@article {pmid40796698,
year = {2025},
author = {Cheng, X and Wang, Z and He, K and Xia, Y and Wang, Y and Guo, Q and Xie, F and Yuan, P},
title = {Plasma neurofilament light reflects more severe manifestation of Alzheimer's disease in men.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {40796698},
issn = {1476-5578},
support = {32371036//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Plasma neurofilament light (NfL) protein is a promising non-invasive biomarker for detecting neuronal damage in Alzheimer's disease (AD). However, its clinical utility is limited by the lack of standardized threshold values. Sex is an important factor that should be considered when setting these thresholds, but only a few studies have examined sex differences in plasma NfL levels in AD, with inconsistent findings. Even fewer have explored whether sex influences the relationship between plasma NfL levels and disease severity. To investigate this, we first analyzed data from 860 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Linear regression models were used to assess sex differences in the correlation between plasma NfL levels, cognitive deficits, and neuroimaging metrics. A Cox model with bootstrap resampling was used to evaluate sex differences in dementia risk, calculating the hazard ratio for men versus women for a given increase in plasma NfL. Our results showed that, compared to women, men with higher plasma NfL levels exhibited more severe cognitive defects and brain hypometabolism, along with smaller hippocampal volume. These findings were validated using data from 619 participants in the Chinese Preclinical Alzheimer's Disease Study (C-PAS) cohort and 86 participants from a publicly available dataset. In addition, we found that increase in plasma NfL levels were predictive of faster cognitive decline and a higher likelihood of AD progression in men compared to women. In conclusion, sex differences influence the relationship between plasma NfL levels and AD symptoms. Men exhibit greater cognitive and neuropathological defects with rising plasma NfL levels, underscoring the need for considering sex when using NfL as a biomarker for neuronal damage in AD.},
}

@article {pmid40796687,
year = {2025},
author = {Kashiyama, R and Watanabe, H and Akasaka, T and Fujimoto, H and Murakami, M and Ooe, K and Toyoshima, A and Nakashima, K and Ono, M},
title = {Feasibility of targeted alpha therapy for Alzheimer's disease using [211]At-labeled agent targeting amyloid-β aggregates.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {40796687},
issn = {1864-6433},
support = {JP24wm0625512h//Japan Agency for Medical Research and Development/ ; JP25wm0625512h//Japan Agency for Medical Research and Development/ ; },
abstract = {OBJECTIVE: Amyloid-β (Aβ) aggregates have been recognized as therapeutic targets for Alzheimer's disease (AD). Targeted alpha therapy (TAT) using α-particles has the potential to be applied as a novel treatment approach for AD by reducing the quantity of Aβ aggregates. In this study, we developed a novel astatine-211-labeled pyridyl benzofuran (PBF) derivative, [[211]At]APBF-2, as a small molecule-based Aβ-TAT agent and evaluated its potential for in vivo use.

METHODS: [[211]At]APBF-2 was synthesized in a one-step astatination process using the tributyltin precursor. In the Aβ aggregation inhibition assay, [[211]At]APBF-2 was added to a sample containing Aβ1-42 monomers and thioflavin-T (ThT) and the mixture was incubated for 24 h. The quantity of Aβ aggregates was evaluated by measuring ThT fluorescence intensity. The biodistribution of [[211]At]APBF-2 (25 kBq/100 μL) was evaluated using ddY mice (n = 5).

RESULTS: [[211]At]APBF-2 was synthesized in radiochemical yield of 57% with a radiochemical purity of over 95%. In the in vitro assay, [[211]At]APBF-2 showed a dose-dependent decrease in ThT fluorescence intensity, suggesting the ability of [[211]At]APBF-2 to inhibit Aβ aggregation. In the biodistribution study using normal mice, the initial brain uptake of [[211]At]APBF-2 was observed (2.95% injected dose/g at 2 min), demonstrating favorable Blood-brain barrier permeability.

CONCLUSIONS: These results suggest the feasibility of using [[211]At]APBF-2 as an Aβ-TAT agent for in vivo applications.},
}

@article {pmid40796563,
year = {2025},
author = {Nakatsuka, N and Adler, D and Jiang, L and Hartman, A and Cheng, E and Klann, E and Satija, R},
title = {Improving reproducibility of differentially expressed genes in single-cell transcriptomic studies of neurodegenerative diseases through meta-analysis.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {7436},
pmid = {40796563},
issn = {2041-1723},
abstract = {False positive claims of differentially expressed genes (DEGs) in scRNA-seq studies are of substantial concern. We found that DEGs from individual Parkinson's (PD), Huntington's (HD), and COVID-19 datasets had moderate predictive power for case-control status of other datasets, but DEGs from Alzheimer's (AD) and Schizophrenia (SCZ) datasets had poor predictive power. We developed a non-parametric meta-analysis method, SumRank, based on reproducibility of relative differential expression ranks across datasets, and found DEGs with improved predictive power. Specificity and sensitivity of these genes were substantially higher than those discovered by dataset merging and inverse variance weighted p-value aggregation methods. Up-regulated DEGs implicated chaperone-mediated protein processing in PD glia and lipid transport in AD and PD microglia, while down-regulated DEGs were in glutamatergic processes in AD astrocytes and excitatory neurons and synaptic functioning in HD FOXP2 neurons. Lastly, we evaluate factors influencing reproducibility of individual studies as a prospective guide for experimental design.},
}

@article {pmid40796457,
year = {2025},
author = {Osset-Malla, M and Martínez-Velasco, A and Sánchez-Benavides, G and Buongiorno, M and de la Sierra, A and Shekari, M and Minguillon, C and Kollmorgen, G and Quijano-Rubio, C and Zetterberg, H and Blennow, K and García, DV and Suárez-Calvet, M and Gispert, JD and Grau-Rivera, O and , },
title = {Blood pressure and Alzheimer's disease biomarkers in cognitively unimpaired adults: a multicenter study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100304},
doi = {10.1016/j.tjpad.2025.100304},
pmid = {40796457},
issn = {2426-0266},
abstract = {BACKGROUND: Hypertension is a modifiable risk factor for dementia, potentially influencing Alzheimer's disease (AD) pathology. Understanding this relationship is essential for developing interventions to reduce dementia risk.

OBJECTIVES: We investigated cross-sectional and longitudinal associations between blood pressure and AD biomarkers in cerebrospinal fluid (CSF) and amyloid (Aβ) positron emission tomography (PET) in cognitively unimpaired adults.

DESIGN: Prospective observational study.

SETTING: We analyzed data from cognitively unimpaired participants from three observational prospective European studies: ALFA+ (NCT02485730), EPAD-LCS (NCT02804789), and AMYPAD PNHS (EudraCT: 2018-002,277-22).

MEASUREMENTS: ALFA+ participants had either CSF biomarkers (CSF Aβ42, Aβ40, p-tau181, t-tau) and/or Aβ PET data. EPAD participants had CSF biomarkers (CSF Aβ42, p-tau181, t-tau), and AMYPAD participants had Aβ PET data. All participants had available data about diabetes, use of hypertensive medication, and waist-to-hip ratio. Multivariable linear regression models were used to analyze cross-sectional associations between systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with CSF biomarkers or Aβ PET (Centiloid units, CL); longitudinal associations were tested by means of delta CL scores between baseline and follow-up to assess Aβ PET changes over time.

RESULTS: We included 405 participants from ALFA+ (mean age 61.1 years; 60 % female), 1104 from EPAD (mean age 64.8 years; 59.1 % female), and 340 from AMYPAD (mean age 71.8 years; 60 % female). In ALFA+, DBP was negatively associated with CSF Aβ40 (p = 0.016) and p-tau181 (p = 0.050), while there was a non-significant trend towards a positive association between SBP and CL over time (p = 0.058). In EPAD, DBP was negatively associated with CSF Aβ42 (p < 0.001) and p-tau181 (p = 0.014), while PP was positively associated with CSF Aβ42 (p = 0.024). In AMYPAD, SBP (p = 0.002) and PP (p = 0.003) were positively associated with CL at baseline, with a similar non-significant trend being found for DBP (p = 0.089). Higher DBP (p = 0.042) was significantly associated to increased CL over time, with a similar non-significant trend being found for SBP (p = 0.072). We did not find significant associations between blood pressure and longitudinal changes in CSF biomarkers.

CONCLUSIONS: Elevated blood pressure was associated with increased Aβ PET accumulation in cognitively unimpaired individuals. Further research is warranted to elucidate potential mechanisms underlying the negative associations between DBP and CSF biomarkers, which do not reflect the typical AD molecular signature. These findings highlight the relevance of high blood pressure as a potential risk factor for cognitive decline.},
}

@article {pmid40796415,
year = {2025},
author = {Mehadji, B and Abdelhafez, YG and Alavi, A and Chung, KJ and Karakatsanis, NA and Omidvari, N and Nardo, L},
title = {Long Axial Field of View PET: A New Era of Quantitative PET Imaging for Prospective Applications Beyond Classical Theranostics.},
journal = {PET clinics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cpet.2025.07.009},
pmid = {40796415},
issn = {1879-9809},
abstract = {The scope of molecular imaging can be expanded beyond pure theranostic pairs, defined as radiolabeled agents sharing the same molecular target or the same label, towards any image-guided therapy scheme regardless of the chemical relationship between the imaging and therapeutic agents.},
}

@article {pmid40796226,
year = {2025},
author = {Skawratananond, S and McCrea, G and Lie, P and Buxton, MB and Daly, SP and Vojtkofsky, NA and Smith, SC and Zhang, C and Hernandez, M and Hindle, A and Logsdon, AF and Lawrence, JJ},
title = {The Synergistic Interplay between Vitamin A, Dietary Fiber, and the Microbiota-Gut-Brain Axis: A Potential Mechanism for Preventing Alzheimer's Disease.},
journal = {American journal of physiology. Gastrointestinal and liver physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpgi.00097.2025},
pmid = {40796226},
issn = {1522-1547},
support = {AG071859//HHS | NIH | National Institute on Aging (NIA)/ ; MSSRP//Texas Tech University Health Sciences Center (TTUHSC)/ ; MSSRP//Texas Tech University Health Sciences Center (TTUHSC)/ ; AG073826//HHS | NIH | National Institute on Aging (NIA)/ ; },
abstract = {The human gastrointestinal tract harbors a vast and diverse microbial community, with the gut microbiome playing a fundamental role in numerous biological processes that influence overall health and disease progression. Emerging evidence has identified bacterial lipopolysaccharides in the hippocampus of Alzheimer's disease (AD) patients, highlighting the intricate relationship between the gastrointestinal tract, gut microbiome, and the central and enteric nervous systems-commonly referred to as the "microbiota-gut-brain axis." In this review, we explore the mechanisms by which the microbiota-gut-brain axis contributes to AD pathogenesis. We propose that sufficient levels of all-trans retinoic acid (ATRA), the bioactive form of vitamin A, enhance intestinal barrier integrity by upregulating tight junction proteins and modulating immune function through the induction of regulatory T-cell differentiation, thereby mitigating inflammation. Furthermore, dietary fiber complements this process by promoting the production of short-chain fatty acids, such as butyrate, via bacterial fermentation. Butyrate, in turn, acts as a histone deacetylase inhibitor, upregulating ATRA bioavailability by elevating aldehyde dehydrogenase gene expression. Our mechanistic framework is supported by the endotoxin hypothesis of AD, which purports that the movement of infectious pathogens across the blood-brain barrier causes a vicious cycle of neuroinflammation, a key factor of AD pathogenesis, leading to amyloid-beta deposition, microglial activation, and CYP26A1-mediated ATRA degradation. Finally, we discuss microbiome-based therapeutic strategies and dietary interventions, including prebiotic compounds, probiotic bacteria, fecal microbiota transplantation, the MIND diet, and a combined approach consisting of vitamins A/D, and dietary fiber, as potential approaches to mitigate AD progression via the microbiota-gut-brain axis.},
}

@article {pmid40796169,
year = {2025},
author = {Yuen, JK and Bernacki, R and Chan, FHW and Chan, TC and Chow, DTY and Shea, YF and Ng, BLH and Chan, KMK and Li, X and Shi, QM and Luk, JKH},
title = {Comparison of Survival and Pneumonia Risk in Advanced Dementia Patients on Nasogastric Tube Feeding versus Careful Hand Feeding.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaf165},
pmid = {40796169},
issn = {1758-535X},
abstract = {BACKGROUND: Nasogastric tube feeding is commonly used for enteral nutrition in individuals with advanced dementia with feeding difficulties, but its impact on survival and pneumonia risk compared to careful hand feeding remains controversial. This study aimed to compare one-year survival and pneumonia risk in individuals with advanced dementia initiated on nasogastric tube feeding versus those receiving careful hand feeding.

METHODS: A prospective propensity score-matched cohort study was conducted. Participants included individuals aged ≥60 years with advanced dementia and feeding problems admitted to two geriatric hospitals between September 2020 and September 2022. Propensity-score matched cohorts were analyzed using Kaplan-Meier survival analysis and Cox proportional hazards regression models.

RESULTS: Among 283 participants (mean age 89.8 years, 62.2% female, 73.5% residential care home residents), 184 (65.0%) were received careful hand feeding and 99 (35.0%) nasogastric tube feeding. A matched subsample of 176 participants (116 careful hand feeding, 60 nasogastric tube feeding) was analyzed. One-year adjusted survival did not differ significantly between the nasogastric tube feeding and careful hand feeding groups (AHR= 0.85, 95% CI, 0.59-1.23, P =.38). However, the nasogastric tube feeding group had a significantly higher one-year adjusted pneumonia risk compared to the careful hand feeding group (AHR 1.60, 95% CI, 1.06-2.42, P =.03).

CONCLUSIONS: Individuals with advanced dementia initiated on nasogastric tube feeding do not have meaningfully improved survival and have a higher risk of pneumonia compared to those receiving careful hand feeding. These findings can guide clinicians and families when considering feeding tube placement for individuals with advanced dementia.},
}

@article {pmid40795904,
year = {2025},
author = {de Oliveira, TB and Galeriani, ACB and Rodrigues de Souza, JR and Kawano, DF and Trevisan, MTS and Almeida, WP},
title = {Mangiferin and norathyriol acting on Alzheimer's disease biomarkers: acetylcholinesterase, β-secretase (BACE-1), and amyloid β-peptide.},
journal = {The Journal of pharmacy and pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jpp/rgaf055},
pmid = {40795904},
issn = {2042-7158},
abstract = {OBJECTIVES: Mangiferin, a chemical constituent of Mangifera indica, has been the subject of extensive investigation due to its diverse biological activities, as detailed in numerous scientific studies. Its aglycone, norathyriol, has similarly garnered attention from researchers. In furtherance of our ongoing research goals, this article presents an evaluation of these compounds in relation to biomarkers associated with Alzheimer's disease.

METHODS: The inhibition of acetylcholinesterase (AChE) and β-secretase (BACE-1), as well as the aggregation of the amyloid beta (Aβ)42 peptide, was assessed using Ellman's colourimetric method, fluorescence resonance energy transfer (FRET), and thioflavin-T fluorescence emission, respectively.

KEY FINDINGS: Mangiferin exhibited no inhibitory effect on AChE, whereas norathyriol demonstrated an inhibitory concentration (IC50) of 6.23 μM. Molecular docking revealed that the mangiferin-AChE and mangiferin-BACE-1 complexes did not interact with sites related to enzyme activity. In contrast, norathyriol showed favourable interactions with Asp72 at the peripheral site of AChE and formed significant interactions with BACE-1 through hydrogen bonds, as suggested by molecular docking. The IC50 of norathyriol for BACE-1 inhibition was found to be 9.75 μM. The reduction in Aβ42 aggregation by norathyriol was only 28%.

CONCLUSION: We conclude that norathyriol is a promising prototype for drug development aimed at treating Alzheimer's disease.},
}

@article {pmid40795816,
year = {2025},
author = {},
title = {Correction to: Modeling familial Alzheimer's disease with induced pluripotent stem cells.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddaf134},
pmid = {40795816},
issn = {1460-2083},
}

@article {pmid40795635,
year = {2025},
author = {Zhou, W and Tian, L and Wang, X and Hou, G and Yu, J and Chen, M and Xu, C and Xue, L and Tan, X and Dai, R},
title = {Integrated untargeted and targeted metabolomics to reveal the mechanisms of herbal medicine HLXLD on Alzheimer's disease.},
journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences},
volume = {1265},
number = {},
pages = {124746},
doi = {10.1016/j.jchromb.2025.124746},
pmid = {40795635},
issn = {1873-376X},
abstract = {Huo-Luo-Xiao-Ling-Dan (HLXLD), a Chinese herbal medicine consisting of 11 herbs, has been shown to be effective in alleviating cognitive and memory impairment in Alzheimer's disease (AD). However, the underlying mechanisms require further investigation. This study aimed to clarify potential therapeutic mechanisms of HLXLD in the treatment of AD from a metabolic perspective. A rat model of AD induced by AlCl3 and D-gal was established, the Morris water maze (MWM) test and hippocampal histopathology were used to evaluate the pharmacological effect of the HLXLD on AD. Subsequently, untargeted metabolomics of brain tissues samples was performed by UHPLC-Q-Exactive-Orbitrap-MS, followed by multivariate statistical analysis. Targeted metabolomics by UHPLC-QQQ-MS was further employed to validate and supplement the untargeted metabolomics finding, involving neurotransmitters, amino acids, arachidonic acid and lipids, to elucidate the relationship between disease, herbal medicine and metabolism pathway. The study found that HLXLD could relieve the progression of AD and regulate metabolic imbalances. The levels of 26 metabolites decreased and 6 increased in brain tissues including lysine, taurine, fumaric acid, prostaglandin E2, choline and so on, these altered metabolites were primarily associated with amino acid metabolism, TCA cycle, arachidonic acid metabolism and lipid metabolism. The targeted metabolomics results showed that compared with the model group, the levels of 8 neurotransmitters, 21 amino acids, 7 arachidonic acids and 16 lipids in brain tissue, 9 neurotransmitters, 20 amino acids, 6 arachidonic acids and 2 lipids in plasma were changed. In summary, HLXLD could improve the levels of endogenous metabolites by regulating multiple metabolic pathways and play a role in energy supply, anti-neuroinflammatory and neuroprotective effects in AD treatment.},
}

@article {pmid40795578,
year = {2025},
author = {Zhai, Y and Cheng, J and Guo, X and Wang, X and Ma, M and Wang, S and Ren, Q},
title = {Generation of APOE ε3/ε4 and APP-mutant human pluripotent stem cell line derived from an Alzheimer's patient.},
journal = {Stem cell research},
volume = {87},
number = {},
pages = {103787},
doi = {10.1016/j.scr.2025.103787},
pmid = {40795578},
issn = {1876-7753},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with mutations in the amyloid precursor protein (APP) gene and the apolipoprotein E (APOE) gene identified as significant risk factors. Here, we generated induced pluripotent stem cells (iPSCs) from an Alzheimer's patient carrying heterozygous mutations in APOE (ε3/ε4) and APP. The derived iPSCs exhibited a normal karyotype, expressed pluripotency markers, and demonstrated the capacity to differentiate into the three germ layers.},
}

@article {pmid40795314,
year = {2025},
author = {Espay, AJ and Ezzat, K and Kepp, KP and Daly, T and Robakis, NK and Meijer, L and Imbimbo, BP},
title = {Restoring amyloid-β42 and γ-secretase function in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf294},
pmid = {40795314},
issn = {1460-2156},
abstract = {Emerging evidence is challenging the long-standing notion that Alzheimer's disease (AD) is caused by increased γ-secretase function and overproduction of 42-amino acid amyloid-beta (Aβ42). Cerebrospinal fluid levels of soluble monomeric Aβ42 in AD are reduced to about half of those in healthy individuals and drop even further at dementia onset in genetic forms (APP, PSEN1, PSEN2 mutations) and in Down's syndrome. Findings supporting a revised AD pathophysiology include: (1) ∼90% of pathogenic PSEN1 mutations reduce γ-secretase activity and Aβ42 production; (2) lower γ-secretase activity is correlated with lower soluble Aβ42 levels, earlier onset of dementia, worse cognition, and faster progression; (3) higher soluble Aβ42 levels associate with preserved cognition and delayed dementia in amyloid-positive sporadic and familial AD; (4) apparent cognitive benefits from anti-amyloid monoclonal antibodies may involve increased soluble Aβ42 levels; and (5) monomeric Aβ42 supports memory and other functions akin to a neuropeptide. These findings suggest that restoring, not reducing, γ-secretase activity and monomeric Aβ42 levels above a compensation threshold could offer disease-modifying therapeutic benefits. Drugs that increase soluble Aβ42, some already approved for other indications and linked to reduced dementia risk, may be repurposed to test whether they can slow disease progression in familial and sporadic AD.},
}

@article {pmid40795090,
year = {2025},
author = {Offer, K and Oglanova, N and Oswald, L and Hertwig, R},
title = {Prevalence and predictors of medical information avoidance: a systematic review and meta-analysis.},
journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine},
volume = {59},
number = {1},
pages = {},
doi = {10.1093/abm/kaaf058},
pmid = {40795090},
issn = {1532-4796},
support = {//BMBF and the Max Planck Society/ ; },
abstract = {BACKGROUND: Medical information avoidance-the prevention or delay of acquiring health-related information-is a growing concern for physicians, healthcare professionals, and policymakers. Yet, its prevalence and predictors have remained poorly understood.

PURPOSE: We conducted a systematic review and meta-analysis to clarify the prevalence and predictors of medical information avoidance, offering key insights into the worldwide empirical evidence.

METHODS: We performed a systematic search, preregistered on the OSF and in accordance with PRISMA and MOOSE reporting guidelines. Additional individual participant datasets were obtained from the National Institutes of Health (NIH). Data analysis was performed using random--effects and mixed-effects models.

RESULTS: A total of 92 studies and 6 individual participant datasets (564 497 unique participants, 25 countries) were analyzed. We found that almost 1 in 3 participants avoided or were likely to avoid information. Specifically, we estimated prevalence rates of 24% for diabetes, 29% for cancer, 32% for HIV, 40% for Huntington's disease, and 41% for Alzheimer's disease. We did not find any reliable association with gender or with race and ethnicity. Instead, we identified 16 significant predictors across cognitive, health-related, and sociodemographic domains. The strongest predictors were all cognitive: information overload (r = 0.26), perceived stigma (r = 0.36), self-efficacy (r = -0.28), and trust in the medical system (r = -0.25).

