén, G and Yang, Y and Mayfield, JE and Castanho, I and Mullin, K and Morgan, S and Hahn, G and Demeo, DL and Hide, W and Bertram, L and Lange, C and Newton, AC and Tanzi, RE},
title = {Protein kinase C eta enhances Golgi-localized signaling and is associated with Alzheimer's disease using a recessive mode of inheritance.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.13.25327562},
pmid = {40463529},
abstract = {UNLABELLED: The identification of Alzheimer's disease (AD)-associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWAS) for AD have successfully identified new targets but have almost exclusively utilized additive genetic models. Here, we performed a family-based GWAS under a recessive inheritance model using whole genome sequencing from families affected by AD. We found that the variant, rs7161410, located in an intron of the PRKCH gene, encoding protein kinase C eta (PKCη), was associated with AD risk (p-value=1.41 × 10-7). Further analysis revealed a rare PRKCH missense mutation K65R in linkage disequilibrium with rs7161410, which was present in homozygous carriers of the rs7161410 risk allele. We show that this mutation leads to enhanced localization and signaling of PKCη at the Golgi. The novel genetically-validated association of aberrant PKCη signaling with AD opens avenues for new therapeutic targets aimed at prevention and treatment.

ONE SENTENCE SUMMARY: Protein kinase C eta enhances Golgi-localized signaling and is associated with Alzheimer's disease.},
}

@article {pmid40463394,
year = {2025},
author = {Barui, AK and Amirrad, F and Goel, V and Ohadi, S and Pala, R and Mohieldin, AM and Nauli, AM and Nauli, SM},
title = {Application of bioactive materials primary cilia as a novel delivery vehicle.},
journal = {Bioactive materials},
volume = {51},
number = {},
pages = {70-82},
pmid = {40463394},
issn = {2452-199X},
abstract = {Primary cilia are hair-like structured cell organelles functioning as cellular antennae with chemosensory and mechanosensory roles. Dysfunction of cilia results in ciliopathies, including renovascular diseases (polycystic kidneys, hypertension, aneurysm), mental impedances (Alzheimer's disease, Parkinson's disease, dementia), metabolic diseases (obesity, developmental skeleton defects), blindness, and so on. With a diameter of 150 nm, cilia can be cleaved, released and circulated in the body as injury biomarkers. We here assessed the potential use of isolated cilia as a novel delivery vehicle. Cilia were isolated from renal epithelial cells, and a specific-targeting chemotherapeutic was designed on the cilia. The data show a remarkable property of cilia to significantly inhibit disease progression with reduced toxicity. These findings emphasize the prospective biomedical applications of primary cilia in generating novel drug, gene, protein, and other delivery systems to treat diverse pathological conditions. While there are many synthetic drug delivery vehicles, our studies demonstrate for the first time that physiologically produced primary cilia can be adapted as a unique carrier system.},
}