CONCLUSIONS: Nearly 1 in 3 participants avoided or were likely to avoid medical information. The highest prevalence rates were found for Huntington's disease and Alzheimer's disease, 2 incurable neurodegenerative diseases. Key cognitive predictors suggest entry points for policy interventions and future research.

LAY SUMMARY: Medical information is more accessible than ever, but many people choose to avoid it. How common is this behavior, and what predicts it? To find out, we analyzed data from over 90 studies involving more than half a million people across 25 countries. We found that nearly 1 in 3 people avoided or were likely to avoid medical information. Avoidance was highest for incurable neurodegenerative diseases (Alzheimer's disease: 41%, Huntington's disease: 40%), moderate for severe but treatable conditions (HIV: 32%, cancer: 29%), and lowest for a chronic, manageable illness (diabetes: 24%). We identified 16 key predictors of medical information avoidance. Surprisingly, gender, race, and ethnicity were not among them. Instead, the strongest predictors were cognitive and emotional: mistrust in the medical system, feeling overwhelmed, low confidence in managing one's health, and fear of being judged. Patterns of avoidance varied across world regions, suggesting that differences in healthcare systems may influence behavior. In this study, we do not judge whether medical information avoidance is good or bad. Instead, we offer the first comprehensive review of how common it is and what predicts it. More research is needed to understand the psychological and medical consequences of avoiding medical information.},
}

@article {pmid40794901,
year = {2025},
author = {Tavakoli, E and Niciforos, E and Amid, P and Cuperfain, AB and Burhan, AM and Colman, S and Chu, L and Davies, SJC and Derkach, P and Gerretsen, P and Graff-Guerrero, A and Hussain, M and Ismail, Z and Kim, D and Krisman, L and Mulsant, BH and Pollock, BG and Rej, S and Rostas, A and Rajji, TK and Van Bussel, L and Kumar, S and Elmi, S},
title = {The impact of lifetime excessive alcohol use on behavioural and psychological symptoms of dementia.},
journal = {Alcohol and alcoholism (Oxford, Oxfordshire)},
volume = {60},
number = {5},
pages = {},
doi = {10.1093/alcalc/agaf048},
pmid = {40794901},
issn = {1464-3502},
support = {//The Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN)/ ; //Brain Canada Foundation/ ; //Centre for Aging and Brain Health Innovation/ ; },
mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; Aged ; *Dementia/psychology/epidemiology ; Aged, 80 and over ; *Alcoholism/psychology/epidemiology/complications ; Alzheimer Disease/psychology ; },
abstract = {INTRODUCTION: Excessive alcohol use (EAU) elevates the risk of dementia through various mechanisms, yet its impact on the behavioural and psychological symptoms of dementia (BPSDs) remains uncertain.

METHODS: In this exploratory cross-sectional analysis of baseline data from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201), we included individuals with Alzheimer's disease and related dementias requiring BPSD treatment. We compared demographic characteristics and presentation of BPSDs (using the total and domain scores on the Neuropsychiatric Inventory-Clinician) in those with and without a lifetime history of EAU.

RESULTS: Among 193 participants [mean (SD) age: 80.6 (9.7) years, male: 48.4%], those in the EAU group (n = 17) and in the comparator group (n = 176) had severe and comparable cognitive impairment, with a median Functional Assessment Staging Tool for Dementia score of 6e. Participants with EAU were significantly younger than comparators [mean age (SD): 72.9 (7.1) years vs. 81.4 (9.5) years] (t = -3.678, df = 181, P < .001), and were more frequently male (76.5% [13 of 17] vs. 46.6% [82 of 176]; P = .036). In a sensitivity analysis, there were no differences in the Neuropsychiatric Inventory-Clinician total or individual domain scores between those with EAU and a subsample of those without EAU matched for age, sex, and recruitment site.

CONCLUSION: This exploratory study found that among individuals with Alzheimer's disease and related dementias and BPSDs, lifetime history of EAU is more frequent in younger males. Future studies may further examine the impact of EAU in individuals with BPSDs.},
}

Humans
Male
Female
Cross-Sectional Studies
Aged
*Dementia/psychology/epidemiology
Aged, 80 and over
*Alcoholism/psychology/epidemiology/complications
Alzheimer Disease/psychology

@article {pmid40794835,
year = {2025},
author = {Fruitman Davidi, A and Shirenova, S and Michaelovich, D and Benedetti, G and Shtrasberg, H and Shoval, I and Hauschner, H and Oz, G and Vardy, K and Hirsh, T and Madar, R and Stern, EA and Rosenmann, H and Biragyn, A and Okun, E},
title = {Dural ectopic lymphatic structures accumulate during aging and exhibit dysregulation in neurodegenerative diseases.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {33},
pages = {e2425081122},
doi = {10.1073/pnas.2425081122},
pmid = {40794835},
issn = {1091-6490},
support = {AARG-22-974362//Alzheimer's Association (AA)/ ; 387/21//Israel Science Foundation (ISF)/ ; },
mesh = {Animals ; *Aging/pathology/immunology ; Mice ; *Neurodegenerative Diseases/pathology/immunology ; *Meninges/pathology/immunology ; Female ; Male ; Alzheimer Disease/pathology/immunology ; *Tertiary Lymphoid Structures/pathology/immunology ; Disease Models, Animal ; Humans ; Tauopathies/pathology ; Down Syndrome/pathology/immunology ; *Dura Mater/pathology ; tau Proteins/metabolism ; Brain/pathology ; Mice, Inbred C57BL ; },
abstract = {The meninges serve as a critical interface between the peripheral immune system and the central nervous system, playing a crucial role in maintaining parenchymal homeostasis. Neurodegenerative disorders, such as amyloidosis and tauopathies, are marked by the accumulation of extracellular neurotoxic amyloid-β (Aβ) plaques and intracellular tau tangles, respectively, leading to neuronal cell death and cognitive decline. The role of the adaptive immune response in these pathologies remains under debate. Adaptive immune cells can manifest as ectopic lymphoid structures (ELS), which resemble secondary lymphoid organs, and form at sites of inflammation or pathology. While ELSs can support immune responses against infections or tumors, they may also have detrimental effects in certain pathological conditions. To explore whether meningeal ELS are implicated in aging and neurodegeneration, we analyzed the meninges of aged wild-type mice and mouse models of early-onset Alzheimer's disease, tauopathy, and Down syndrome-related neurodegenerative disorders. Our findings suggest that the accumulation of dural ELS varies according to age, brain pathology, and sex. Meningeal myeloid cells may contribute to the initiation and maintenance of ELS during aging. These results demonstrate the potential contribution of meningeal ELS to healthy aging and neurodegenerative conditions, offering directions for future research.},
}

Animals
*Aging/pathology/immunology
Mice
*Neurodegenerative Diseases/pathology/immunology
*Meninges/pathology/immunology
Female
Male
Alzheimer Disease/pathology/immunology
*Tertiary Lymphoid Structures/pathology/immunology
Disease Models, Animal
Humans
Tauopathies/pathology
Down Syndrome/pathology/immunology
*Dura Mater/pathology
tau Proteins/metabolism
Brain/pathology
Mice, Inbred C57BL

@article {pmid40794806,
year = {2025},
author = {Yoon, DM and Plante, D and Fleming, V and Handen, B and Lao, P and Peven, J and Christian, B and Okonkwo, O and Laymon, C and Ances, B and Hom, C and Helsel, B and Hartley, SL and , },
title = {Preliminary Investigation of Obstructive Sleep Apnea and Alzheimer's Disease in Down Syndrome.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zpaf044},
pmid = {40794806},
issn = {1550-9109},
abstract = {This study provided a preliminary examination of indices of obstructive sleep apnea (OSA) and sleep disruptions in adults with Down syndrome (DS), and their associations with Alzheimer's disease (AD) pathology and symptomatology. Ninety-three adults with DS (aged 25-61 years) from the Alzheimer Biomarker Consortium - Down Syndrome completed cognitive assessments, MRI and PET scans (assessing amyloid-beta [Aβ] and tau), and a one-night home sleep study using the WatchPAT-300 device. Study partners also reported on depressive symptoms and diagnoses. Correlational analyses examined relationships between sleep variables, PET biomarkers, and AD symptomatology (cognitive functioning and depressive mood), controlling for sociodemographics. Eighty-one participants (87%) completed valid WatchPAT data. Of these, 60 (74%) screened positive for OSA, and an additional 11 had a prior OSA diagnosis and used CPAP during the test night. Nearly half (45%) of those screening positive for OSA had no prior diagnosis, indicating under-detection. Among the 22 participants using OSA treatment, 50% continued to show sleep-disordered breathing, suggesting suboptimal treatment effectiveness. Higher wake percentage and shorter total sleep time were associated with greater Aβ and tau burden. Cognitive performance was negatively associated with wake percentage, total sleep time, and oxygenation indices (minimum oxygen, desaturation, and time ≤ 88% oxygen). Depressive symptoms were negatively related to total sleep time. These findings add preliminary evidence linking sleep disruption and OSA with AD-related pathology and symptomatology. Larger, longitudinal studies are needed to confirm these associations and evaluate whether improving sleep quality and treating OSA may help delay AD onset in this high-risk population.},
}

@article {pmid40794785,
year = {2025},
author = {Bridgeford, EW and Chung, J and Anderson, RJ and Mahzarnia, A and Stout, JA and Moon, HS and Han, ZY and Vogelstein, JT and Badea, A},
title = {Network biomarkers of Alzheimer's disease risk derived from joint volume and texture covariance patterns in mouse models.},
journal = {PloS one},
volume = {20},
number = {8},
pages = {e0327118},
doi = {10.1371/journal.pone.0327118},
pmid = {40794785},
issn = {1932-6203},
mesh = {*Alzheimer Disease/genetics/pathology/metabolism/diagnostic imaging ; Animals ; Disease Models, Animal ; Mice ; Male ; *Biomarkers/metabolism ; Humans ; Female ; *Brain/pathology/metabolism/diagnostic imaging ; Risk Factors ; Apolipoproteins E/genetics ; Mice, Transgenic ; Magnetic Resonance Imaging ; Genotype ; },
abstract = {Alzheimer's disease (AD) lacks effective cures and is typically detected after substantial pathological changes have occurred, making intervention challenging. Alzheimer's disease (AD) intervention requires early detection of risk factors and understanding their complex interactions before substantial pathological changes manifest. Current research often examines individual risk factors in isolation, limiting our understanding of their combined effects. We present a novel multivariate analytical framework to simultaneously assess multiple AD risk factors using mouse models expressing human ApoE alleles. Our methodological innovation lies in combining high-resolution magnetic resonance diffusion imaging with a comprehensive multifactorial analysis that integrates genotype, age, sex, diet, and immunity as interacting variables. This approach enables the simultaneous examination of regional brain volume and fractional anisotropy changes across multiple risk factors, providing a more holistic view than traditional univariate analyses. Our proposed method effectively identified how these factors converge on specific brain regions - with genotype influencing the caudate putamen, pons, cingulate cortex, and cerebellum; sex affecting the amygdala and piriform cortex; and immune status impacting association cortices and cerebellar nuclei. Importantly, our integrated approach revealed factor interactions that would remain undetected in single-variable studies, particularly in the amygdala, thalamus, and pons. While many findings align with previous research, our multidimensional framework offers a methodological advancement for studying AD risk factors by modeling their combined effects rather than isolated impacts. This approach creates a template for future studies to investigate mechanisms underlying coordinated changes in brain structure through network analyses of gene expression, metabolism, and structural pathways involved in neurodegeneration.},
}

*Alzheimer Disease/genetics/pathology/metabolism/diagnostic imaging
Animals
Disease Models, Animal
Mice
Male
*Biomarkers/metabolism
Humans
Female
*Brain/pathology/metabolism/diagnostic imaging
Risk Factors
Apolipoproteins E/genetics
Mice, Transgenic
Magnetic Resonance Imaging
Genotype

@article {pmid40794774,
year = {2025},
author = {M'Bra, PEH and Hamilton, LK and Moquin-Beaudry, G and Mangahas, CL and Pratesi, F and Castonguay, A and Mailloux, S and Galoppin, M and Avila Lopez, J and Bernier, M and Turri, M and Mayhue, M and Aumont, A and Tétreault, M and Cunnane, SC and Fernandes, KJL},
title = {Medium-chain triglycerides improve cognition and systemic metabolism in mouse models of Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf267},
pmid = {40794774},
issn = {1460-2156},
abstract = {Lifestyle-based interventions, including dietary modifications, can reduce dementia risk. In this regard, dietary supplementation with medium-chain triglycerides (MCT) has shown potential therapeutic benefits in individuals with Alzheimer's disease (AD). These effects are widely presumed to be mediated by hepatic conversion of MCT into circulating ketones. However, the physiological and cellular mechanisms underlying the benefits of MCT remain understudied, particularly in the context of AD. Here, we investigated the cellular and molecular changes occurring in the brain and systemically in response to dietary supplementation with MCT versus a ketogenic diet (KD). The experimental design consisted of comparing a 70% carbohydrate control diet to either a control diet supplemented with 10% MCT or a carbohydrate-free high fat KD. Diets were tested in two AD mouse models, slow-progressing 3xTg-AD mice that model pre-symptomatic/early stages and rapidly-progressing 5xFAD mice that model late stages of the disease. We found that MCT supplementation and KD both improved hippocampal-dependent spatial learning and memory, increased dendritic spine density of hippocampal neurons, and modulated hippocampal expression of genes associated with mitochondrial functions, synaptic structure, and insulin signaling in AD mouse models. However, unlike KD, MCT supplementation did not elevate circulating ketones, suggesting different mechanisms. Indeed, MCT enhanced the peripheral insulin response of AD mice, while KD conversely unveiled their latent metabolic vulnerability, increasing their hyperglycaemia, body weight gain, and adiposity. The systemic metabolic disturbances of AD mice correlated with transcriptomic alterations in hepatic lipid metabolism and ketogenesis genes and increased lipid droplet accumulation. These liver metabolic abnormalities were partially reversed by both MCT supplementation and KD, but in distinct ways. Notably, KD selectively triggered hepatic neutral lipid depletion and prominent proinflammatory gene expression while MCT down-regulated expression of cholesterol-related genes. Collectively, these findings reveal that MCT supplementation in the context of AD improves cognition and systemic metabolism without elevating circulating ketone levels.},
}

@article {pmid40794557,
year = {2025},
author = {Bybee, SG and Clayton, J and Aruscavage, N and Utz, R and Bigger, SE and Iacob, E and Dassel, K},
title = {Engaging in the Life-Planning in Early Alzheimer's and other Dementias (LEAD) Advance Care Planning (ACP) intervention is associated with perceived ACP concordance and interpersonal connectedness.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf179},
pmid = {40794557},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Persons living with dementia often rely upon a care partner as their surrogate medical decision maker, yet little is known about how dementia care dyads achieve advance care planning (ACP) concordance: when a care partner fully understands a care recipient's values and preferences as best they can. Examining data from a pilot study of the online Life-planning in Early Alzheimer's and other Dementias (LEAD) intervention to better understand how dyads achieve perceived ACP concordance, we hypothesized that: (1) engaging in ACP was associated with perceived ACP concordance, (2) perceived ACP concordance was associated with interpersonal connectedness, and (3) engaging in ACP was associated with interpersonal connectedness.

RESEARCH DESIGN AND METHODS: Dyads completed the LEAD intervention and answered open-ended survey questions. After aggregating data supporting and or not supporting each hypothesis, process codes and subcodes were used to identify the elements involved in each supported hypothesis (Cohen's Kappa 0.65-0.82).

RESULTS: N = 48 community-based dyads completed the LEAD intervention, with N = 43 answering open-ended questions. Care recipients averaged 65.1 years of age (Standard deviation =14.8); care partners averaged 54.9 years (SD = 14.6) and were primarily spouses (n = 32, 66.7%) or children (n = 12, 25.0%). Engaging in ACP was associated with higher interpersonal connectedness and with perceived ACP concordance. Perceived ACP concordance was not associated with higher interpersonal connectedness.

DISCUSSION AND IMPLICATIONS: These findings suggest that clinicians should focus on facilitating ACP discussions with dyads, as these conversations appear crucial for fostering understanding and agreement between dyad members, ultimately leading to perceived ACP concordance.},
}

@article {pmid40794555,
year = {2025},
author = {Berson, E and Perna, A and Bukhari, S and Kim, Y and Xue, L and Seong, D and Mataraso, S and Ghanem, M and Chang, AL and Montine, KS and Keene, CD and Kasowski, M and Aghaeepour, N and Montine, TJ},
title = {Deep learning-based cell type profiles reveal signatures of Alzheimer's disease resilience and resistance.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf285},
pmid = {40794555},
issn = {1460-2156},
abstract = {Neurological disorders result from the complex and poorly understood contributions of many cell types, essential for uncovering mechanisms behind these disorders and identifying specific therapeutic targets. Single-nucleus technologies have advanced brain disease research, but remain limited by their low nuclear transcriptional coverage, high cost, and technical complexity. To address this, we applied a transformer-based deep learning model that restores cell type-specific investigation transcriptional programs from bulk RNA-seq, significantly outperforming previous methods. This enables large-scale and cost-effective investigation of cell type-specific transcriptomes in complex and heterogeneous phenotypes such as cognitive resilience or brain resistance to Alzheimer's disease. Our analysis identified astrocytes as the major cell mediator of Alzheimer's disease resilience across cerebral cortex regions, while excitatory neurons and oligodendrocyte progenitor cells emerged as the major cell mediators of resistance, maintaining synaptic function and preserving neuron health. Finally, we show that our approach could restore the whole tissue transcriptome, offering an unbiased framework for exploring cell-specific functions beyond single nucleus data.},
}

@article {pmid40794238,
year = {2025},
author = {Jellinger, KA},
title = {Comorbid pathologies and their impact on progressive supranuclear palsy: current view.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {40794238},
issn = {1435-1463},
support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; },
abstract = {Progressive supranuclear palsy, a four-repeat tauopathy, is clinically characterized by early postural instability and falls, vertical supranuclear palsy, levodopa poorly-responsive parkinsonism, pseudobulbar palsy, and cognitive impairment. It is morphologically featured by accumulation of hyperphosphorylated tau protein in neurons and glia predominantly in the basal ganglia, brainstem tegmentum and frontal cortex, associated with degeneration of the extrapyramidal system and cortical atrophy. Isolated PSP neuropathology is uncommon, with nearly 70% showing co-neuropathologies including Alzheimer-type, Lewy body, TDP-43 pathologies, argyrophilic grains, and other tauopathies and neurodegenerative disorders (Parkinson disease, amyotrophic lateral sclerosis). The most common comorbid conditions are hypertension, cardiovascular and cerebrovascular diseases, diabetes mellitus, polyneuropathies, muscular and urological disorders. Due the increased prevalence of comorbidities and their eminent impact on the progress and outcome of the disease, clinical trials should account for them in their design and selection. However, currently little is known about co-pathologies in these patients. In view of the eminent burden of comorbidities and resulting therapeutic consequences, the frequency of the different co-pathologies in PSP and their clinical impact will be discussed. It should provide insight into their pathogenic backgrounds as a basis for adequate treatment procedures to improve the quality of life of patients with this fatal disease.},
}

@article {pmid40794118,
year = {2025},
author = {Yen, H and Chen, MW and Lim, JX and Chew, KY},
title = {"Exploring Lymphovenous Anastomosis for Alzheimer's Disease: Addressing Brain Lymphatic Dysfunction, Feasibility, and Outcome Metrics".},
journal = {Plastic and reconstructive surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/PRS.0000000000012364},
pmid = {40794118},
issn = {1529-4242},
abstract = {Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, tau tangles, and neuroinflammation, with emerging evidence highlighting a potential role for brain lymphatic dysfunction. Lymphovenous anastomosis (LVA), a microsurgical technique traditionally used in lymphedema management, offers a novel solution to enhance brain metabolite clearance by bypassing impaired lymphatic pathways and enhancing glymphatic outflow. By connecting lymphatic vessels to veins, LVA compensates for aging-related declines in lymphatic/glymphatic flow, with preliminary studies supporting this theory. This review evaluates the feasibility of LVA, emphasizing key anatomical targets such as cervical lymphatic vessels, while proposing robust patient selection criteria. It also aims to address the controversies in outcome measures including advanced imaging, biomarker analysis, and cognitive assessments. While early findings are promising, further research is essential to optimize surgical protocols, clarify biological mechanisms, and ensure safety. LVA represents a novel therapeutic strategy that may complement existing treatments, offering new hope for addressing the inevitable outcome of AD.},
}

@article {pmid40793986,
year = {2025},
author = {Good, CJ and Bowman, AP and Klein, C and Awwad, K and Buck, WR and Yang, J and Wagner, DS},
title = {Spatial Mapping of Gangliosides and Proteins in Amyloid Beta Plaques at Cellular Resolution Using Mass Spectrometry Imaging and MALDI-IHC.},
journal = {Journal of mass spectrometry : JMS},
volume = {60},
number = {9},
pages = {e5161},
doi = {10.1002/jms.5161},
pmid = {40793986},
issn = {1096-9888},
support = {//AbbVie/ ; },
mesh = {Animals ; *Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods ; *Plaque, Amyloid/chemistry/metabolism/pathology ; Mice ; *Gangliosides/analysis/metabolism ; *Amyloid beta-Peptides/analysis/metabolism ; Brain/metabolism/pathology/diagnostic imaging ; Alzheimer Disease/metabolism/pathology ; Disease Models, Animal ; Immunohistochemistry/methods ; Mice, Transgenic ; },
abstract = {In pharmaceutical research and development, technologies like mass spectrometry imaging (MSI) offer spatially resolved compound distributions to aid in the discovery of drug targets and development of drug candidates. Through traditional and immunohistochemical approaches centered around MSI, distributions of endogenous lipids and proteins can be mapped on the same tissue section at cellular resolution. To highlight the cellular resolution capability of the integrated MSI workflow leveraged here, an animal model of Alzheimer's disease (AD) was interrogated due to the relationship of lipid dysregulation and extracellular protein deposition in driving disease pathology, especially at the site of amyloid beta (Aβ) plaques. Gangliosides, Aβ peptides, and microglia were imaged at 5 μm spatial resolution in the brains of an APPPS1 mouse model. GM3 and GM2 gangliosides displayed plaque-associated accumulation as supported by previous studies of a range of AD models. Advanced methods for achieving cellular resolution imaging of lipids and proteins have revealed heterogeneity in molecular distributions, which appears to be influenced by the microenvironment surrounding Aβ plaques. While these data could support future biological conclusions of AD, a central aim of this study was to emphasize the potential impact of an MSI workflow, which fuses spatial lipidomic and proteomic data at cellular resolution, on translational drug discovery research. This dual molecular imaging approach and data mining strategy can not only support efforts in the discovery of novel drug targets, but also in evaluating drug-target engagement when the distribution of a small molecule drug is simultaneously investigated.},
}

Animals
*Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
*Plaque, Amyloid/chemistry/metabolism/pathology
Mice
*Gangliosides/analysis/metabolism
*Amyloid beta-Peptides/analysis/metabolism
Brain/metabolism/pathology/diagnostic imaging
Alzheimer Disease/metabolism/pathology
Disease Models, Animal
Immunohistochemistry/methods
Mice, Transgenic

@article {pmid40792619,
year = {2025},
author = {Xiang, Y and Tanwar, V and Singh, P and La Follette, L and Narayan, VP and Kapahi, P},
title = {Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans.},
journal = {eLife},
volume = {13},
number = {},
pages = {},
doi = {10.7554/eLife.102447},
pmid = {40792619},
issn = {2050-084X},
support = {R01AG068288/AG/NIA NIH HHS/United States ; R01AG045835/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Menarche/genetics ; Female ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; *Aging/genetics ; *Parturition ; *Genetic Pleiotropy ; Middle Aged ; Adult ; Pregnancy ; Aged ; },
abstract = {BACKGROUND: Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited.

METHODS: Mendelian randomization (MR) was applied to investigate the associations between the ages of menarche or first childbirth and age-related outcomes and diseases. Ingenuity Pathway Analysis was employed to explore gene-related aspects associated with significant single-nucleotide polymorphisms (SNPs) detected in MR analysis. The associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes were validated in the UK Biobank by conducting regression analysis of nearly 200,000 subjects.

RESULTS: Using MR, we demonstrated that later ages of menarche or first childbirth were genetically associated with longer parental lifespan, decreased frailty index, slower epigenetic aging, later menopause, and reduced facial aging. Moreover, later menarche or first childbirth was also genetically associated with a lower risk of several age-related diseases, including late-onset Alzheimer's disease, type 2 diabetes, heart disease, essential hypertension, and chronic obstructive pulmonary disease. We identified 158 significant SNPs that influenced age-related outcomes, some of which were involved in known longevity pathways, including insulin-like growth factor 1, growth hormone, AMP-activated protein kinase, and mTOR signaling. Our study also identified higher body mass index as a mediating factor in causing the increased risk of certain diseases, such as type 2 diabetes and heart failure, in women with early menarche or early pregnancy. We validated the associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes in the UK Biobank by conducting regression analysis of nearly 200,000 subjects. Our results demonstrated that menarche before the age of 11 and childbirth before 21 significantly accelerated the risk of several diseases and almost doubled the risk for diabetes, heart failure, and quadrupled the risk of obesity, supporting the antagonistic pleiotropy theory.

CONCLUSIONS: Our study highlights the complex relationship between genetic legacies and modern diseases, emphasizing the need for gender-sensitive healthcare strategies that consider the unique connections between female reproductive health and aging.

FUNDING: Hevolution Foundation (PK). National Institute of Health grant R01AG068288 and R01AG045835 (PK). Larry L. Hillblom Foundation (PK), Larry L. Hillblom Foundation (PS), Glenn Foundation (VN).},
}

Humans
*Menarche/genetics
Female
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
*Aging/genetics
*Parturition
*Genetic Pleiotropy
Middle Aged
Adult
Pregnancy
Aged

@article {pmid40792517,
year = {2025},
author = {Roy, R and Khatua, MM and Ghosh, S and Nandi, S and Ram, H and Ghosh, S},
title = {Endogenous Pigment Mimicking Engineered Nanovesicle Targets Extrasynaptic NMDA Receptors against Ca[2+]-Mediated Excitotoxicity in Alzheimer's Disease.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c08303},
pmid = {40792517},
issn = {1944-8252},
abstract = {In Alzheimer's disease (AD), deposition of toxic Aβ42 oligomers causes excessive internalization of 2A subunit dominant NMDA receptors (GluN2A subtype) from the synaptic region. This causes a significant reduction of the synaptic glutamate interaction site. The absence of GluN2A propagates spillage of glutamate to the extrasynaptic space, where it interacts with the 2B subunit dominant NMDA receptor (GluN2B subtype). This interaction causes excessive Ca[2+] influx and perturbation of autophagy, thus disrupting mitochondrial membrane potential and producing reactive oxygen species, causing neuronal death. In this context, our hypothesis suggests that selective inhibition of extrasynaptic GluN2B receptors could produce multifaceted outcomes against AD. Our aim is to devise a neuromelanin mimicking nanovesicle, particularly targeting extrasynaptic GluN2B. A conceptualized nanovesicle is designed to be larger than the synaptic cleft space (>100 nm) with the decoration of novel GluN2B targeting peptides. Therefore, we envision that this engineered nanomaterial will only inhibit the extrasynaptic GluN2B-mediated Ca[2+] excitotoxicity and also revive homeostatic autophagy.},
}

@article {pmid40792495,
year = {2025},
author = {Eskioglu, Eİ and Karali, FS and Tosun, S and Cinar, N and Macoir, J},
title = {Normative Data for the Adult Turkish Population and Validation Study in Mild Cognitive Impairment and Alzheimer's Disease of the TDQ-30 Tr, a Color Picture-naming Test for Adults and the Elderly.},
journal = {Brain and behavior},
volume = {15},
number = {8},
pages = {e70718},
doi = {10.1002/brb3.70718},
pmid = {40792495},
issn = {2162-3279},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; *Alzheimer Disease/diagnosis/psychology ; Aged ; Male ; Female ; Turkey ; Middle Aged ; *Neuropsychological Tests/standards ; Adult ; Aged, 80 and over ; Reproducibility of Results ; Reference Values ; },
abstract = {BACKGROUND: Individuals with mild anomia often have difficulty finding words during conversations, even when they get normal results on standard language evaluations. The high frequency and familiarity of target objects may lead to the insensitivity of some naming assessments, complicating diagnosis. This study aims to adapt the Test de dénomination de Québec-30 images (TDQ-30) into Turkish, develop normative data adapted to the Turkish population, and determine its validity in Turkish-speaking patients.

METHODS: Data were collected from a total of 464 participants (414 healthy controls, 25 with Alzheimer's disease (AD), and 25 with mild cognitive impairment (MCI)) by using the Montreal Cognitive Assessment (MoCA), Boston Naming Test (BNT), Detection Test for Language Impairments in Adults and the Aged-Turkish version (DTLA-Tr), and Test de dénomination de Québec-30-Turkish version (TDQ-30 Tr).

RESULTS: In Study 1, TDQ-30 was translated into Turkish and checked for cultural appropriateness for the Turkish community. In study 2, the adapted version, TDQ-30 tr, was applied to 414 healthy adults and elderly individuals to establish normative data for the test. In study 3, the analyses made known the validity of TDQ-30 Tr, and it was found that TDQ-30 can differentiate between healthy participants and those with AD and MCI, with healthy participants showing better results.

CONCLUSION: In summary, the TDQ-30 Tr is an effective and dependable tool for identifying mild anomia associated with neurological impairments in Turkish-speaking adults and the elderly. Its ease of use makes it a vital instrument for improving evaluation tools in research and clinical settings in Turkey.},
}

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

@article {pmid40792479,
year = {2025},
author = {Onigbinde, S and Solomon, J and Gutierrez-Reyes, CD and Daramola, O and Fowowe, M and Adeniyi, M and DuBois, KN and Bakulski, KM and Kanaan, NM and Lubman, DM and Mechref, Y},
title = {Serum N-Glycan Profiling Identifies Candidate Glycan Biomarkers for Early Detection and Prediction of Alzheimer's Disease.},
journal = {Journal of proteome research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jproteome.5c00018},
pmid = {40792479},
issn = {1535-3907},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive decline, affecting millions worldwide. Early diagnosis and intervention are crucial yet challenging, particularly in distinguishing between Mild Cognitive Impairment (MCI) subtypes, which often precede AD. Recent studies have highlighted the significant role of glycosylation, specifically N-glycan alterations, in the pathogenesis of AD. This study utilizes advanced LC-MS/MS techniques to profile N-glycan changes between serum samples from participants with normal cognition denoted as (CTRL), nonamnestic MCI (naMCI), amnestic MCI (aMCI), and AD. The analysis identified 99 unique N-glycans and revealed distinct glycan expression patterns among the groups. Notably, sialylation was significantly upregulated in AD, while fucosylation was downregulated, suggesting their involvement in AD pathology. Additionally, the study examined the role of isomeric N-glycans, identifying several isomers that differentiate naMCI from aMCI and those that can monitor progression from aMCI to AD dementia. These findings emphasize the potential of N-glycans as biomarkers for early detection of AD and its precursors, offering new avenues for therapeutic intervention. The differential expression of specific N-glycans and their isomers could serve as valuable biomarkers for distinguishing MCI subtypes and predicting progression to AD dementia, thereby aiding in the development of targeted therapies aimed at mitigating cognitive decline in affected individuals.},
}

@article {pmid40792175,
year = {2025},
author = {Godfrey, DA and Wong, B and Thompson, AD and Coleman, ME and Sparks, C and Utz, RL},
title = {Respite time-use among dementia caregivers.},
journal = {Frontiers in health services},
volume = {5},
number = {},
pages = {1598518},
pmid = {40792175},
issn = {2813-0146},
abstract = {UNLABELLED: Caregiving for family members with Alzheimer's disease and related dementias (ADRD) places significant burden on family members, leaving them at risk for a variety of mental and physical issues. While engaging in sufficient respite is generally considered an important resiliency factor for caregivers, recent research has demonstrated that caregivers are not satisfied with their respite and are not gaining much benefit during the limited respite time available to them.

OBJECTIVES: The current study examines whether goal-oriented respite planning, facilitated by a mobile intervention, can improve caregivers' subjective experience of their respite time-use.

METHOD: Caregivers (N = 85) used a mobile intervention to help them plan and evaluate their weekly respite time-use. Ecological Momentary assessments (weekly) monitored number of respite hours, respite goal achievement, and subjective assessment of their respite experience.

RESULTS: Respite goal achievement on a given week predicted improvements in participants' ratings of their respite time-use outcomes one week later. Specifically, one week after reporting improved respite goal achievement, caregivers' ratings on happiness with their respite activities, feeling that their respite made them a better caregiver, and feeling like they had enough respite all increased. These effects were independent of the number of respite hours they reported per week.

DISCUSSION: Engaging in weekly goal-setting and goal-review activities is associated with caregivers' subjective evaluation of their respite time-use. Interventions that help caregivers implement goal setting and achievement into their daily lives would likely benefit subjective evaluations and experiences with respite.},
}

@article {pmid40792123,
year = {2025},
author = {Zhi, N and Ren, R and Qi, J and Liu, X and Yun, Z and Lin, S and Hu, Y and Li, H and Xie, X and Wang, J and Li, J and Zhu, Y and Gao, M and Yang, J and Wang, Y and Jing, Y and Geng, J and Cao, W and Xu, Q and Yu, X and Zhu, Y and Zhou, Y and Wang, L and Gao, C and Li, B and Chen, S and Yuan, F and Dou, R and Liu, X and Li, X and Yin, Y and Chang, Y and Xu, G and Zhong, Y and Li, C and Wang, Y and Zhou, M and Wang, G},
title = {The China Alzheimer Report 2025.},
journal = {General psychiatry},
volume = {38},
number = {4},
pages = {e102020},
pmid = {40792123},
issn = {2517-729X},
abstract = {With the sustained growth of the economy and significant changes in social demographics, the issue of elderly-related diseases has increasingly drawn attention, particularly. Alzheimer's disease (AD), as a representative disease of neurodegenerative diseases, has become a major challenge, affecting the health and quality of life of the elderly population severely. In recent years, the incidence, prevalence and mortality rates of AD have increased in China, imposing substantial economic burdens on families, society and the entire healthcare system. To proactively address this challenge and respond to the national 'Healthy China Action' initiative, leading experts from authoritative institutions jointly authored the China Alzheimer Report 2025. Building on previous editions, this report updates epidemiological data on AD in China, thoroughly analyses the latest economic burdens of the disease and comprehensively evaluates the current status of AD diagnosis and treatment services, as well as the allocation of public health resources in our country. Its release reflects China's progress in AD research and prevention, underscores societal concern for elderly health and aims to provide scientific guidance and data support for AD prevention, diagnosis and treatment. It also facilitates academic exchanges and cooperation, enhancing public awareness and promoting active participation in elderly healthcare, towards achieving 'healthy ageing' in China.},
}

@article {pmid40792064,
year = {2025},
author = {Chooi, C and Gavett, BE and Ames, D and Maruff, P and Doré, V and Villemagne, VL and Bourgeat, P and Xia, Y and Masters, CL and Martins, RN and Taddei, K and Rowe, CC and Weinborn, M and Rainey-Smith, SR},
title = {Sex differences in the association between episodic memory residual reserve index and change in executive function.},
journal = {Aging brain},
volume = {8},
number = {},
pages = {100146},
pmid = {40792064},
issn = {2589-9589},
abstract = {Sex differences in cognitive reserve might contribute to females being disproportionately affected by Alzheimer's disease (AD). We investigated sex differences in the protective effects of cognitive reserve, and whether brain beta-amyloid accounts for differences. Older adults (n = 997 from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing) diagnosed as Cognitively Normal, Mild Cognitive Impairment, or AD at baseline were assessed every 18 months for up to a maximum of seven visits. Cognitive reserve was calculated from the variance in episodic memory not explained by demographic or brain measures. Executive functioning (EF) intercept and slope were regressed onto the main and interaction effects of cognitive reserve x brain integrity x sex, plus covariates (age, number of APOE ε4 alleles). A three-way interaction was observed between cognitive reserve, brain integrity, and sex on the EF slope. Females benefitted more than males from the protective effects of cognitive reserve at low levels of brain integrity. Sex differences in the protective effect of cognitive reserve were not moderated by brain beta-amyloid burden.},
}

@article {pmid40792047,
year = {2025},
author = {Mannai, A and Ressaissi, A and Merghni, A and Chahdoura, H and Mnif, W and Alelyani, Z and Ben-Attia, M and El-Bok, S and Serralheiro, ML},
title = {Phytochemical Profile and Evaluation of Antioxidant Activity, Enzyme Inhibition and Cell Viability of Leaves Extracts of Three Tunisian Varieties of Diospyros kaki L.},
journal = {Food science & nutrition},
volume = {13},
number = {8},
pages = {e70775},
pmid = {40792047},
issn = {2048-7177},
abstract = {Because of their biological qualities, the leaves of Diospyros kaki L., also known as persimmon, have long been used in traditional Chinese medicine for the treatment of ischemic stroke, angina, internal hemorrhage, hypertension, atherosclerosis, and some infectious diseases. It has also been used in cosmetics, as well as in refreshing drink preparations. In the present study, we have compared the aqueous extract effects of the leaves of the three Tunisian varieties of D. kaki, namely Triumph, Jiro, and Rojo Brillante, prepared by decoction and then filtered. The obtained filtrates were lyophilized and kept cold until analysis. Phytochemical profile and biological activities were performed on the freeze-dried fractions of the different varieties of D. kaki. Analysis of the results shows that the leaf extracts of the three varieties are rich in total phenols and flavonoids (ranking: Rojo Brillante > Triumph > Jiro) and have a high antioxidant activity (EC50 values of 3.8, 8.0 and 12.1 μg/mL respectively for Rojo Brillante, Triumph and Jiro). Using a quadrupole time-of-flight interface and high-resolution tandem liquid chromatography, 29 secondary metabolites of D. kaki leaf decoctions were identified in the three varieties, including several polyphenols such as flavonoids, tannins, organic acids, and others. In addition, these extracts were found to inhibit the function of two key enzymes, acetylcholinesterase (IC50 values of 58, 96 and 210 μg/mL respectively for Rojo Brillante, Triumph and Jiro) and inhibition percentages of 3-hydroxy-3-methylglutaryl-CoA reductase were 61.44%, 57.35%, and 46.28% for Jiro, Triumph, and Rojo Brillante, respectively. However, we noted that these different extracts had no cytotoxic effect on human liver or breast cancer cells in culture until 10 μg/mL. The results reveal that the D. kaki leaves are a potential matrix for the launch of future nutraceuticals, cosmetics, and pharmaceutical specialties such as drugs to combat Alzheimer's disease or to reduce cholesterol levels, as well as an attractive source of ingredients beneficial to health. Comparative analysis of D. kaki leaves showed that the Rojo Brillante variety has a higher content of secondary metabolites than the other two varieties, thus increasing its antioxidant activity and enzyme inhibitory effect, although it is not as cytotoxic as the other two varieties.},
}

@article {pmid40792034,
year = {2025},
author = {Li, J and Wu, C and Liu, Q and Liu, M and Liu, T and Li, A and Fu, G and Zou, Z and Guo, D and Chen, K and Xia, Y and Yao, D},
title = {Mozart's rhythm influence on Alzheimer's disease progression via modulation of pathological damage and cognition.},
journal = {iScience},
volume = {28},
number = {8},
pages = {113168},
pmid = {40792034},
issn = {2589-0042},
abstract = {Rhythm perception is considered a conserved trait across species, and musical rhythm exposure (MRE) has been demonstrated to enhance cognitive functions in healthy individuals. Alzheimer's disease (AD), characterized by cognitive decline and pathological degeneration, may potentially be delayed by MRE. In this study, the APP/PS1 AD mouse model was exposed to Mozart's K.448 rhythm for six months, with APP/PS1 and wild-type C57BL/6J mice serving as controls. The Morris water maze test was employed to assess the impact of MRE on spatial learning and memory. Pathological damage was evaluated through amyloid-beta and phosphorylated tau levels. Additionally, hippocampal microglia activation, inflammatory markers, and gut microbiota composition were analyzed. The study revealed that MRE improves cognitive function, reduces amyloid plaque accumulation, suppresses microglial activation and neuroinflammation, and modulates gut microbiota composition. This suggests that MRE offers a promising non-pharmacological approach to slowing cognitive decline and pathological damage in AD.},
}

@article {pmid40791874,
year = {2025},
author = {Frings, L and Hellwig, S and Brumberg, J and Rau, A and Mix, M and Blazhenets, G and Urbach, H and Meyer, PT},
title = {Divergent effects of age on imaging-based ATN biomarkers and cognition in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70142},
pmid = {40791874},
issn = {2352-8729},
abstract = {INTRODUCTION: We investigated whether age of patients with Alzheimer's disease (AD) at first visit to a memory clinic predicts biomarker findings along the amyloid beta deposition, pathologic tau, and neurodegeneration (ATN) scheme and moderates the association between ATN biomarkers and cognition.

METHODS: We evaluated [[11]C]Pittsburgh compound B positron emission tomography (PET), florzolotau ([18]F) PET, [[18]F]fluorodeoxyglucose PET, T1-weighted magnetic resonance imaging, and cognitive assessments (N = 190/63/252/687/2198) of a total of 2355 AD patients. We assessed direct and moderating effects of age.

RESULTS: Tau burden and hypometabolism were more severe in younger AD patients. Gray matter volume of the medial temporal lobe (MTL) was reduced to a greater extent in older patients. Relationships between different imaging modalities or between single imaging modalities and cognition were not moderated by age.

DISCUSSION: In contrast to more severe tau burden and hypometabolism in younger patients, MTL atrophy was more pronounced in older patients. Relationships between markers of pathology and those of neurodegeneration were not associated with age.

HIGHLIGHTS: Amyloid beta load as a biomarker of pathology burden was not associated with age at first visit to a memory clinic.Tau burden was higher, and glucose metabolism was lower in younger Alzheimer's disease (AD) patients.By contrast, medial temporal lobe atrophy was less severe in younger AD patients.Younger AD patients showed more severe memory deficits with respect to age-appropriate normative data.Age had no moderating effect on relationships between different imaging variables or between single imaging variables and cognition.},
}

@article {pmid40791780,
year = {2025},
author = {Mahendrarajan, V and Lazarus, HPS and Muthukaliannan, GK and Varghese, S and Easwaran, N},
title = {Membrane vesicles from Red Complex bacteria: key players in oral pathogenesis, immune disruption, systemic diseases, and therapeutic insights.},
journal = {Frontiers in oral health},
volume = {6},
number = {},
pages = {1607931},
pmid = {40791780},
issn = {2673-4842},
abstract = {The oral cavity serves as a habitat for a diverse array of microorganisms, each performing distinct functions, thereby constituting a vibrant and intricate ecological community. The most common pathogenic bacteria in the oral ecosystem are the Red Complex group, which includes Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. These bacteria have several ways to inflict damage, such as creating biofilms and secreting nano-sized vesicles from their outer membrane, called Outer Membrane Vesicles (OMV). OMVs are nano structures that carry proteins, lipids, and toxins from the outer membrane of Gram-negative bacteria. The OMVs of Red Complex bacteria play a role in the onset and development of oral pathological conditions such as gingivitis and periodontitis. Additionally, a substantial body of evidence supports the notion that these OMVs may exert influence on systemic pathologies, including atherosclerosis, alzheimer's, rheumatoid arthritis, and diabetes mellitus. This review will discuss the formation and composition of Red Complex bacterial OMVs, their impacts on the oral environment, the immune response, and their correlations with various systemic diseases. The suggested treatment approach by probiotics and bioactives focuses on the genetic elements that induce the production of OMVs by the Red Complex bacteria, offering a potent means to hinder the advancement of diseases propagated through these OMVs.},
}

@article {pmid40791767,
year = {2025},
author = {Wang, X and Li, J and Fu, Q and Zheng, H and Duan, S and Gao, Y and Luo, H and Xu, Y},
title = {Cerebral Amyloid Angiopathy-Related Inflammation: Clinical Characteristics and Treatment Experience.},
journal = {Clinical interventions in aging},
volume = {20},
number = {},
pages = {1181-1190},
pmid = {40791767},
issn = {1178-1998},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/complications/diagnosis/diagnostic imaging/therapy/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; Aged, 80 and over ; Adult ; *Inflammation/etiology ; Neuroimaging ; Cognitive Dysfunction/etiology ; },
abstract = {OBJECTIVE: The present study aims to analyze the clinical manifestations, laboratory results, neuroimaging features, treatment interventions, and outcomes in a cohort of patients with cerebral amyloid angiopathy-related inflammation (CAA-ri), providing a deeper understanding of this rare subtype of CAA and enhancing diagnostic precision in clinical practice.

METHODS: We conducted a systematic retrospective review of clinical records from 13 consecutive patients who met the diagnostic criteria for probable CAA-ri and were evaluated at the First Affiliated Hospital of Zhengzhou University between January 2021 and August 2024.

RESULTS: The study cohort comprised 13 patients (7 males, 6 females; mean age 65.2 years, range 42-81), predominantly presenting with subacute onset (53.8%, n=7). Cognitive impairment (61.5%, n=8) emerged as the most frequent clinical manifestation, followed by headache (46.2%, n=6), epileptic seizures (30.8%, n=4), and focal neurological deficits (23.1%, n=3). Neuroimaging findings across all patients demonstrated asymmetric white matter hyperintensities in conjunction with cortical-subcortical cerebral microbleeds. A subset of patients exhibited cortical superficial siderosis lobar hemorrhage, and/or punctate acute infarction. Among the nine patients who underwent lumbar puncture, five showed elevated cerebrospinal fluid (CSF) pressure and protein levels. All four patients assessed for CSF Alzheimer's disease biomarkers showed reduced Aβ42 and Aβ40 levels, alongside elevated total tau and phosphorylated tau levels. Furthermore, over 70% of the patients who treated with immunosuppressive therapy achieved favorable clinical outcomes.

CONCLUSION: Clinical manifestations and neuroimaging abnormalities serve as pivotal non-invasive criteria for guiding clinicians in the diagnosis of CAA-ri. Timely initiation of immunosuppressive therapy in CAA-ri patients can lead to favorable outcomes.},
}

Humans
*Cerebral Amyloid Angiopathy/complications/diagnosis/diagnostic imaging/therapy/drug therapy
Male
Female
Aged
Middle Aged
Retrospective Studies
Aged, 80 and over
Adult
*Inflammation/etiology
Neuroimaging
Cognitive Dysfunction/etiology

@article {pmid40791766,
year = {2025},
author = {Funari, A and De Smaele, E and Paci, P and Fiscon, G},
title = {Prioritizing repurposable drugs for Alzheimer's disease using network-based analysis with concurrent assessment of Long QT syndrome risk.},
journal = {Biotechnology reports (Amsterdam, Netherlands)},
volume = {47},
number = {},
pages = {e00909},
pmid = {40791766},
issn = {2215-017X},
abstract = {Alzheimer's disease affects 6.9 million Americans aged 65 and older, a number expected to double by 2060. Eight FDA-approved drugs target Alzheimer's, but no cure is available, and most treatments are symptomatic. Drug repurposing, the use of FDA-approved drugs for new indications, is a promising strategy to address this lack of effective therapies. However, despite prior safety approval, repurposable drugs may still trigger unexpected side-effects in new contexts. This study introduces a network-based approach to minimize side-effect risk in drug repositioning, focusing on QT interval prolongation, a cardiac side-effect observed in Alzheimer's patients treated with acetylcholinesterase inhibitors. The method integrates Mode-of-Action and Random Walk with Restart analyses to identify repositioning candidates while assessing QT-related risk. This strategy identified promising compounds including acamprosate, tolcapone, sitagliptin, and diazoxide, with potential to mitigate disease pathology. Gene set enrichment analysis was used to computationally assess the compounds' ability to reverse disease-related gene expression signatures.},
}

@article {pmid40791717,
year = {2025},
author = {Andrews, SJ and Mitchell, BA and Tong, T and Bonham, LW and Renton, AE and Zhang, X and Sirota, M and Tosun, D and Yaffe, K and , },
title = {Integrative effects of Telomere Length, Epigenetic Age, and Mitochondrial DNA abundance in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.16.25331683},
pmid = {40791717},
abstract = {BACKGROUND AND OBJECTIVES: Biological age, reflecting the cumulative molecular and cellular damage such as telomere attrition, epigenetic alterations and mitochondrial dysfunction, may better capture age-related decline and Alzheimer's disease (AD) risk than chronological age. Most studies have focused on one measure of biological age and not investigated joint or interactive contributions to AD pathogenesis.

METHODS: We estimated blood-derived telomere length (TL) via qPCR, epigenetic age (DNAm age) using the CausAge clock, and mitochondrial DNA copy number (mtDNAcn) from whole genome sequencing in 640 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; Age: 74.91±7.56, Female: 44.8%, Cognitively Unimpaired: 34.3%, Mild Cognitive Impairment: 52%, AD: 12.9%). Linear mixed-effects models examined the associations and interactions of these markers with cognitive decline for memory, executive function, language ability, visuospatial ability, and global cognition, while linear regression tested associations with cross-sectional AD biomarkers (CSF Aβ 42 , total-tau, pTau 181 , and meta-ROI for cortical thickness and gray matter volume). Models adjusted for baseline age, sex, clinical dementia rating scale, APOE , blood cell composition, and outcome-specific covariates (education and intracranial volume).

RESULTS: Individually, TL and DNAm age, were not associated with cognition, CSF biomarkers, or neuroimaging outcomes, while higher mtDNAcn was associated with lower CSF tau and ptau 181 . Interaction models revealed that mtDNAcn modified the effects of both TL and DNAm age: at higher mtDNAcn, shorter TL predicted poorer global cognition (β = 0.033 ± 0.014, p = 0.020) and older DNAm age predicted poorer language performance (β = -0.059 ± 0.028, p = 0.038). A significant three-way interaction showed that the combination of higher mtDNAcn, longer TL, and older DNAm age was associated with lower grey-matter volume.

DISCUSSION: These findings suggest that increased mtDNAcn may act as a compensatory response to accelerated epigenetic aging and telomere attrition. Our results underscore the importance of evaluating the interplay among multiple biological aging markers when investigating AD pathogenesis.},
}

@article {pmid40791715,
year = {2025},
author = {Xu, Y and Qiao, M and Gunasekaran, TI and Gu, Y and Reyes-Dumeyer, D and Piriz, A and Sanchez, D and Soriano, B and Franco, Y and Coronado, ZD and Recio, P and Mejia, DR and Medrano, M and Lantigua, RA and Honig, L and Wilson, R and Manly, JJ and Brickman, AM and Engelman, CD and Johnson, S and Asthana, S and Vardarajan, B and Mayeux, R},
title = {Polygenic Scores of Core-1 Alzheimer's Disease Biomarkers Predict Early Cognitive and Pathological Change.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.12.25331438},
pmid = {40791715},
abstract = {BACKGROUND: Core-1 biomarkers, such as amyloid PET, capture the earliest biological changes leading to Alzheimer's disease (AD). While APOE is a major genetic factor, the contribution of other variants to Core-1 biomarkers remains unclear. The goal of this study is to determine whether genetic regulators of Core-1 biomarker levels predict AD pathology better than genetic regulators of clinical AD.

METHODS: Among 955 non-Hispanic white individuals, PGSs were built using GWAS of amyloid PET, plasma P-tau181, CSF P-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma P-tau181 and clinical AD GWAS. Baseline and longitudinal associations with plasma biomarkers and cognition were assessed, and replication was conducted in separate cohorts.

RESULTS: The Core-1 biomarker PGSs predicted AD pathology and associated cognitive performance better than the AD PGS in both populations.

DISCUSSION: The Core-1 PGS show improved predictive value for AD-related plasma biomarkers and early cognitive changes.

HIGHLIGHTS: APOE -ε4 explained more variance in plasma P-tau217 than in plasma P-tau181. PGSs based on Core-1 biomarkers outperformed AD PGSs in predicting plasma biomarkers and cognitive decline among asymptomatic individuals in white non-Hispanic and Hispanic individuals. However, the improvement in predictive power was modest and may vary by age.While the variance in P-tau181 and P-tau217 explained by individual Core-1 PGSs remains limited, the distinct genetic signals captured by the best-performing PGSs across different Core-1 biomarkers may provide an opportunity for developing an integrative Core-1 PGS that more effectively predicts plasma P-tau181 and P-tau217 levels than AD-based PGS.

RESEARCH IN CONTEXT: SYSTEMATIC REVIEW: Core-1 biomarkers, such as amyloid PET, capture the earliest biological changes in Alzheimer's disease (AD). The authors reviewed the literature on the association between core-1 biomarker-based polygenic scores (PGS) and plasma biomarkers using traditional sources (e.g., PubMed), meeting abstracts, and presentations. While several studies examined the association between PGS and plasma P-tau181 and P-tau217, most PGSs were based on AD genetic studies and performed poorly in predicting these biomarkers-especially in asymptomatic individuals. No studies have comprehensively assessed Core-1 biomarker-based PGSs in relation to P-tau181, P-tau217, other plasma biomarkers, and cognitive change.INTERPRETATION: Our findings show that Core-1 biomarker-based PGSs outperform AD PGSs in predicting early changes in plasma P-tau181, P-tau217, other non-tau plasma biomarkers, and cognition in asymptomatic White and Caribbean Hispanic individuals.FUTURE DIRECTIONS: The Core-1 PGS offers improved predictive value for AD-related plasma biomarkers and early cognitive changes. Future research should validate these findings using larger genome-wide association studies and explore integrated Core-1 PGSs for P-tau217 and P-tau181, especially as more Core-1 biomarker genetic data become available.},
}

@article {pmid40791680,
year = {2025},
author = {Patel, PJ and Yan, Z},
title = {Epigenomic Aberrations of Histone Methylation in Prefrontal Cortex of Humans with Mild Cognitive Impairment and Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.17.25331659},
pmid = {40791680},
abstract = {Epigenetic mechanisms, particularly histone modifications at gene promoters, are crucial for controlling gene transcription. During the progression of neurodegenerative disorders, epigenomic aberrations may contribute to gene dysregulation, leading to manifestation of symptoms. To test this, we employed a multifaceted approach to investigate how the two key histone methylation marks, H3K4me3 (linked to gene activation) and H3K27me3 (linked to gene suppression), are altered in postmortem prefrontal cortex of humans with Mild Cognitive Impairment (MCI) or Alzheimer's Disease (AD). Compared to controls, MCI and AD exhibited pronounced losses of permissive H3K4me3 peaks at promoters of genes enriched in synaptic plasticity and neurotransmission, and significant gains of H3K4me3 peaks at promoters of genes enriched in transcriptional regulation. AD displayed more substantial H3K4me3 losses on synaptic genes than MCI. Conversely, significant gains of repressive H3K27me3 peaks were observed at synaptic gene promoters in both disease groups, with MCI exhibiting more pronounced H3K27me3 gains on synaptic genes than AD. Weighted Gene Correlation Network Analysis (WGCNA) revealed multiple modules characterizing distinct patterns of gains and losses of H3K4me3 and H3K27me3 during the transition from MCI to AD. Integrative analysis of epigenomic and transcriptomic data indicated that these histone mark alterations were well correlated with the downregulation of synaptic genes and upregulation of transcriptional regulators in AD. This comprehensive profiling uncovers a stage-dependent reorganization of histone modifications at critical gene loci, implicating these events in the molecular cascade of AD pathogenesis. Targeting dysregulated chromatin states may offer novel therapeutic avenues for early intervention of AD.},
}

@article {pmid40791670,
year = {2025},
author = {Perales-Puchalt, J and Mansel, CO and Veatch, OJ},
title = {Variation in APOE ε4 Prevalence and Brain Health Associations by European Descent in White All of Us Participants.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.16.25331679},
pmid = {40791670},
abstract = {IMPORTANCE: The APOE ε4 allele is among the best-established genetic risk factor for Alzheimer's disease. Different ethnic and racial groups have varying APOE ε4 prevalences. The prevalence of APOE ε4 also varies among European regions, yet White Americans are treated as a monolith, potentially impacting recruitment decisions and risk profile estimations.

OBJECTIVE: To test whether White Americans of Southern European descent have a lower prevalence of APOE ε4 than their Northern European descent peers, and secondarily, if APOE ε4-brain health outcomes vary by European descent.

Cross-sectional analyses of the nationwide All of Us cohort study in the United States. Overall inclusion criteria were reporting only White race, and countries of descent from Northern, Central or Southern Europe without overlap. Enrollment opened in May 2018. Analyses were conducted April-June 2025.

EXPOSURES: Regions of European descent (Northern, Central and Southern) from the Basics Survey.

MAIN OUTCOMES AND MEASURES: APOE ε4 using variants rs429358 and rs7412, coded as zero, one or two copies.

RESULTS: Among those aged ≥18 (n=77,676), the percentage of European descent was 7.7% Southern and 64.7% Northern. Age and female sex at birth were 55.5 years and 55.8% among Americans of Southern and 56.3 years and 57.4% among those of Northern European descent. APOE ε4 allele frequency was 17.4% for one and 0.1% for two copies among Americans of Southern, and 24.9% and 2.0% for Northern European descent. Logistic regression models confirmed these differences: compared to Americans of Southern European descent, those of Northern European descent had an Odds Ratio of having one APOE ε4 allele of 1.60 (1.49-1.71), and 2.21 (1.71-2.88) of having two APOE ε4 alleles. European descent moderated associations between APOE ε4 allele frequency and two brain health outcomes (interaction p≤0.10).

CONCLUSIONS AND RELEVANCE: The frequency of APOE ε4 among Americans of Southern European descent was lower than that of Northern European descent and associations with some brain health outcomes varied. Future studies need to use probabilistic samples to confirm these findings. The concept of White race might be too broad when making racial comparisons of APOE ε4 frequency and its effects.

KEY POINTS: Question: Is the prevalence of APOE ε4 reduced when comparing Southern European to Northern European descent American adults who identify as only White race? Findings: In this cross-sectional analysis of a cohort study (n=77,676 American adults), those of Northern European descent had 60% higher odds of having one, and 120% of having two copies of APOE ε4 compared to those of Southern European descent. Meaning: Among White American adults, the prevalence of APOE ε4 differs by region of European descent; future studies need to confirm these findings using genetically inferred ancestry and probabilistic samples with stronger external validity.},
}

@article {pmid40791515,
year = {2025},
author = {Nagarajan, V and Libowitz, CL and Ackley, BD and Wolfe, MS},
title = {A C. elegans model of familial Alzheimer's disease shows age-dependent synaptic degeneration independent of amyloid β-peptide.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.16.665161},
pmid = {40791515},
issn = {2692-8205},
abstract = {UNLABELLED: The membrane-embedded γ-secretase complex is involved in the intramembrane cleavage of ∼ 150 substrates. Cleavage of amyloid precursor protein (APP)-derived substrate C99 generates 38-43-residue secreted amyloid β-peptides (Aβ), with the aggregation-prone 42-residue form (Aβ42) particularly implicated in the pathogenesis of Alzheimer's Disease (AD). However, whether Aβ42 is the primary driver of neurodegeneration in AD remains unclear. Dominant mutations in APP or presenilin-the catalytic component of γ-secretase-cause early-onset familial AD (FAD) and reduce one or more steps in the multi-step processive proteolysis of C99 to Aβ peptides, apparently through stabilization of γ-secretase enzyme-substrate (E-S) complexes. To investigate mechanisms of neurodegeneration in FAD, we developed new C. elegans models co-expressing wild-type or FAD-mutant C99 substrate and presenilin-1 (PSEN1) variants in neurons, allowing intramembrane processing of C99 to Aβ in vivo. We demonstrate that while FAD-mutation of either C99 or PSEN1 leads to age-dependent synaptic loss, proteolytically inactive PSEN1 did not. Designed mutations that allow stable E-S complex formation without Aβ42 or Aβ production likewise result in synaptic degeneration. Moreover, replacement of C99 with variants of a Notch1-based substrate revealed that disrupted processing of another γ-secretase substrate can similarly lead to synaptic degeneration. These results support a model in which synaptic loss can be triggered by toxic, stalled γ-secretase E-S complexes in the absence of Aβ production and not by simple loss of proteolytic function. This new C. elegans system provides a powerful platform to study the role of dysfunctional γ-secretase substrate processing in FAD pathogenesis.

SIGNIFICANCE: Dominantly inherited familial Alzheimer's disease (FAD) is caused by mutations in the enzyme or substrate that produces amyloid β-peptides (Aβ). These mutations alter enzyme processing of substrate to Aβ and can skew production of Aβ to aggregation-prone forms that deposit as pathological plaques. Nevertheless, whether Aβ is the primary driver of AD remains unresolved. Recent evidence supports a model in which loss of neuronal connections in FAD is due to the stalled enzymatic process of Aβ production, rather than the Aβ products. Using the roundworm C. elegans as a genetic model system, we show here that the stalled process itself, rather than Aβ or reduced enzyme activity, can trigger loss of neuronal connections with age in this simple model animal.},
}

@article {pmid40791511,
year = {2025},
author = {Franklin, TC and Bitarafan, S and King, AT and Goodson, M and Rutledge, C and Gajelli, T and Prichard, A and Zepeda, H and Kye, N and Sloan, SA and Wood, L and Singer, AC},
title = {Sensory neurostimulation promotes stress resilience with frequency-specificity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.12.664223},
pmid = {40791511},
issn = {2692-8205},
abstract = {Chronic stress is a major risk factor for neuropsychiatric disorders, acting via increased neuroinflammation and disrupted synaptic plasticity. While non-invasive visual or audiovisual neurostimulation (AV flicker) at 40Hz has been shown to modulate brain immune signaling and improve cognitive performance in mouse models of Alzheimer's disease, its effects in the context of stress remain unknown. Here we show that AV flicker protects against stress-induced behavioral, microglial, astrocytic, and synaptic changes in a sex- and frequency-specific manner. Male and female mice underwent 28 days of chronic unpredictable stress with concomitant daily AV flicker exposure at 10Hz, 20Hz, or 40Hz. Stress-induced behaviors were most effectively mitigated by 10Hz AV flicker in males and 40Hz AV flicker in females. In the medial prefrontal cortex, AV flicker normalized the balance of mature and immature dendritic spines and counteracted stress-induced molecular changes in neurons, microglia, and astrocytes, including in key neuropsychiatric risk genes. These findings show that frequency optimized AV flicker induces resilience to chronic stress.},
}

@article {pmid40791487,
year = {2025},
author = {Pradhan, B and Kumar, ST and Wagner, J and Gallardo, R and Orlando, G and Vleeschouwer, M and Madine, J and Louros, N and Neher, JJ and Rousseau, F and Schymkowitz, J},
title = {Medin drives Aβ40 to adopt Aβ42-like fibril polymorphs in vitro.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.17.665283},
pmid = {40791487},
issn = {2692-8205},
abstract = {Medin, a vascular amyloid derived from MFG-E8, is the most prevalent form of localized human amyloid and co-localizes with Aβ in Alzheimer's disease and, in particular, cerebral amyloid angiopathy (CAA). While it was shown that medin can promote Aβ aggregation, it remains unclear whether this amyloid-amyloid interaction affects the structure of the resulting fibrils. Here, we investigate how medin modulates Aβ40 fibril assembly in vitro using cryo-electron microscopy, aggregation kinetics, and immunogold electron microscopy. We show that medin accelerates Aβ40 aggregation, co-assembles into hybrid fibrils, and modulates fibril morphology. Cryo-EM analysis reveals two fibril populations: one corresponding to a previously described in vitro Aβ40 morphology, and a second, previously unobserved polymorph with Aβ42-like features, including a structured N-terminus and a compact hydrophobic C-terminal core. The presence of a peripheral, unresolved cryo-EM density near the fibril surface suggests that the new polymorph is stabilised through heterotypic interactions, yet the atomic details remain unresolved, likely due to substantial structural heterogeneity. Rather than representing a limitation, this highlights how not all determinants critical for fibril assembly are necessarily ordered or resolvable in the final fibril structure, reflecting the inherent dynamic and heterogeneous nature of amyloid interactions. Our findings provide structural evidence that heterotypic co-aggregation can redirect Aβ40 into distinct conformational states and suggest that dynamic or transient interactions contribute to fibril polymorphism beyond what can be fully captured in static structural models.},
}

@article {pmid40791427,
year = {2025},
author = {Qiu, Y and Hou, Y and Wetzel, L and Caldwell, JZK and Zhu, X and Pieper, AA and Liu, T and Cheng, F},
title = {Cell type-specific master metabolic regulators of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.11.664443},
pmid = {40791427},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) exhibits metabolic heterogeneity; yet, the consequences on metabolic dynamics in a cell-type-specific manner and the underlying metabolite-sensor network basis remain unclear. Here, we show that neurons exhibit a striking decrease in energy and lipid-related metabolic activity, contrasted by an increase in microglial metabolism associated with neuroinflammation. To identify cell-type specific master metabolic regulators of AD underlying the metabolic alterations in AD, we introduce scFUMES (s ingle c ell FU nctional ME tabolite- S ensor), an algorithm integrating single-cell RNA sequencing, interactomics, genomics, transcriptomics, and metabolomics from human brain biobanks. Applied to two AD-vulnerable regions (middle temporal gyrus and dorsolateral prefrontal cortex), scFUMES uncovers hundreds of AD-associated regulators, with neurons and microglia showing the most interactions. Particularly, scFUMES pinpoints genetics-informed master metabolic regulators across AD severity, sex and APOE genotype (e.g., PPARD-glycerol in microglia). Experimental testing reveals that two interaction pairs predicted by scFUMES, neuronal palmitic acid bound fatty acid binding protein 3 and gut metabolite indole-3-propionic acid binding to kynurenine aminotransferase 1, both lower pathological tau species in AD. Collectively, scFUMES systematically maps AD master metabolic regulators, offering insights into cellular metabolic heterogeneity and therapeutic strategies for AD and other AD-related dementia if broadly applied.},
}

@article {pmid40791424,
year = {2025},
author = {Adaikkan, C and Islam, MR and Bozzelli, PL and Sears, M and Parro, C and Pao, PC and Sun, N and Kim, T and Abdelaal, K and Sedgwick, M and Kellis, M and Tsai, LH},
title = {A multimodal approach of microglial CSF1R inhibition and GENUS provides therapeutic effects in Alzheimer's disease mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.04.27.648471},
pmid = {40791424},
issn = {2692-8205},
abstract = {The CSF1R inhibitor PLX3397, an FDA-approved treatment for a rare cancer, has been shown to reduce microglia count, lower inflammation, and increase synaptic markers in mouse models of Alzheimer's disease (AD). However, the effects of PLX3397 on neural function in AD remain largely unknown. Here, we characterized the effects of PLX3397 treatment in 5xFAD mice. While PLX3397 increased synaptic density, it reduced the percentage of neurons phase-locked to gamma oscillations. This neural decoupling was closely associated with gene expression changes related to synapse organization. We investigated whether Gamma ENtrainment Using Sensory (GENUS) stimulation could counterbalance the neural circuit alterations induced by PLX3397. GENUS + PLX3397 restored gamma phase-locking, reshaped gene expression signatures, and improved learning and memory better than either treatment alone in 5xFAD mice. These findings suggest that CSF1R inhibitors like PLX3397 may benefit from a multimodal approach combining microglial targeting with non-invasive sensory stimulation to support neural physiology and improve cognitive function in AD.},
}

@article {pmid40791417,
year = {2025},
author = {Chong Chie, JAK and Persohn, SA and Pandey, RS and Simcox, OR and Salama, P and Territo, PR and , },
title = {Multiscale Metabolic Covariance Networks Uncover Stage-Specific Biomarker Signatures Across the Alzheimer's Disease Continuum.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.10.663714},
pmid = {40791417},
issn = {2692-8205},
abstract = {BACKGROUND: Connectomics studies analyze neural connections and their roles in cognition and disease. Beyond regional comparisons, recent research has revealed inter-regional brain relationships via graph theory of brain network connectivity. Within these networks, path length measures a network's efficiency in communication. These connections can be quantified as inter-subject covariance networks related to functional connectivity, with alterations reported in neurodegenerative diseases.

METHODS: Retrospective analysis of ADNI [18] F-FDG PET images using metabolic covariance analysis and hierarchical clustering was used to assess regional brain networks in subjects from cognitively normal (CN) to AD. We evaluated AD stage changes by calculating whole brain entropy, connection strength, and clustering coefficients. Additionally, estimates of shortest path for positive and negative correlations as a measure of network efficiency. We also developed a novel region set enrichment analysis (RSEA) to detect brain functional changes based on metabolic variations. Results were aligned with transcriptomic signatures and clinical cognitive assessments.

FINDINGS: In AD subjects, whole brain metabolic connectivity revealed an increase in entropy, connection strength, and clustering coefficients, which indicates brain network reorganization as compensatory mechanisms of pathological disruption. As AD advances, path lengths between brain regions decrease from CN to MCI; however, path lengths significantly increased in AD. RSEA indicated functional changes in motor, memory, language, and cognition functions related to disease progression.

INTERPRETATION: Metabolic covariance analysis of whole brain, and regional connectomics, track with AD progression. Moreover, path lengths permitted AD stages determination via alterations in brain connectivity. Furthermore, RSEA facilitated the identification of functional changes based on metabolic readouts.

FUNDING: NIH grant T32AG071444.},
}

@article {pmid40791364,
year = {2025},
author = {Sloand, TJ and Dunham, BP and Niedringhaus, M and West, EA},
title = {Aberrant medial prefrontal cortex activity and flexible behavior in the TgF344-AD rat model of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.10.664159},
pmid = {40791364},
issn = {2692-8205},
abstract = {Cognitive deficits, including deficits in the ability to shift behavior following negative consequences, often precede the accumulation of canonical neuropathological markers (Aβ plaques and tauopathy) and severe dementia in Alzheimer's disease (AD) patients. The Tg-F344-AD rat model exhibits age-dependent AD pathology and memory deficits that recapitulate AD, However, it is unknown how medial prefrontal cortex activity is altered in awake and behaving AD rats during learning and/or flexible behavior. Here we determine the ability of in 6-7month-old TgF344-AD rats to learn reward predictive cues and to shift behavior away from reward-predictive cues following outcome devaluation while recording mPFC neurons. Specifically, AD rats (n=17) and wild-type littermates (n=17) were presented with two distinct cues as conditioned stimuli (CS+) predicting distinct outcomes. A conditioned taste aversion to one outcome was induced, after which the rats were tested post-devaluation to evaluate their ability to avoid the CS+ associated with the devalued outcome. We found a loss of motivated behavior during learning and a loss of flexible behavior during testing in 6-7-month-old AD rats relative to WT littermate controls. In addition, there was differential aberrant mPFC encoding of cue-outcome associations in AD rats during conditioning and following outcome devaluation. Specifically, AD animals show fewer neurons during conditioning that encode both the cue and the outcome than WT animals. Also, AD animals also showed a greater proportion of neurons that exhibited an excited response to reward predictive cues post-outcome devaluation. Together, these data contribute to our understanding of alterations in mPFC that may underline prodromal AD behavioral deficits to inform future treatments.},
}

@article {pmid40791248,
year = {2025},
author = {Liu, Y and Sundman, MH and Hinderaker, D and Yu-Chin Chen, A and Green, JM and Haaheim, LG and Siu, HM and Jezerc, C and Lai, K and Chen, C and Guss, P and Chou, YH},
title = {Advancing the modified face name associative memory exam in cognitive aging research: insights into connectomic correlates and task reliability.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1592678},
pmid = {40791248},
issn = {1663-4365},
abstract = {INTRODUCTION: The shift toward earlier detection in the Alzheimer's disease (AD) continuum underscores the need for more sensitive cognitive outcome assessments (COAs). Traditional COAs may lack precision in capturing cognitive dysfunction during preclinical stages. The Face-Name Associative Memory Exam (FNAME), a cross-modal task that integrates verbal and non-verbal memory, offers enhanced sensitivity and has shown associations with amyloid-β burden across the AD continuum, even in asymptomatic older adults.

METHODS: This manuscript reports on two experiments, broadening insights into this promising COA. Experiment 1 (descriptive observational, repeated-measures design) (N = 85) evaluates the alternate form reliability of a modified FNAME (mFNAME) by serially administering eight distinct versions of the task, revealing good reliability for mFNAME metrics and the absence of significant practice effects. Experiment 2 (cross-sectional observational design) (N = 32) examines structural and functional network topology to investigate neural correlates of mFNAME performance in non-demented older adults.

RESULTS: Experiment 1 demonstrated good alternate form reliability with no significant practice effect. Experiment 2 revealed significant associations between mFNAME performance and network properties like global efficiency, local efficiency, and system segregation in the default mode network (DMN) and medial temporal network (MTN). Subsequent analyses into more granular elements of the MTN and DMN revealed latent variables accounting for up to 44% of the covariance in mFNAME performance.

DISCUSSIONS: These findings deepen the understanding of the FNAME's psychometric properties and the neural correlates underlying task performance, providing insights into its utility as a sensitive COA early in the continuum of AD and related dementias.},
}

@article {pmid40791247,
year = {2025},
author = {Zou, B and Xiang, J and Zhang, M and Huang, J and Feng, C},
title = {A bibliometric analysis of the immune system and cognitive impairment: trends from 1985 to 2024.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1587575},
pmid = {40791247},
issn = {1663-4365},
abstract = {BACKGROUND: Cognitive impairment is closely linked to immune system dysfunction, with increasing research interest in the underlying mechanisms and potential therapeutic targets. Bibliometric analysis provides a comprehensive approach to understanding research trends, influential contributions, and emerging topics in this interdisciplinary field.

METHODS: This study conducted a bibliometric analysis of publications related to the immune system and cognitive impairment from 1985 to 2024, retrieved from the Web of Science Core Collection. CiteSpace (6.4. R1), VOSviewer (1.6.20), and R-bibliometrix (R 4.3.0) were employed to analyze publication trends, co-authorship networks, keyword clustering, and co-citation patterns. Key metrics, including the H-index, G-index, and M-index, were computed to assess academic influence.

RESULTS: A total of 3,737 publications were analyzed, revealing a significant increase in research output since 2021. The United States and China emerged as leading contributors, with a robust presence of collaborative networks. Keyword and co-citation analysis identified core research themes, including neuroinflammation, microglia activation, gut microbiota, TREM2-mediated immune responses, and inflammasomes. Emerging topics such as the gut-brain axis, metabolic syndromes, and immune regulation in neurodegenerative diseases have gained prominence in recent years. Highly cited papers highlighted the role of immune dysregulation in Alzheimer's disease, multiple sclerosis, and HIV-associated neurocognitive disorders.

CONCLUSION: This bibliometric analysis provides a comprehensive overview of research trends in immune-related cognitive impairment. The findings indicate an increasing focus on neuroinflammatory mechanisms, immune cell interactions, and novel immunotherapeutic strategies. Future research is expected to further explore the gut-immune-brain axis and precision medicine approaches in managing cognitive disorders. These findings may facilitate early detection strategies and novel interventions targeting immune-cognitive interactions, such as gut-brain axis modulation.},
}

@article {pmid40791246,
year = {2025},
author = {Yu, P and Shen, L and Tang, L},
title = {Multimodal DTI-ALPS and hippocampal microstructural signatures unveil stage-specific pathways in Alzheimer's disease progression.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1609793},
pmid = {40791246},
issn = {1663-4365},
abstract = {OBJECTIVE: Develop a multimodal biomarker framework integrating DTI-ALPS (Diffusion Tensor Imaging along the Perivascular Space), hippocampal diffusivity, and CSF profiles for staging Alzheimer's disease (AD) progression across the HC → MCI → AD continuum.

METHODS: Cross-sectional analysis of 60 age-matched participants [18 healthy controls (HC), 20 with mild cognitive impairment (MCI), and 22 with Alzheimer's disease (AD)] combining 3 T MRI-derived biomarkers (bilateral hippocampal fractional anisotropy (FA) and mean diffusivity (MD), and DTI-ALPS). Cerebrospinal fluid (CSF) analysis (Aβ42, p-tau181, t-tau), and cognitive assessments (MMSE, MoCA). Statistical analyses included ANOVA with Bonferroni correction, Pearson correlations, and ROC curve evaluation for disease classification.

RESULTS: DTI-ALPS exhibited a progressive decline (HC: 1.31 ± 0.12 → MCI: 1.26 ± 0.09 → AD: 0.87 ± 0.19; p < 0.001 for AD vs. HC/MCI). Bilateral FA reductions plateaued in MCI (left: 0.57 ± 0.11 vs. HC: 0.82 ± 0.07, p < 0.001; right: 0.57 ± 0.11 vs. HC: 0.80 ± 0.07, p < 0.001) without further progression at the AD stage. MD showed a right-lateralized progression (HC → MCI → AD: left 0.53 → 0.74 → 0.78, right 0.51 → 0.71 → 0.77; p < 0.001), with a significant increase only in right MD from MCI to AD (p = 0.014). CSF biomarkers revealed a hierarchical depletion of Aβ42 (AD: 370.7 ± 145.9 vs. HC: 910.8 ± 191.5 pg./mL, p < 0.001) and accumulation of tau (t-tau: AD>MCI > HC, p < 0.001). Receiver operating characteristic (ROC) analysis identified right hippocampal MD and t-tau as optimal classifiers for AD.

CONCLUSION: The framework reveals distinct biomarker trajectories: DTI-ALPS distinguishes symptomatic AD from preclinical stages, while right hippocampal MD progression reflects tau-mediated neurodegeneration. Early FA reductions in MCI combined with CSF profiles suggest a hierarchical staging model: amyloid-associated perivascular dysfunction is associated with asymmetric tau-driven hippocampal degeneration. This multimodal approach provides clinically actionable biomarkers for AD progression monitoring.},
}

@article {pmid40791147,
year = {2025},
author = {Ji, X and Wang, J and Lan, T and Zhao, D and Xu, P},
title = {Gut microbial metabolites and the brain-gut axis in Alzheimer's disease: A review.},
journal = {Biomolecules & biomedicine},
volume = {},
number = {},
pages = {},
doi = {10.17305/bb.2025.12921},
pmid = {40791147},
issn = {2831-090X},
abstract = {Alzheimer's disease (AD) is increasingly recognised as a disorder that extends beyond the brain, with accumulating evidence implicating gut microbiota-derived metabolites in its onset and progression. This narrative review synthesises 92 peer-reviewed animal, human and meta-analytic studies published between 2010 and 2025 that investigated short-chain fatty acids (SCFAs), tryptophan-derived indoles and kynurenines, trimethylamine N-oxide (TMAO) and secondary bile acids in the context of AD. Collectively, the literature shows that SCFAs support blood-brain-barrier integrity, dampen microglial reactivity and enhance synaptic plasticity, yet can paradoxically amplify β-amyloid (Aβ) deposition under germ-free or supraphysiological conditions, highlighting the importance of host status and dosing. Beneficial indole metabolites such as indole-3-propionic acid counter oxidative stress, strengthen intestinal and cerebral barriers and suppress pro-inflammatory cascades, whereas a shift toward neurotoxic kynurenines correlates with cognitive decline. TMAO emerges as a consistently deleterious metabolite that aggravates endothelial dysfunction, neuroinflammation and Aβ aggregation; dietary precursor restriction and microbial enzyme inhibitors are therefore being explored as mitigation strategies. Secondary bile acids and polyphenol derivatives further modulate mitochondrial bioenergetics and NF-κB signalling, broadening the therapeutic landscape. Multi-omics profiling reveals that AD patients typically exhibit reduced SCFAs and indoles but elevated TMAO, changes that scale with Mini-Mental State Examination scores, brain atrophy and cerebrospinal Aβ42 levels. Early probiotic and faecal-microbiota-transplant trials have begun to normalise these metabolite profiles and yield modest cognitive benefits, underscoring translational potential. Altogether, gut-derived metabolites are not passive by-products but active modulators of neural, immune and metabolic circuits along the microbiota-gut-brain axis; their targeted manipulation and standardised metabolomic assessment could enable earlier diagnosis and precision microbiome-based interventions for AD, a promise that now warrants validation in large, longitudinal and mechanistically informed clinical studies.},
}

@article {pmid40791103,
year = {2025},
author = {Chu, C and Wang, Y and Ma, L and Jin, L and Pan, Y},
title = {Development and validation of a predictive model to forecast the cerebrovascular risk burden in older people using the NACC and ROSMAP dataset.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70543},
doi = {10.1002/alz.70543},
pmid = {40791103},
issn = {1552-5279},
support = {23AARF-1020292/ALZ/Alzheimer's Association/United States ; GNT2022203//National Health and Medical Research Council/ ; GNT2007912//National Health and Medical Research Council/ ; },
mesh = {Humans ; Male ; Female ; Aged ; *Cerebrovascular Disorders/epidemiology/diagnosis ; Risk Assessment/methods ; Aged, 80 and over ; Risk Factors ; Algorithms ; },
abstract = {INTRODUCTION: The integrity of the brain's vascular system is vital for neuronal health. Cerebrovascular microbleeds, microinfarcts, and infarcts (defined as cerebrovascular disease burden) contribute to stroke and cognitive impairment. Here, we developed and validated the first model, the Cerebrovascular Disease Burden Risk Score (CDBRS) for individualized risk prediction.

METHODS: Leveraging the AutoScore and AutoScore-Ordinal algorithms, the CDBRS was developed using National Alzheimer's Coordinating Center (NACC) data and externally validated on Religious Orders Study and Memory and Aging Project (ROSMAP) data. The CDBRS was evaluated using mean area under the receiver operating characteristic curve (mAUC), Harrell's generalized c-index, sensitivity, and specificity.

RESULTS: The CDBRS achieved a promising predictive performance and outperformed the respective baseline models. The performance of the CDBRS remains good on external validation.

DISCUSSION: CDBRS can possibly aid in identifying individuals with high risks of cerebrovascular microbleeds, microinfarcts, and infarcts, to enable closer monitoring and personalized management. Further validation of CDBRS in a diverse population is warranted.

HIGHLIGHTS: Microbleeds, microinfarcts, and infarcts often precede clinical stroke and vascular dementia. We developed and validated the Cerebrovascular Disease Burden Risk Score (CDBRS), a new and interpretable model for stratifying the risk of microbleeds, microinfarcts, and infarcts in older adults. This tool developed using National Alzheimer's Coordinating Center (NACC) participants data achieved promising predictive performance in Religious Orders Study and Memory and Aging Project (ROSMAP) participants. The robust predictive performance warrants its clinical validation is prospective studies.},
}

Humans
Male
Female
Aged
*Cerebrovascular Disorders/epidemiology/diagnosis
Risk Assessment/methods
Aged, 80 and over
Risk Factors
Algorithms

@article {pmid40791093,
year = {2025},
author = {Montoliu-Gaya, L and Valeriano-Lorenzo, E and Ashton, NJ and López-González, FJ and Lantero-Rodriguez, J and Ruiz-González, A and Pastor, AB and Frades, B and Zea-Sevilla, MA and Valentí, M and Ruiz-Valderrey, P and Saiz, L and Burgueño-García, I and López-Martínez, MJ and Del Ser, T and Brinkmalm, G and Zetterberg, H and Rábano, A and Gobom, J and Blennow, K and Sánchez-Juan, P},
title = {Plasma tau biomarkers are distinctly associated with tau tangles and decreased with Lewy body pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70562},
doi = {10.1002/alz.70562},
pmid = {40791093},
issn = {1552-5279},
support = {A2022015F//Brightfocus Foundation/ ; //Swedish Dementia Foundation/ ; //Gun and Bertil Stohnes Foundation/ ; //Åhlén-stifelsen/ ; AF-968621//Alzheimerfonden/ ; //Gamla Tjänarinnor Foundation/ ; #2017-00915//Swedish Research Council/ ; #RDAPB-201809-2016615//Alzheimer Drug Discovery Foundation/ ; #AF-742881//Swedish Alzheimer Foundation/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; #1R01AG068398-01/NH/NIH HHS/United States ; ZEN-21-848495//Alzheimer's Association 2021 Zenith Award/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #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//NEuroBioStand/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; //Familjen Rönströms Stiftelse/ ; //Stiftelsen för Gamla Tjänarinnor/ ; #FO2017-0243//Hjärnfonden, Sweden/ ; #FO2022-0270//Hjärnfonden, Sweden/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; //Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; //Queen Sofia Foundation/ ; },
mesh = {Humans ; *tau Proteins/blood ; Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/pathology/blood ; Aged ; *Neurofibrillary Tangles/pathology ; Phosphorylation ; *Lewy Bodies/pathology ; Brain/pathology ; Aged, 80 and over ; *Lewy Body Disease/pathology/blood ; Cohort Studies ; },
abstract = {INTRODUCTION: Plasma-to-autopsy studies are essential to understand how tau blood biomarkers change in relation to Alzheimer's disease (AD) brain pathology and how they are influenced by brain co-pathologies and comorbidities.

METHODS: Plasma samples from 102 brain donors of the Vallecas Alzheimer Reina Sofia cohort were analyzed using a mass spectrometry method to measure the levels of six phosphorylated and two non-phosphorylated tau biomarkers.

RESULTS: In cases with high pathological burden of AD, phosphorylated tau (p-tau)217 showed associations with neurofibrillary tangle counts across all regions, while p-tau205 was primarily linked to the frontal cortex, and the non-phosphorylated tau peptides were linked to the temporal cortex. Plasma tau levels decreased as Lewy body pathology progressed, even among individuals at the same tau Braak stage. All plasma biomarkers correlated with creatinine levels, as a marker of renal dysfunction, but this effect was mitigated when using the ratios phospho/non-phospho.

DISCUSSION: Understanding how plasma tau biomarkers are influenced by co-pathologies and comorbidities is crucial for their accurate implementation.

HIGHLIGHTS: The plasma phosphorylated tau (p-tau)217 ratio, followed by the p-tau205 ratio and p-tau217, were the best-performing biomarkers for detecting neuropathologically confirmed Alzheimer's disease (AD). In high AD cases, p-tau217 showed associations with neurofibrillary tangle (NFT) counts across all regions, while p-tau205 was primarily linked to the frontal cortex, and non-phosphorylated tau peptides were linked to the temporal cortex. We observed a decline in plasma tau levels as Lewy body pathology progressed, even among individuals at the same tau Braak stage. All plasma biomarkers correlated with creatinine levels, as a marker of renal dysfunction, but this effect was mitigated when using the ratios. Plasma p-tau199 displayed a distinct behavior compared to other p-tau species, showing no association with NFT counts in any brain region, but demonstrating significant correlations with brain volume and an effect on survival time.},
}

Humans
*tau Proteins/blood
Biomarkers/blood
Male
Female
*Alzheimer Disease/pathology/blood
Aged
*Neurofibrillary Tangles/pathology
Phosphorylation
*Lewy Bodies/pathology
Brain/pathology
Aged, 80 and over
*Lewy Body Disease/pathology/blood
Cohort Studies

@article {pmid40791064,
year = {2025},
author = {Rodrigues, CC and Carvalho, V and Sotero, FD and Mulroy, E and Guedes, LC},
title = {Efficacy and safety of cholinesterase inhibitors and memantine for cognitive symptoms in patients with Huntington's disease: A systematic review.},
journal = {Journal of Huntington's disease},
volume = {},
number = {},
pages = {18796397251367689},
doi = {10.1177/18796397251367689},
pmid = {40791064},
issn = {1879-6400},
abstract = {BackgroundHuntington's Disease (HD) is an autosomal dominant neurodegenerative disorder. Clinical features encompass a broad spectrum of movement disorders, psychiatric and cognitive symptoms, often progressing to dementia and imposing a substantial burden on patients and their families. While cholinesterase inhibitors and memantine are often used for symptomatic treatment of Alzheimer's Disease and other dementias, there is currently no approved medication for treating cognitive symptoms in HD.ObjectiveWe aim to review, summarize, and appraise evidence from the literature for the use of cholinesterase inhibitors and memantine in the treatment of cognitive symptoms in patients with HD.MethodsA searched was conducted in PubMed and SCOPUS, from inception until February 2024, for Randomized Clinical Trials (RCTs), open-label, and case-control studies. Quality appraisal was performed using ROBINS-I and ROB2 for non-randomized studies and RCTs, respectively.ResultsFive eligible studies (three RCTs, one extension study, and one retrospective case-control), exploring the use of rivastigmine (n = 3), memantine (n = 1), and donepezil (n = 1) were found. Only two had a follow-up period longer than eight months. Previous cognitive functioning was not specified in three out of five studies. Cognitive measures varied widely, with Unified Huntington's Disease Rating Scale and Mini-Mental State Exam being used more frequently. None of the studies showed a significant improvement in cognitive function. Side effects occurred in up to 50% of patients and were usually considered mild.ConclusionsThere is insufficient evidence in the literature to support the use of cholinesterase inhibitors or memantine for cognitive symptoms in patients with HD.},
}

@article {pmid40791046,
year = {2025},
author = {Sun, Q and Ma, L and Zhao, L and Ye, M and Zhu, S and Zhou, J},
title = {Investigating the Correlation Between Gray Matter Volume Changes and Cognitive Function Among Alzheimer's Disease Patients: An MRI-Based Analysis.},
journal = {Actas espanolas de psiquiatria},
volume = {53},
number = {4},
pages = {756-765},
doi = {10.62641/aep.v53i4.1914},
pmid = {40791046},
issn = {1578-2735},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/physiopathology ; *Gray Matter/diagnostic imaging/pathology ; *Magnetic Resonance Imaging ; Male ; Female ; Aged ; Retrospective Studies ; *Cognitive Dysfunction/diagnostic imaging/pathology ; *Cognition/physiology ; Middle Aged ; Organ Size ; Aged, 80 and over ; Case-Control Studies ; },
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and memory dysfunction. This study aims to explore changes of gray matter volume and their relationship with cognitive and memory function in AD patients using magnetic resonance imaging-based analysis.

METHODS: This retrospective study analyzed the clinical data from 80 AD patients (AD group) and 45 patients with mild cognitive impairment (MCI group) treated in the hospital between January 2021 and December 2022. Furthermore, 43 healthy adults (control group) were also included for comparison. All the participants underwent a brain magnetic resonance imaging (MRI) examination. These three groups were comparatively analyzed for brain MRI imaging characteristics, changes of gray matter volume, as well as their cognitive and memory functions. Based on gray matter volume, AD patients were divided into the low-volume (37 cases) and high-volume (43 cases) groups using the K-mean clustering method. Furthermore, changes of cognitive and memory function across these two subgroups were compared. The correlation among gray matter volume, cognitive, and memory function across AD patients was assessed using Pearson correlation analysis. Additionally, predictive abilities of gray matter volume in severe cognitive impairment were determined employing receiver operating characteristic (ROC) curve analysis.

RESULTS: The gray matter volume, percentage of gray matter volume, scores of mini-mental state examination (MMSE), and California verbal learning test (CVLT-II) were significantly decreased across the control, MCI, and AD groups (p < 0.05). Compared to the control group, gray matter volume was reduced in the AD and MCI groups. Compared to the high-volume group, gray matter volume, percentage of gray matter volume, scores of MMSE and CVLT-II were decreased in the low-volume group (p < 0.05). Gray matter volume and gray matter volume percentage were positively correlated with scores of MMSE, immediate memory, delayed recall, cue recall, and long-delayed recognition (gray matter volume r = 0.384/0.334/0.308/0.251/0.333; percentage of gray matter volume r = 0.584/0.319/0.299/0.257/0.298; p < 0.001). The area under curve (AUC) for gray matter volume and gray matter volume percentage in predicting severe cognitive impairment were 0.833 (95% CI: 0.747-0.919) and 0.810 (95% CI: 0.715-0.904), respectively (p < 0.001), with sensitivity of 95.24% and 90.48%, and specificity of 66.10% and 67.80%, respectively.

CONCLUSION: MRI is a useful tool for evaluating changes of gray matter volume in AD patients. The changes in gray matter volume are strongly correlated with cognitive and memory functions, which serve as a reliable predictor of severe cognitive impairment in AD patients. Furthermore, MRI provides robust imaging evidence for identifying AD patients at risk of severe cognitive impairment.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology/physiopathology
*Gray Matter/diagnostic imaging/pathology
*Magnetic Resonance Imaging
Male
Female
Aged
Retrospective Studies
*Cognitive Dysfunction/diagnostic imaging/pathology
*Cognition/physiology
Middle Aged
Organ Size
Aged, 80 and over
Case-Control Studies

@article {pmid40791040,
year = {2025},
author = {Yin, C and Chen, L and Wang, J and Zhao, W},
title = {Study on Serological Markers and Brain Structural Changes in Early Clinical Stage of Alzheimer's Disease in Cold Regions.},
journal = {Actas espanolas de psiquiatria},
volume = {53},
number = {4},
pages = {669-682},
doi = {10.62641/aep.v53i4.1936},
pmid = {40791040},
issn = {1578-2735},
mesh = {Humans ; *Alzheimer Disease/blood/pathology/diagnostic imaging/diagnosis ; Male ; Female ; Biomarkers/blood ; *Cognitive Dysfunction/blood/diagnostic imaging/pathology ; Amyloid beta-Peptides/blood ; Retrospective Studies ; Aged ; *Brain/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Middle Aged ; MicroRNAs/blood ; Peptide Fragments/blood ; Apolipoproteins E/blood/genetics ; },
abstract = {BACKGROUND: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) represent early clinical manifestations of Alzheimer's disease (AD). Recent research has highlighted serum markers and changes in brain structure as promising tools for diagnosing cerebral disorders. This study investigated serum biomarkers and brain structural changes in the early clinical stage of AD affected individuals residing in a cold region.

METHODS: Clinical data from patients with SCD or MCI and from normal controls, who were tested at Hongqi Hospital Affiliated to Mudanjiang Medical College from January 2018 to December 2023, were retrospectively analysed. According to clinical classification, the patients were categorised into SCD (n = 60), MCI (n = 60) and normal control groups (n = 70). The magnetic resonance imaging data, serum levels of amyloid β 1-40/42, exosomal miRNA (34a/34c/135a) and apolipoprotein E (ApoE) genotype were collected and analysed.

RESULTS: The mean diffusivity values in the bilateral parahippocampal gyrus, inferior longitudinal bundle, right inferior fronto-occipital tract and posterior cingulate gyrus in the SCD group decreased relative to those of the MCI group (all p < 0.05). Conversely, the fractional anisotropy values in the bilateral parahippocampal gyrus, inferior fronto-occipital tract, inferior longitudinal tract and posterior cingulate gyrus in the SCD group increased (all p < 0.05). Compared with the normal control group, the MCI and SCD groups showed elevated levels of serum Aβ1-40 and Aβ1-42 and exosomal miRNA-34a and miRNA-34c (all p < 0.05) and decreased exosomal miRNA-135a expression (p < 0.05). The serum levels of Aβ1-40, Aβ1-42 and exosomal miRNA-34a and miRNA-34c in the SCD group were lower than those in the MCI group (all p < 0.05), whereas miRNA-135a level was higher (p < 0.05). The proportions of ApoE ε3/3 in the normal control group was the highest (62.86%), and the proportions of ApoE ε2/4, ε3/4 and ε4/4 in the MCI group were the highest (38.33%, 26.67% and 10.00%, respectively).

CONCLUSION: Changes in brain structure and serum biomarkers (miRNAs and Aβ) are evident in the early stages of AD, and the proportion of ApoE alleles vary in early AD. These findings may contribute to the development of an early recognition model for AD.},
}

Humans
*Alzheimer Disease/blood/pathology/diagnostic imaging/diagnosis
Male
Female
Biomarkers/blood
*Cognitive Dysfunction/blood/diagnostic imaging/pathology
Amyloid beta-Peptides/blood
Retrospective Studies
Aged
*Brain/pathology/diagnostic imaging
Magnetic Resonance Imaging
Middle Aged
MicroRNAs/blood
Peptide Fragments/blood
Apolipoproteins E/blood/genetics

@article {pmid40791028,
year = {2025},
author = {Li, W and Jiang, J and Ren, Q and Zhao, M and Wang, L and Yang, S and Jiang, S and Jiang, T and Zhang, H and Xu, J},
title = {Development of a Predictive Model for the Progression of Subjective Cognitive Decline: A Longitudinal Study.},
journal = {Brain and behavior},
volume = {15},
number = {8},
pages = {e70719},
doi = {10.1002/brb3.70719},
pmid = {40791028},
issn = {2162-3279},
support = {2023ZD0505804//Noncommunicable Chronic Diseases-National Science and Technology Major project/ ; 2024YFF0507503//National key R&D Program of China/ ; 202301AS070037//Key Project of Yunnan Provincial Department of Science and Technology/ ; 202305AK340001//Key Project of Yunnan Provincial Department of Science and Technology/ ; 81870821//National Natural Science Foundation of China/ ; 82071187//National Natural Science Foundation of China/ ; 82360387//National Natural Science Foundation of China/ ; 82471212//National Natural Science Foundation of China/ ; 7254343//Beijing Municipal Natural Science Foundation/ ; },
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnosis/diagnostic imaging ; Male ; Female ; Disease Progression ; Longitudinal Studies ; Aged ; Middle Aged ; Alzheimer Disease/physiopathology ; Sleep Quality ; Risk Factors ; Cerebrovascular Circulation/physiology ; Nomograms ; },
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is a preclinical stage of Alzheimer's disease (AD). However, the factors influencing SCD progression remain unclear. It is necessary to develop a model for predicting cognitive progression in SCD.

METHODS: 96 participants with SCD and 36 healthy controls (HCs) were enrolled from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1 and June 30, 2022. Of these, 70 completed approximately 12 months of follow-up visits. Clinical, cognitive assessment, and neuroimaging data were collected. Cox proportional-hazard regression models were used to investigate the risk factors and construct a nomogram.

RESULTS: Compared to HCs, participants with SCD had higher Pittsburgh Sleep Quality Index (PSQI) scores, indicating they had poorer sleep quality, and had higher cerebral blood flow (CBF) in bilateral hippocampus, thalamus, and left precuneus (all p < 0.05). Poorer sleep quality and left precuneus CBF were independently associated with SCD progression (all p < 0.05). The nomogram constructed with these factors achieved good discriminative ability, with an AUC of 0.785 (95% CI: 0.609-0.960) and a coherence index of 0.840 (95% CI: 0.733-0.948). The calibration curves showed significant agreement between the model and actual observations, and the decision curve analysis of the model showed clinical benefit.

CONCLUSIONS: A predictive model for SCD progression constructed based on risk factors including PSQI scores and left precuneus CBF showed good accuracy and discrimination ability, and it may provide valuable insights for early stage screening of AD.},
}

Humans
*Cognitive Dysfunction/physiopathology/diagnosis/diagnostic imaging
Male
Female
Disease Progression
Longitudinal Studies
Aged
Middle Aged
Alzheimer Disease/physiopathology
Sleep Quality
Risk Factors
Cerebrovascular Circulation/physiology
Nomograms

@article {pmid40791001,
year = {2025},
author = {Moon, H and Kim, YJ and Seo, SW and Shin, JS and Na, DL and Chin, J and Jang, H},
title = {Utility of the Seoul Cognitive Status Test to detect amyloid status in mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251360401},
doi = {10.1177/13872877251360401},
pmid = {40791001},
issn = {1875-8908},
abstract = {BackgroundInvestigating amyloid-β (Aβ) status could offer clinical implications for the identification of and intervention for individuals at higher risk of dementia due to Alzheimer's disease (AD). The use of computerized cognitive tests has been considered valuable in detecting Aβ positivity.ObjectiveThis study aims to examine the predictive accuracy of the Seoul Cognitive Status Test (Seoul CST) for Aβ-positive mild cognitive impairment (Aβ+ MCI).MethodsA total of 138 patients with MCI who completed the Seoul CST and underwent Aβ positron emission tomography (PET) were included in this study.ResultsParticipants with Aβ+ MCI performed worse in the backward task of the Visual Span Test and all memory tasks except the immediate recall of the Word Place Association Test. The composite score was developed by averaging the age-, sex-, and education-adjusted Z-scores of the tasks showing significant differences between Aβ+ and Aβ- (Aβ-negative) MCI. This composite score exhibited adequate accuracy in distinguishing between Aβ+ and Aβ- MCI (area under the curve: 0.788, 95% confidence interval: 0.703-0.872).ConclusionsThe findings suggest that the Seoul CST may contribute to screening MCI patients who are likely to be Aβ+.},
}

@article {pmid40790925,
year = {2025},
author = {Dodel, R and Frölich, L},
title = {Donanemab for Alzheimer's disease: from preclinical research to the clinical application.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737175.2025.2546868},
pmid = {40790925},
issn = {1744-8360},
abstract = {INTRODUCTION: Donanemab (donanemab; Kisunla) is a humanized IgG1 monoclonal antibody specifically targeting a modified form of β-amyloid found predominantly within plaques (characterized as N-terminal pyroglutamate Aβ). Recently, it has gained approval for the use in early -stage Alzheimer's disease (AD) encompassing mild cognitive impairment due to AD or mild AD with confirmed brain amyloid pathology.

AREAS COVERED: This drug profile discusses donanemab's function, clinical effectiveness, safety, tolerability, health economics, access challenges, and future prospects. This article is based on literature that was derived from PubMed.

EXPERT OPINION: Donanemab is the third monoclonal antibody introduced for the treatment of individuals in the early stage of AD. While critical dialogue continues regarding the potential impacts and role of antibody therapies, its approval signifies considerable progress in addressing the underlying pathology of AD. The authors are confident in the potential of antibodies against Aβ as a promising treatment option and foresee exciting advancements. However, further research is needed on trials extending beyond 18 months of follow-up, postmarketing surveillance, and the application of donanemab in combination with existing treatments and lifestyle interventions. Additionally, significant knowledge gaps and implementation limitations persist and must be addressed.},
}

@article {pmid40790826,
year = {2025},
author = {},
title = {In brief: A new donanemab (Kisunla) dosing regimen for Alzheimer's disease.},
journal = {The Medical letter on drugs and therapeutics},
volume = {67},
number = {1735},
pages = {134-135},
doi = {10.58347/tml.2025.1735d},
pmid = {40790826},
issn = {1523-2859},
}

@article {pmid40790741,
year = {2025},
author = {McGeachan, RI and Ewbank, L and Watt, M and Sordo, L and Malbon, A and Salamat, MKF and Tzioras, M and De Frias, JM and Tulloch, J and Houston, F and Gunn-Moore, D and Spires-Jones, TL},
title = {Amyloid-Beta Pathology Increases Synaptic Engulfment by Glia in Feline Cognitive Dysfunction Syndrome: A Naturally Occurring Model of Alzheimer's Disease.},
journal = {The European journal of neuroscience},
volume = {62},
number = {3},
pages = {e70180},
doi = {10.1111/ejn.70180},
pmid = {40790741},
issn = {1460-9568},
support = {ARUK-EG2016A-6//Alzheimer's Research UK/ ; UKDRI-Edin005//UK Dementia Research Institute/ ; 225442/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cats ; *Amyloid beta-Peptides/metabolism ; *Synapses/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; Disease Models, Animal ; *Cognitive Dysfunction/pathology/metabolism ; *Neuroglia/pathology/metabolism ; Male ; Female ; Plaque, Amyloid/pathology ; Microglia/pathology/metabolism ; *Cat Diseases/pathology/metabolism ; Brain/pathology/metabolism ; },
abstract = {Feline cognitive dysfunction syndrome (CDS; a.k.a. feline dementia) is an age-related neurodegenerative disorder, comparable to dementia in people, characterised by behavioural changes such as increased vocalisation, altered social interactions, sleep-wake cycle, disorientation and house-soiling. Although the underlying mechanisms remain poorly understood, pathologies similar to those observed in Alzheimer's disease (AD) have been identified in the brains of aged or CDS-affected cats, including brain atrophy, neuronal loss, amyloid-beta plaques, tau pathology and cerebral amyloid angiopathy. Neuroinflammation and synapse loss, other important hallmarks of AD, may also play important roles in feline ageing and CDS, but these are yet to be explored. Several mechanisms of synapse loss have been described in human AD and mouse models of amyloidopathy, including synaptic accumulation of amyloid-beta and the aberrant induction of synaptic engulfment by microglia and astrocytes. In this study, immunohistochemistry and confocal microscopy were used to examine the parietal cortex of young (n = 7), aged (n = 10) and CDS-affected (n = 8) cats. Linear mixed effect modelling revealed that amyloid-beta accumulates within synapses in the aged and CDS-affected brain. Additionally, in the aged and CDS groups, there was microgliosis, astrogliosis and increased synaptic engulfment by microglia and astrocytes in regions with Aβ plaques. Further, microglia and astrocytes show increased internalisation of amyloid-beta-containing synapses near plaques. These findings suggest that amyloid-beta exerts a pathogenic effect in the feline brain, with mechanisms mirroring those seen in human AD. Importantly, these results support the use of feline CDS as a naturally occurring, translational model of Alzheimer's disease, offering valuable insights into AD pathogenesis and potential therapeutic targets.},
}

Animals
Cats
*Amyloid beta-Peptides/metabolism
*Synapses/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
Disease Models, Animal
*Cognitive Dysfunction/pathology/metabolism
*Neuroglia/pathology/metabolism
Male
Female
Plaque, Amyloid/pathology
Microglia/pathology/metabolism
*Cat Diseases/pathology/metabolism
Brain/pathology/metabolism

@article {pmid40790613,
year = {2025},
author = {Li, B and Wang, S and Kerman, B and Hugo, C and Shwab, EK and Shu, C and Chiba-Falek, O and Arvanitakis, Z and N Yassine, H},
title = {Microglial States Are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70189},
doi = {10.1111/acel.70189},
pmid = {40790613},
issn = {1474-9726},
support = {//Tiny Foundation/ ; //Vranos Foundation/ ; P30AG066530/AG/NIA NIH HHS/United States ; P30AG72975/AG/NIA NIH HHS/United States ; R01AG054434/AG/NIA NIH HHS/United States ; R01AG055770/AG/NIA NIH HHS/United States ; R01AG057522/AG/NIA NIH HHS/United States ; R01AG067063/AG/NIA NIH HHS/United States ; R01AG15819/AG/NIA NIH HHS/United States ; R21AG056518/AG/NIA NIH HHS/United States ; RF1AG076124/AG/NIA NIH HHS/United States ; RF1AG077695/AG/NIA NIH HHS/United States ; //Ms. Lynne Nauss/ ; GC-201711-2014197//Alzheimer's Drug Discovery Foundation/ ; AARFD-24-1313939/ALZ/Alzheimer's Association/United States ; },
abstract = {Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis. We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from iPSC-derived microglia（iMGs) exposed to myelin, Aβ, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs. This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.},
}

@article {pmid40790356,
year = {2025},
author = {Evans, LD and Strano, A and Tuck, E and Campbell, A and Smith, J and Hung, C and Behr, TS and Ghetti, B and Ryskeldi-Falcon, B and Karakoc, E and Iorio, F and Reith, A and Bassett, AR and Livesey, FJ},
title = {Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {},
pmid = {40790356},
issn = {1460-2075},
support = {OTAR036//OpenTargets/ ; Stem Cell Research Centre//Alzheimer's Research UK (ARUK)/ ; WT101052MA//Wellcome Trust (WT)/ ; Stem Cell Professorship//Great Ormond Street Hospital Charity (GOSH)/ ; N/A//NIHR | NIHR Great Ormond Street Hospital Biomedical Research Centre (BRC)/ ; },
abstract = {Extracellular release and uptake of pathogenic forms of the microtubule-associated protein tau contribute to the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease. Defining the cellular mechanisms and pathways for tau entry to human neurons is essential to understanding tauopathy pathogenesis and enabling the rational design of disease-modifying therapeutics. Here, whole-genome, loss-of-function CRISPR screens in human iPSC-derived excitatory neurons, the major neuronal cell type affected in these diseases, provide insights into the different cellular pathways for uptake of extracellular monomeric and fibrillar tau. Monomeric and fibrillar tau are both taken up by human neurons by receptor-mediated endocytosis, but involve different routes of entry at the neuronal surface: the low-density lipoprotein LRP1 is the primary receptor for monomeric tau, but contributes less to fibrillar tau entry. Similarly, endocytosis of monomeric tau is dependent on the familial Parkinson's disease gene LRRK2, but not required for endocytosis of fibrillar tau. These findings implicate LRP1 and LRRK2 in the pathogenesis of tauopathies and Parkinson's disease, and identify LRRK2 as a potential therapeutic target for altering progression of these diseases.},
}

@article {pmid40790282,
year = {2025},
author = {Higuchi, M and Tagai, K and Takahata, K and Endo, H},
title = {Advances in PET imaging of protein aggregates associated with neurodegenerative disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {40790282},
issn = {1759-4766},
abstract = {Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins - amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) - are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are determined by factors such as the protein type, fibril structure, degree of multimerization and post-translational modifications. This article reviews the latest advances in PET technologies aimed at visualizing neurodegenerative proteinopathies, and highlights the importance of these technologies for emerging diagnostic and therapeutic approaches. PET allows Aβ deposition to be visualized throughout the natural history of AD and following anti-Aβ immunotherapies. However, whether this technology can visualize specific Aβ assembly subspecies primarily targeted by the treatment remains inconclusive. Various PET radiotracers can capture AD-type tau deposits, although only a few are known to react with non-AD tau pathologies, and cryo-electron microscopy has revealed the mode of binding of these compounds to different tau protofibrils. High-contrast PET imaging of α-synuclein lesions in MSA is a recent development in the field, and gradual progress is being made towards visualization of other, less abundant α-synuclein pathologies. Imaging of TDP43 and FUS deposits presents particular challenges, which might be overcome by establishing public-private partnerships focused on biomarker development.},
}

@article {pmid40790270,
year = {2025},
author = {Pagano Zottola, AC and Martín-Jiménez, R and Lavanco, G and Hamel-Côté, G and Ramon-Duaso, C and Rodrigues, RS and Mariani, Y and Khan, M and Drago, F and Jean, S and Río, IB and Jimenez-Blasco, D and Egaña-Huguet, J and Eraso-Pichot, A and Beriain, S and Cannich, A and Vidal-Palencia, L and Infantino, R and Julio-Kalajzić, F and Gisquet, D and Goncalves, A and Al-Younis, I and Baussan, Y and Duvezin-Caubet, S and Devin, A and Soria-Gomez, E and Puente, N and Bolaños, JP and Grandes, P and Pouvreau, S and Busquets-Garcia, A and Marsicano, G and Bellocchio, L and Hebert-Chatelain, E},
title = {Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {40790270},
issn = {1546-1726},
abstract = {Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (Gs) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction. Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-Gs) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-Gs abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer's disease and frontotemporal dementia. Thus, mitoDREADD-Gs enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment.},
}

@article {pmid40789853,
year = {2025},
author = {Jasodanand, VH and Kowshik, SS and Puducheri, S and Romano, MF and Xu, L and Au, R and Kolachalama, VB},
title = {AI-driven fusion of multimodal data for Alzheimer's disease biomarker assessment.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {7407},
pmid = {40789853},
issn = {2041-1723},
support = {R01-AG062109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01-AG083735//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01-HL159620//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology/diagnosis ; Positron-Emission Tomography/methods ; Biomarkers/metabolism ; tau Proteins/metabolism ; Male ; Female ; Amyloid beta-Peptides/metabolism ; Aged ; Brain/diagnostic imaging/pathology/metabolism ; Aged, 80 and over ; *Artificial Intelligence ; Plaque, Amyloid/diagnostic imaging/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) diagnosis hinges on detecting amyloid beta (Aβ) plaques and neurofibrillary tau (τ) tangles, typically assessed using PET imaging. While accurate, these modalities are expensive and not widely accessible, limiting their utility in routine clinical practice. Here, we present a multimodal computational framework that integrates data from seven distinct cohorts comprising 12, 185 participants to estimate individual PET profiles using more readily available neurological assessments. Our approach achieved an AUROC of 0.79 and 0.84 in classifying Aβ and τ status, respectively. Predicted PET status was consistent with various biomarker profiles and postmortem pathology, and model-identified regional brain volumes aligned with known spatial patterns of tau deposition. This approach can support scalable pre-screening of candidates for anti-amyloid therapies and clinical trials targeting Aβ and τ, offering a practical alternative to direct PET imaging.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/pathology/diagnosis
Positron-Emission Tomography/methods
Biomarkers/metabolism
tau Proteins/metabolism
Male
Female
Amyloid beta-Peptides/metabolism
Aged
Brain/diagnostic imaging/pathology/metabolism
Aged, 80 and over
*Artificial Intelligence
Plaque, Amyloid/diagnostic imaging/metabolism/pathology

@article {pmid40789514,
year = {2025},
author = {Yang, Y and Ji, Q and Cao, JJ and Zhang, YJ and Li, QQ and Liu, SH and Kong, MH and Xiong, Y and Xie, MM and Zhu, ZR},
title = {Overactivation of the inward rectifier K[+] channel 2.1 modulates intrinsic excitability of adult-born granule cells in the male Alzheimer's APP/PS1 mouse model.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.08.011},
pmid = {40789514},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction, with spatial memory impairments among the earliest detectable deficits. The dentate gyrus (DG), a critical region for spatial discrimination, exhibits functional alterations in patients with AD. Adult-born granule cells (abGCs) with higher intrinsic excitability are involved in DG-dependent spatial memory. However, it remains unclear the changes in intrinsic excitability of abGCs and underlying mechanisms at early stage of AD. In this study, 4-month-old APP/PS1 male mice exhibited spatial memory impairment and alterations in DG network activity. The inward rectifier K[+] channel 2.1 (Kir 2.1) channels were upregulated in the hippocampus of the APP/PS1 mouse model of AD. Pharmacological inhibition of Kir 2.1 using ML133 significantly ameliorated spatial memory impairment and reversed the network activity of DG region. Whole-cell patch clamp recordings of 6-week-old abGCs revealed that intrinsic excitability was decreased in APP/PS1 mice relative to wild-type controls, which was attributable to excessive activation of Kir 2.1. These findings suggest that aberrant intrinsic excitability in the subgroup of abGCs may contribute to DG network activity alterations and induce spatial memory impairment. Our results identify Kir 2.1 overactivation in abGCs as a potential pathogenic mechanism and therapeutic target for early cognitive decline in early stage of AD.},
}

@article {pmid40789377,
year = {2025},
author = {Vecchio, F and Pappalettera, C and Cacciotti, A and Frasca, F and Marcon, G and Rossini, PM},
title = {Electrical Brain Activity in Centenarians: Neurophysiological EEG Markers in resilient brain Ageing.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112100},
doi = {10.1016/j.mad.2025.112100},
pmid = {40789377},
issn = {1872-6216},
abstract = {Centenarians are an increasing population, in particular in high income countries. Studying cognitively intact Centenarians' brain becomes fundamental to understand physiological ageing and how it diverges from pathological one. Resting state EEG were recorded using 27 channels in more than 130 subjects (referred to Young, Adults, Elderly, Centenarians and Alzheimer Disease patients), and the power spectral density (PSD) was computed. The paper demonstrates that Centenarians electrical brain activity is more similar to Elderly's than expected, despite approximately 30 years of age gap, provided they are cognitively intact. Centenarians EEG signal was expected to progressively approach AD one, but surprisingly they seem to slow-down their ageing and maintain non-pathological and resilient EEG patterns, particularly in Alpha bands: occipital region Centenarians PSD has lower values than Young and Adults but not than Elderly, and higher values than AD. These interesting results suggests that Centenarians brain needs to be investigated to extrapolate its characteristics and try to replicate its mechanisms for a widespread healthy ageing.},
}

@article {pmid40789203,
year = {2025},
author = {Candia, J and Fantoni, G and Delgado-Peraza, F and Shehadeh, N and Tanaka, T and Moaddel, R and Walker, KA and Ferrucci, L},
title = {SomaModules: A Pathway Enrichment Approach Tailored to SomaScan Data.},
journal = {Journal of proteome research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jproteome.4c01114},
pmid = {40789203},
issn = {1535-3907},
abstract = {Motivated by the lack of adequate tools to perform pathway enrichment analysis, this work presents an approach specifically tailored to SomaScan data. Starting from annotated gene sets, we developed a greedy, top-down procedure to iteratively identify strongly intracorrelated SOMAmer modules, termed "SomaModules", based on 11K SomaScan data. We generated two repositories based on the latest MSigDB and MitoCarta releases, containing more than 40,000 SOMAmer-based gene sets combined. These repositories can be utilized by any unstructured pathway enrichment analysis tool. We validated our results with two case examples: (i) Alzheimer's disease specific pathways in a 7K SomaScan case-control study, and (ii) mitochondrial pathways using 11K SomaScan data linked to physical performance outcomes. Using gene set enrichment analysis (GSEA), we found that, in both examples, SomaModules had significantly higher enrichment than the original gene set counterparts. These findings were robust and not significantly affected by the choice of enrichment metric or the Kolmogorov enrichment statistic used in the GSEA procedure. We provide users with access to all code, documentation and data needed to reproduce our current repositories, which also will enable them to leverage our framework to analyze SomaModules derived from other sources, including custom, user-generated gene sets.},
}

@article {pmid40789142,
year = {2025},
author = {Kang, JM and Manjavong, M and Diaz, A and Ashford, MT and Aaronson, A and Eichenbaum, J and Mackin, S and Tank, R and Miller, MJ and Landavazo, B and Cavallone, E and Truran, D and Camacho, MR and Fockler, J and Flenniken, D and Farias, ST and Weiner, MW and Nosheny, R},
title = {Evaluating the Accuracy of Web-Based and In-Clinic Subjective Cognitive Decline Assessments in Detecting Cognitive Impairment: Multicohort Study.},
journal = {Journal of medical Internet research},
volume = {27},
number = {},
pages = {e69689},
doi = {10.2196/69689},
pmid = {40789142},
issn = {1438-8871},
mesh = {Humans ; *Internet ; *Cognitive Dysfunction/diagnosis ; Male ; Female ; Aged ; Alzheimer Disease/diagnosis ; Aged, 80 and over ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Scalable tools to efficiently identify individuals likely to have cognitive impairment (CI) are critical in the Alzheimer disease and related dementias field. The Everyday Cognition scale (ECog) and its short form (ECog12) assess subjective cognitive and functional changes and are useful in predicting CI. Recent advances in online technology have enabled the use of web-based cognitive tests and questionnaires to identify CI with greater convenience and scalability. While the effectiveness of the ECog has been demonstrated in clinical settings, its potential to detect CI in remote, unsupervised formats remains underexplored.

OBJECTIVE: This study aimed to compare the ability of the web-based ECog and the in-clinic ECog in distinguishing between individuals with CI and those who are cognitively unimpaired (CU), and to evaluate the effectiveness of the ECog12-the short version of the ECog-compared to the full-length ECog in a web-based setting.

METHODS: Participants were recruited from the Brain Health Registry (BHR; web-based) and Alzheimer's Disease Neuroimaging Initiative (ADNI; in-clinic) settings with available clinical diagnoses. The ability of the self-reported ECog (Self-ECog), study partner-reported ECog (SP-ECog), Self-ECog12, and SP-ECog12 to discriminate individuals with CI from CU was assessed using receiver operating characteristic (ROC) curves. Area under the ROC curves (AUCs) between BHR and ADNI were compared using the DeLong test, as were AUCs between ECog12 and ECog in BHR.

RESULTS: Web-based Self-ECog and SP-ECog scores effectively discriminated CI from CU with AUCs of 0.722 and 0.818, respectively. Similarly, the abbreviated web-based versions, Self-ECog12 and SP-ECog12, also demonstrated discriminative ability (AUC=0.709 and 0.777, respectively). When compared to in-clinic ECog scores, there were no significant differences in the ability to distinguish CI from CU between web-based and in-clinic versions (BHR Self-ECog AUC=0.722 vs ADNI Self-ECog AUC=0.769, DeLong P=.06; BHR SP-ECog AUC=0.818 vs ADNI SP-ECog AUC=0.840, DeLong P=.50). Additionally, the comparison between web-based ECog and ECog12 showed no significant difference in AUCs (BHR Self-ECog AUC=0.722 vs BHR Self-ECog12 AUC=0.709, DeLong P=.18).

CONCLUSIONS: Web-based ECog scores, both the full-length and short-form, were as valid as in-clinic ECog scores for identifying clinically diagnosed CI. In addition, Self-ECog12 was as effective as full-length Self-ECog to identify CI in a web-based setting, offering a cost-effective and accessible screening tool for large-scale studies. These results highlight the value of the web-based ECog as a valid tool for identifying older adults with CI in a remote clinical study, facilitating early detection and referral for comprehensive evaluations for identifying potential candidates for disease-modifying therapy.},
}

Humans
*Internet
*Cognitive Dysfunction/diagnosis
Male
Female
Aged
Alzheimer Disease/diagnosis
Aged, 80 and over
Neuropsychological Tests

@article {pmid39950284,
year = {2025},
author = {Zheng, C and Wu, L and Luo, L and Cai, J and Huang, Z and Tian, K},
title = {Therapeutic Effects and Mechanisms of Icaritin in Parkinson's Disease.},
journal = {Current pharmaceutical design},
volume = {31},
number = {25},
pages = {1983-1989},
pmid = {39950284},
issn = {1873-4286},
support = {31960190//National Natural Science Foundation of China/ ; 20192BAB205117//Jiangxi Natural Science Foundation/ ; 202212550//Science and Technology Plan Project of Jiangxi Provincial Health Care Commission/ ; GZ2021ZSF340//Science and Technology Guidance Project of Ganzhou/ ; 2020-2-48//Science and Technology Plan Project of Ganzhou Health Care Commission/ ; },
mesh = {Humans ; *Parkinson Disease/drug therapy/metabolism ; *Flavonoids/pharmacology/therapeutic use/chemistry/isolation & purification ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification/chemistry ; Oxidative Stress/drug effects ; },
abstract = {Parkinson's Disease (PD) is a neurodegenerative disorder of the central nervous system (CNS). Given the increasing age of the general population, PD has emerged as a significant public health and societal concern, impacting both individual well-being and socioeconomic progress. The present interventions have proven insufficient in impeding the progressive nature of PD. Consequently, it is imperative to promptly identify efficacious strategies for the prevention and treatment of PD. Icaritin (ICT) is a flavonoid extracted from Epimedium Brevicornu Maxim that is a phytoestrogen with antitumour, anti-inflammatory, antioxidant, antiaging, and neuroprotective properties. This paper reviews the protective effect of ICT on dopaminergic neurons through anti-oxidative stress, improving mitochondrial function, inhibiting neuroinflammatory responses, reducing Lewy body formation, and decreasing apoptosis. The primary objective of this article is to provide valuable insights and serve as a reference for the potential use of ICT in the prevention and treatment of PD.},
}

Humans
*Parkinson Disease/drug therapy/metabolism
*Flavonoids/pharmacology/therapeutic use/chemistry/isolation & purification
Animals
*Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification/chemistry
Oxidative Stress/drug effects

@article {pmid40788702,
year = {2025},
author = {Castegnaro, A and Dior, A and Burgess, N and King, J},
title = {Continuous updating via self-motion compensates for weak allocentric spatial memory in aging.},
journal = {Psychology and aging},
volume = {},
number = {},
pages = {},
doi = {10.1037/pag0000926},
pmid = {40788702},
issn = {1939-1498},
support = {/WT_/Wellcome Trust/United Kingdom ; //University College London; Institute for Communications and Connected Systems/ ; /DH_/Department of Health/United Kingdom ; },
abstract = {Navigational skills are essential for interacting with our environment, supported by multiple types of spatial representations. We investigated age-related differences in spatial memory using a virtual reality task that manipulated viewpoints between the encoding and retrieval of one or four-object locations. The task investigates compensatory mechanisms in aging, specifically how spatial updating via self-motion affects spatial memory. We tested 21 young adults (ages 19-36) and 23 older adults (ages 63-80). The task involved three movement conditions: same-viewpoint condition, where participants walked away and returned to the same viewpoint; shifted-viewpoint (walking) condition where participants walked to a different viewpoint, enabling continuous updates of their egocentric representations through self-motion; and shifted-viewpoint (teleport) condition where participants teleported to the other viewpoint, involving both a virtual translation and rotation of the participant's view. Retrieval was tested by asking participants to place each object at its previously seen location. Average displacement error was affected by age group, object configuration, and movement condition, with an interaction between age and movement condition. Differences in movement conditions were primarily driven by older participants, who were most accurate from the same viewpoint. In shifted-viewpoint conditions, teleportation-where self-motion cues were absent-led to significantly greater errors than walking in the older group. Our results highlight the role of spatial updating in supporting spatial memory and suggest that age-related decline in allocentric representations can be mitigated by continuous updating of egocentric representations by self-motion. We speculate that the use of spatial updating might be impaired early in the progression to Alzheimer's dementia due to entorhinal cortical pathology. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid40788534,
year = {2025},
author = {Zarei, S and Saffar, M and Shalbaf, R and Hassani Abharian, P and Shalbaf, A},
title = {Explainable hierarchical machine-learning approaches for multimodal prediction of conversion from mild cognitive impairment to Alzheimer's disease.},
journal = {Physical and engineering sciences in medicine},
volume = {},
number = {},
pages = {},
pmid = {40788534},
issn = {2662-4737},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that challenges early diagnosis and intervention, yet the black-box nature of many predictive models limits clinical adoption. In this study, we developed an advanced machine learning (ML) framework that integrates hierarchical feature selection with multiple classifiers to predict progression from mild cognitive impairment (MCI) to AD. Using baseline data from 580 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), categorized into stable MCI (sMCI) and progressive MCI (pMCI) subgroups, we analyzed features both individually and across seven key groups. The neuropsychological test group exhibited the highest predictive power, with several of the top individual predictors drawn from this domain. Hierarchical feature selection combining initial statistical filtering and machine learning based refinement, narrowed the feature set to the eight most informative variables. To demystify model decisions, we applied SHAP-based (SHapley Additive exPlanations) explainability analysis, quantifying each feature's contribution to conversion risk. The explainable random forest classifier, optimized on these selected features, achieved 83.79% accuracy (84.93% sensitivity, 83.32% specificity), outperforming other methods and revealing hippocampal volume, delayed memory recall (LDELTOTAL), and Functional Activities Questionnaire (FAQ) scores as the top drivers of conversion. These results underscore the effectiveness of combining diverse data sources with advanced ML models, and demonstrate that transparent, SHAP-driven insights align with known AD biomarkers, transforming our model from a predictive black box into a clinically actionable tool for early diagnosis and patient stratification.},
}

@article {pmid40788127,
year = {2025},
author = {Wang, Y and Wang, Q and Zhou, M and Liang, J and You, L and Asken, B and Zhou, X and Song, Q},
title = {Integration of Genetic and Imaging Data for Alzheimer's Disease Diagnosis and Interpretation.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e07629},
doi = {10.1002/advs.202507629},
pmid = {40788127},
issn = {2198-3844},
support = {NSF2217515//National Science Foundation/ ; #2138286//National Science Foundation/ ; #2138307//National Science Foundation/ ; #2137603//National Science Foundation/ ; #2138296//National Science Foundation/ ; R01LM014156/NH/NIH HHS/United States ; R01GM153822/NH/NIH HHS/United States ; R01CA241930/NH/NIH HHS/United States ; R35GM151089/GM/NIGMS NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by complex interactions between genetic risk factors and structural brain changes. Traditional diagnostic approaches that rely on single-modality data, such as imaging or genomics alone, often fall short in both predictive accuracy and biological interpretability. To address these limitations, AlzCLIP, a novel contrastive learning framework that integrates single nucleotide polymorphism (SNP) profiles and MRI-derived imaging features into a unified embedding space is introduced. This joint representation captures disease-relevant interactions between genetic variation and brain structure, enabling both accurate diagnosis and mechanistic insight into AD. AlzCLIP is trained and evaluated on two large-scale cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the UK Biobank (UKB), and demonstrated robust diagnostic performance, outperforming state-of-the-art baselines by up to 19%. More importantly, the model yields interpretable outputs through feature importance and interaction analyses, identifying key contributors to AD risk, including rs1135173, rs7575209, and rs66763080, as well as structural markers such as hippocampal volume and precuneus surface area. Notably, AlzCLIP uncovered genotype-specific effects on imaging phenotypes. Specifically, rs11077054 is associated with increased white matter hyperintensity burden and amygdala atrophy, suggesting a potential link between this variant and AD-related structural brain changes. Together, the results highlight AlzCLIP's potential to enhance AD risk prediction and provide biologically grounded insights by integrating multi-modal genomic and imaging data.},
}

@article {pmid40787633,
year = {2025},
author = {Hossain, MK and Ashraf, A and Islam, MM and Sourav, SH and Shimul, MMH},
title = {Optimizing Alzheimer's disease prediction through ensemble learning and feature interpretability with SHAP-based feature analysis.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70162},
pmid = {40787633},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Early diagnosis is vital. We developed an interpretable machine learning (ML) model for early AD prediction using open clinical data.

METHODS: Data from 2149 adults (60-90 years) were obtained from Kaggle. After preprocessing and feature engineering, tree-based models were trained. A stacking ensemble model combining Gradient Boosting and XGBoost was trained, with Logistic Regression as the meta-learner. SHapley Additive exPlanations (SHAP) provided interpretability. Performance was measured by accuracy, precision, recall, F1 score, ROC and AUC.

RESULTS: The stacked ensemble achieved 97% accuracy (AUC 0.97), with 0.97 precision, 0.94 recall, and 0.96 F1 score for AD. SHAP identified memory complaints, Mini-Mental State Examination (MMSE), functional assessment, behavioral symptoms, cholesterol, and lifestyle factors (activity, diet, sleep) as top predictors.

CONCLUSION: The ensemble model, enhanced by SHAP analysis, provides accurate and interpretable AD risk predictions with potential applicability in future clinical decision support systems.

HIGHLIGHTS: Developed an ensemble machine learning (ML) model for early Alzheimer's disease (AD) prediction.Achieved 97% accuracy using stacked XGBoost and Gradient Boosting.SHapley Additive exPlanations (SHAP) analysis identified key cognitive and lifestyle-related risk factors.Model interprets AD risk using explainable artificial intelligence (AI) for clinical applicability.Utilized open-access dataset to ensure reproducibility and transparency.},
}

@article {pmid40787599,
year = {2025},
author = {Jiang, C and van der Lee, SJ and Tesi, N and van der Flier, WM and Tijms, BM and Reus, LM},
title = {Identification of novel candidate loci for Alzheimer's disease and related dementias by leveraging the shared genetic basis with hippocampal volume.},
journal = {Aging brain},
volume = {8},
number = {},
pages = {100147},
pmid = {40787599},
issn = {2589-9589},
abstract = {Alzheimer's disease and related dementias (ADRD) are complex neurodegenerative disorders of which the genetic basis remains incompletely understood. Hippocampal volume loss is a core hallmark of AD. Hippocampal volume also has a strong heritable component and its genetic underpinnings may help us to understand the complex biological mechanism underlying ADRD. To identify shared genetic risk loci across late-onset ADRD and bilateral hippocampal volumes, we conducted a cross-trait analysis of existing GWAS data on the two traits using the conjunctional false discovery rate (conjFDR) framework. Functional annotation and phenome-wide association studies (PheWAS) were performed on the identified shared loci to characterize their biological relevance. We identified 11 unique lead genetic loci, of which 7 loci showed discordant directional effects (loci associated with increased risk for ADRD and smaller hippocampal volumes). We found that SHARPIN and TNIP1 genes play a role in ADRD by affecting hippocampal volumes. In addition, we observed 9 novel ADRD-hippocampus loci in genes previously implicated in AD (IGIP and ACE) and novel ADRD-genes (KCTD13, HINT1, SH3TC2, FAM53B, TPM1, IL34 and SSH2). PheWAS results show that most shared loci associated with neuroimaging measurements, white blood cell markers, red blood cell markers, and lipids. This study shows a shared genetic basis between ADRD and bilateral hippocampal volumes. By integrating summary statistics for these two traits, we identified both novel and previously reported ADRD-hippocampus loci. Functional analysis highlights the role of immune cells and lipid markers in the shared loci, suggesting a shared neurobiological basis for ADRD and bilateral hippocampal volumes.},
}

@article {pmid40787538,
year = {2025},
author = {Muili, AO and Temilola, AV and Itunu, OO and Olajide, OA and Ngozi, CD and Kuol, PP},
title = {Exploring Cognitive Enhancers: from neurotherapeutics to ethical and regulatory challenges: a mini review.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {8},
pages = {4975-4981},
pmid = {40787538},
issn = {2049-0801},
abstract = {This manuscript provides an outlook on using cognitive enhancers and their ethical implications. Cognitive enhancers, including prescription medications like modafinil and methylphenidate, over-the-counter supplements such as ginseng and caffeine, and novel nootropic agents like gene therapy and stem cell interventions, improve cognitive functions such as memory, focus, and learning. While they have shown efficacy in treating neurodegenerative disorders like Alzheimer's disease and attention-deficit/hyperactivity disorder (ADHD), their growing use by healthy individuals raises ethical concerns. This paper addresses the benefits of cognitive enhancers, such as improved academic and professional performance, and the associated risks, including addiction, dependence, and long-term health consequences. It also delves into social and ethical issues, including disparities in access, fairness, coercion in competitive environments, and distinguishing between genuine and substance-enhanced achievements. Additionally, the paper examines current regulations and proposes stronger legal frameworks to address the increasing use of cognitive enhancers. In conclusion, while cognitive enhancers have potential therapeutic benefits, a balanced approach is needed to regulate their use and ensure they are not misused to gain unfair advantages, particularly in non-medical settings.},
}

@article {pmid40787447,
year = {2025},
author = {Li, MM and Yang, YX and Huang, YL and Wu, SJ and Huang, WL and Ye, LC and Xu, YY},
title = {Programmed cell death signatures-driven microglial transformation in Alzheimer's disease: single-cell transcriptomics and functional validation.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1610717},
pmid = {40787447},
issn = {1664-3224},
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/genetics/pathology/metabolism ; Humans ; Single-Cell Analysis ; *Apoptosis/genetics ; *Transcriptome ; Animals ; Mice ; *S100 Calcium-Binding Protein A4/genetics/metabolism ; Gene Expression Profiling ; Machine Learning ; Male ; Cell Line ; Gene Regulatory Networks ; },
abstract = {BACKGROUND: This study aims to develop and validate a programmed cell death signature (PCDS) for predicting and classifying Alzheimer's disease (AD) using an integrated machine learning framework. We further explore the role of S100A4 in AD pathogenesis, particularly in microglia.

METHODS: A total of one single-cell RNA sequencing (scRNA-seq) and four bulk RNA-seq datasets from multiple GEO datasets were analyzed. Weighted Gene Co-expression Network Analysis (WGCNA) was utilized to identify PCD-related genes. An integrated machine learning framework, combining 12 algorithms was used to construct a PCDS model. The performance of PCDS was validated using multiple independent cohorts. In vitro experiments using BV2 microglia were conducted to validate the role of S100A4 in AD, including siRNA transfection, Western blot, qRT-PCR, cell viability and cytotoxicity assay, flow cytometry, and immunofluorescence.

RESULTS: ScRNA-seq analysis revealed higher PCD levels in microglia from AD patients. Seventy-seven PCD-related genes were identified, with 70 genes used to construct the PCDS model. The optimal model, combining Stepglm and Random Forest, achieved an average AUC of 0.832 across five cohorts. High PCDS correlated with upregulated pathways related to inflammation and immune response, while low PCDS associated with protective pathways. In vitro, S100A4 knockdown in AbetaO-treated BV2 microglia improved cell viability, reduced LDH release, and partially alleviated apoptosis. S100A4 inhibition attenuated pro-inflammatory responses, as evidenced by the reduced expression of pro-inflammatory mediators (IL-6, iNOS, TNF-α) and promoted an anti-inflammatory state, indicated by increased expression of markers such as IL-10, ARG1, and YM1/2. Furthermore, S100A4 knockdown mitigated oxidative stress, restoring mitochondrial function and decreasing ROS levels.

CONCLUSION: This study developed a robust PCDS model for AD prediction and identified S100A4 as a potential therapeutic target. The findings highlight the importance of PCD pathways in AD pathogenesis and provide new insights for early diagnosis and intervention.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/genetics/pathology/metabolism
Humans
Single-Cell Analysis
*Apoptosis/genetics
*Transcriptome
Animals
Mice
*S100 Calcium-Binding Protein A4/genetics/metabolism
Gene Expression Profiling
Machine Learning
Male
Cell Line
Gene Regulatory Networks

@article {pmid40787376,
year = {2025},
author = {Gebeş-Alperen, B and Evren, AE and Sağlik Özkan, BN and Karaburun, AC and Gundogdu-Karaburun, N},
title = {Novel Benzofuran-3-yl-methyl and Aliphatic Azacyclics: Design, Synthesis, and In Vitro and In Silico anti-Alzheimer Disease Activity Studies.},
journal = {ACS omega},
volume = {10},
number = {30},
pages = {32829-32843},
pmid = {40787376},
issn = {2470-1343},
abstract = {Neurological disorders represent a significant burden on human health, particularly as global life expectancy continues to rise. Among these conditions, Alzheimer's disease is notably prevalent. Of greater concern, if left untreated or unaddressed, Alzheimer's disease can progress to dementia, leading to severe cognitive decline and a substantial reduction in quality of life. In this study, 15 novel benzofuran-azacyclic hybrids were designed and synthesized. The final compounds were evaluated for their inhibitory potency on AChE and BACE-1 enzymes, and in silico studies were performed to clarify their binding modes. Finally, structure-activity relationships (SARs) were proposed for future studies. The results indicated that the most promising compound is 4m, which contains N-(2-hydroxyethyl)-piperazine and benzofuran moieties. These moieties effectively occupied the substrate channel of the AChE enzyme and the catalytic cleft of the BACE-1 enzyme. Additionally, compounds 4e (benzyl piperidine) and 4h (2-furoyl piperazine) showed dual inhibitory activity on both enzymes. In conclusion, the tubular form with a stopper group shows great potential for the treatment of Alzheimer's disease, as it blocks the entrance cavity of the AChE active pocket for the substrate and increases the stability of the inactive BACE-1 enzyme. Moreover, electrolytes, specifically sodium ions in this case, play a crucial role in stabilizing the 4m-BACE-1 protein complex. For further studies, we suggest that the tubular form with a stopper can serve as a potential pharmacophore and an appropriate starting point for drug development.},
}

@article {pmid40787193,
year = {2025},
author = {Kumar, P and Lele, VR and Akhtar, MJ},
title = {Prospective Assessment of Alzheimer's Disease-Like Hypometabolism Pattern in the Brain of Diabetics in Contrast to Non-diabetics on Positron Emission Tomography-Computed Tomography Images Using Fluorodeoxyglucose in India.},
journal = {Cureus},
volume = {17},
number = {8},
pages = {e89682},
pmid = {40787193},
issn = {2168-8184},
abstract = {BACKGROUND: Diabetes mellitus (DM) is a known risk factor for cognitive decline and Alzheimer's disease (AD), possibly due to insulin resistance and impaired cerebral glucose metabolism. Fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) imaging has shown AD-like hypometabolism patterns in diabetic individuals in various global studies. However, such data is lacking in the Indian population. This study investigated the presence of AD-like hypometabolism in Indian diabetic patients compared to non-diabetic controls.

AIM AND OBJECTIVE: This study aimed to evaluate whether the Indian diabetic patients show AD-like reduction in brain glucose metabolism, as several studies reported AD-like hypometabolism in the brain at very early stages before making a clinical diagnosis of probable AD.

MATERIALS AND METHODS: A prospective, observational study was conducted on 78 patients (39 diabetics and 39 non-diabetics; age range 43-87 years) at a tertiary care center. After excluding patients with a recent history of stroke, transient ischemic attack, or structural brain abnormalities, all participants underwent dedicated brain FDG PET-CT imaging just after a whole-body scan. Scans were analyzed using CORTEX-ID software (GE Healthcare, Chicago, IL, USA), comparing cerebral glucose metabolism to age-matched normative data. Regional hypometabolism was normalized to thalamic activity. Appropriate tests of significance were used, and P< 0.05 was considered statistically significant.  Results: The study included 78 patients, 39 diabetics and 39 non-diabetic controls, matched for sex (19 males and 20 females in each group). Diabetic patients had a higher mean age (66.4 ± 10.6 years). The Mini-Mental State Examination (MMSE) score was lower in diabetics (25.3 ± 2.3) than in controls (26.8 ± 1.9). About 5.1% of diabetic patients showed an AD-like pattern, and the remaining 94.9% did not show an AD-like pattern on the FDG PET-CT scan. An AD-like pattern was not seen in any patient among the non-diabetic control group. No statistically significant association was found between the AD-like pattern in the brain on FDG PET-CT and diabetes (P = 0.494).

CONCLUSIONS: No significant incidence of "AD-like pattern" in the brain on PET-CT images using FDG was seen in this research study on the Indian diabetic populations. However, abnormal brain scans with no AD-like hypometabolism patterns possibly suggested other etiologies, likely depression. More prospective multicentric research studies on a large Indian diabetic population with age-matched non-diabetic control groups need to be explored for definite conclusions.},
}

@article {pmid40787159,
year = {2025},
author = {Jarchow, M and Driscoll, I and Breidenbach, BM and Cook, N and Gallagher, CL and Johnson, SC and Asthana, S and Hermann, BP and Sager, MA and Blennow, K and Zetterberg, H and Carlsson, CM and Kollmorgen, G and Quijano-Rubio, C and Cook, DB and Dubal, DB and Okonkwo, OC},
title = {More fit KL-VS heterozygotes have more favorable AD-relevant biomarker profiles.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70133},
pmid = {40787159},
issn = {2352-8737},
abstract = {INTRODUCTION: Although hallmarked by β-amyloid plaques (Aβ) and neurofibrillary tangles (tau), Alzheimer's disease (AD) is a multifactorial disorder that involves neuroinflammation, neurodegeneration, and synaptic dysfunction. AD-associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the KLOTHO gene (KL-VSHET). Independently, better cardiorespiratory fitness (CRF) is associated with better health outcomes related to AD pathology. Here we investigate whether the relationships between CRF (peak oxygen consumption (VO2peak)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VSHET compared to noncarriers (KL-VSNC).

METHODS: The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (n = 136; MeanAGE(SD) = 62.5(6.7)) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center. Covariate-adjusted (age, sex, parental AD history, apolipoprotein E (APOE) 4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO2peak and KLOTHO genotype on CSF core AD biomarker levels (phosphorylated tau 181 [pTau181], Aβ42/Aβ40, pTau181/Aβ42). Analyses were repeated for CSF biomarkers of neurodegeneration (total tau [tTau], α-synuclein [α-syn], neurofilament light polypeptide [NfL]), synaptic dysfunction (neurogranin [Ng]), and neuroinflammation (glial fibrillary acidic protein [GFAP], soluble triggering receptor expressed in myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], interleukin 6 [IL-6], S100 calcium-binding protein B [S100B]).

RESULTS: The interaction between VO2peak and KL-VSHET was significant for tTau (p = 0.05), pTau181 (p = 0.03), Ng (p = 0.02), sTREM2 (p = 0.03), and YKL-40 (p = 0.03), such that lower levels of each biomarker were observed for KL-VSHET who were more fit. No significant KL-VSxVO2peak interactions were observed for Aβ42/Aβ40, pTau181/Aβ42, α-syn, NfL, GFAP, IL-6 or S100B (all Ps>0.09).

CONCLUSIONS: We report a synergistic relationship between KL-VSHET and CRF with pTau181, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VSHET and better CRF against unfavorable AD-related changes. Their potentially shared biological mechanisms require future investigations.

HIGHLIGHTS: KLOTHO KL-VSHET and higher cardiorespiratory fitness (CRF) may protect against unfavorable Alzheimer's disease (AD)-related changes.Higher CRF attenuates neurodegeneration and synaptic dysfunction in KL-VSHET.More fit KL-VSHET also has lower levels of pTau and less neuroinflammation.},
}

@article {pmid40786855,
year = {2025},
author = {Zhang, H and Yin, M and Nan, X and Liu, X and Zhang, R},
title = {In-home respite care in dementia: An evolutionary concept analysis.},
journal = {International journal of nursing sciences},
volume = {12},
number = {4},
pages = {352-360},
pmid = {40786855},
issn = {2352-0132},
abstract = {OBJECTIVE: To clarify the concept of in-home respite care in dementia care and identify changes in the service content over time to help providers and users better understand this sustainable service.

METHOD: A literature search was conducted through Chinese databases China National Knowledge Infrastructure (CNKI), Wanfang, VIP, and SinoMed, as well as English databases PubMed, the Cochrane Library, Web of Sciences, and Embase. Articles published from January 1980 to December 2024 were identified. Rogers' conceptual analysis of evolution was used for this concept analysis, including six steps: identifying the concept and its context, selecting appropriate databases, determining relevant literature, identifying the concept's attributes, antecedents, and consequences, choosing a concept exemplar if appropriate, and defining hypotheses and implications for further concept development.

RESULTS: Thirty-one articles were included. This conceptual analysis revealed the evolution of in-home respite care service content over time and summarized three key attributes. The antecedents included factors related to people with dementia, family caregivers, and the social environment (aging society, government support). The consequences of in-home respite services include delayed institutional placement and reduced security risk events for people with dementia. For family caregivers, consequences include reduced caregiving stress, improved quality of life, and perceived benefits from rest periods.

CONCLUSION: In-home respite care can be interpreted as family-centered home care that provides temporary relief from family caregivers' responsibilities in caring for people with dementia to reduce caregiver burden. The trend of service specialization and attention on dementia families' needs in service provision are future research focus.},
}

@article {pmid40786701,
year = {2025},
author = {Dhaliwal, K and Wong, A and Wright, T and Bizheva, K},
title = {Combined optical coherence tomography and electroretinography system for imaging neurovascular coupling in the human retina.},
journal = {Neurophotonics},
volume = {12},
number = {3},
pages = {035004},
pmid = {40786701},
issn = {2329-423X},
abstract = {SIGNIFICANCE: During their early stages of development, neurological and neurodegenerative diseases cause changes to the biological tissue's morphology, physiology and metabolism at the cellular level, and acute, transient changes in the local blood flow. The development of optical methods that can image and quantify such changes simultaneously and investigate the relationship among them (neurovascular coupling) in neural tissues can have a profound effect on furthering our understanding of neurodegeneration.

AIM: Our aim is to develop an optical imaging platform for imaging and characterization of neurovascular coupling in the human retina with high spatial and temporal resolutions.

APPROACH: A compact, clinically viable optical coherence tomography technology was developed for in vivo, simultaneous structural, functional, and vascular imaging of the human retina and was integrated with a clinical electroretinography system. Image processing algorithms were developed to measure visually evoked physiological and blood flow changes in the living retina and explore neurovascular coupling in the healthy human retina.

RESULTS: Both intensity and optical path length changes were measured with optical coherence tomography from most major retinal layers (nerve fiber layer, plexiform layers, inner and outer segments of the photoreceptors, and the retinal pigmented epithelium) in response to a visual stimulation with a 4-ms single white light flash. The visual stimulus also caused fast transient changes in the retinal blood flow in the local blood vessels. The time courses of these changes were similar, and their magnitude was proportional to the intensity of the visual stimulus.

CONCLUSIONS: We have developed an optical imaging modality for non-invasive probing of neurovascular coupling in the living human retina and demonstrated its utility and clinical potential in a pilot study on healthy subjects. This imaging platform could serve as a useful clinical research tool for investigation of potentially blinding retinal diseases, as well as neurodegenerative brain diseases that are expressed in the retina such as Alzheimer's and Parkinson's diseases.},
}

@article {pmid40786560,
year = {2024},
author = {Zhou, Y and Jiang, F},
title = {Heterogeneous Functional Regression for Subgroup Analysis.},
journal = {Journal of computational and graphical statistics : a joint publication of American Statistical Association, Institute of Mathematical Statistics, Interface Foundation of North America},
volume = {},
number = {},
pages = {},
pmid = {40786560},
issn = {1061-8600},
abstract = {With ever increasing number of features of modern datasets, data heterogeneity is gradually becoming the norm rather than the exception. Whereas classical regressions usually assume all the samples follow a common model, it becomes imperative to identify the heterogeneous relationship in different subsamples. In this article, we propose a new approach to model heterogeneous functional regression relations. We target at the association between a response and a predictor, whose relationship can vary across underlying subgroups and is modeled as an unknown functional of an auxiliary predictor. We introduce a procedure which performs simultaneous parameter estimation and subgroup identification through a fusion type group-wise penalization. We establish the statistical guarantees in terms of non-asymptotic convergence of the parameter estimation. We also establish the oracle property and asymptotic normality of the estimators. We carry out intensive simulations, and illustrate with a new dataset from an Alzheimer's disease study. Supplementary materials for this article are available online.},
}

@article {pmid40786525,
year = {2025},
author = {Haran, JP and Barrett, AM and Lai, Y and Odjidja, SN and Dutta, P and McGrath, PM and Samari, I and Romeiro, L and Lopes, A and Bucci, V and McCormick, BA},
title = {Executive functioning and processing speed as predictors of global cognitive decline in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251363549},
pmid = {40786525},
issn = {2542-4823},
abstract = {BACKGROUND: Better cognitive tools to predict disease progression in mild cognitive impairment (MCI) and Alzheimer's disease (AD) are needed.

OBJECTIVE: In this prospective longitudinal cohort, we are testing if changes in the cognitive domains of executive functioning and processing speed can predict global cognitive decline.

METHODS: We assessed patients with MCI, AD, and cognitively healthy controls (cHC) using NIH toolbox assessments for processing speed and executive functioning and overall cognitive decline by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog).

RESULTS: Among 184 participants over a median follow-up of 540 days, both between- and within-subjects variance in NIH toolbox and ADAS-Cog assessments increased from cHC to MCI to AD patients. Among patients with AD (n = 24), pattern comparison processing speed (PCPS) and dimensional change card sort tests (DCCS) declined at 3 and 6 months prior to global cognitive decline (p = 0.008 and 0.0012). A 5-point decrease in either PCPS or DCCS increased risk of global cognitive decline (HR 1.32 (1.08-1.60) and 1.62 (1.16-2.26)).

CONCLUSIONS: Testing for cognitive domains of processing speed and executive functioning may predict subsequent global cognitive.},
}

@article {pmid40786362,
year = {2025},
author = {Chowdhury, A and Bhasin, G and Ganti, L},
title = {Bibliometric Analysis of the Epidemiological Research on Alzheimer's Disease Treatment.},
journal = {Cureus},
volume = {17},
number = {7},
pages = {e87484},
pmid = {40786362},
issn = {2168-8184},
abstract = {Alzheimer's disease presents a complex global health issue. It is characterized by a decline in cognitive function, starting with memory impairment, and extending to impact reasoning, language abilities, and spatial awareness. Despite decades of research, Alzheimer's disease remains a global challenge lacking long-term treatments. Institutions like the Karolinska Institutet, Columbia University, the University of California San Francisco (UCSF), and the University of Pittsburgh contribute significantly to Alzheimer's research, with a growth in publications in 2022 post-COVID-19. While current treatments offer symptomatic relief, there's a need for disease-modifying therapies targeting its mechanisms. This analysis aims to provide a comprehensive overview of the available research and medical literature on Alzheimer's disease by employing bibliometric methods to identify publication trends, leading research institutions, and the evolving focus from symptomatic treatments to disease-modifying therapies. This paper seeks to analyze the research papers on Alzheimer's disease and catalog the metadata associated with each paper.},
}

@article {pmid40786281,
year = {2025},
author = {Subhani, MK and Sabani, A and Omer, O and Kheirelsid, F and Srour, AK},
title = {Impact of Renin-Angiotensin-Aldosterone System Modulation on Cognitive and Neuropsychiatric Outcomes: A Systematic Review of Clinical and Mechanistic Evidence.},
journal = {Cureus},
volume = {17},
number = {7},
pages = {e87557},
pmid = {40786281},
issn = {2168-8184},
abstract = {This systematic review explores the influence of the renin-angiotensin-aldosterone system (RAAS) on cognitive and neuropsychiatric outcomes, synthesizing evidence from clinical and preclinical studies investigating RAAS-modulating therapies such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). A comprehensive literature search across four major databases yielded seven studies that met the inclusion criteria, including randomized controlled trials, observational studies, and one animal model experiment. The findings suggest that RAAS modulation, particularly through ARBs, may offer cognitive benefits in certain populations, especially those with hypertension, type 2 diabetes, or vascular risk factors. Some studies demonstrated improvements in executive function, memory, and global cognition, while others found no statistically significant effect on neurodegeneration or cognitive decline. Mechanistic insights indicate that RAAS-targeting interventions may reduce neuroinflammation, oxidative stress, and microvascular dysfunction, which are pathways implicated in cognitive impairment. Although promising, the evidence is varied in methodological quality and consistency, highlighting the need for future trials with cognitive endpoints as primary outcomes.},
}

@article {pmid40786216,
year = {2025},
author = {Dubey, S and Sengupta, S and Chatterjee, S and Ghosh, R and Dewasi, S and Das, S and Pandit, A and Dubey, MJ},
title = {From triple-mode network to triple-layered model - novel insights in social cognition.},
journal = {Indian journal of psychiatry},
volume = {67},
number = {7},
pages = {710-720},
pmid = {40786216},
issn = {0019-5545},
abstract = {Modern studies have revealed various pathophysiological mechanisms underlying neurodegenerative dementias. Among these, disruption of the "triple mode network" is widely recognized as a pivotal common pathway leading to the development of the neurodegenerative dementias including Alzheimer's dementia. Contemporary studies have shown strong association of impaired social cognition with various dementias. However, how the misaligned social cognition leads to neurocognitive decline is still enigmatic. Herein, the authors introduce the term "triple-layered model of social cognition", which encompasses the three pillars, that is, the basic "core cognitive constructs", the value-based "higher-level cognitive constructs", and instinct-driven "lower-level cognitive constructs (i.e., the bottom circuit)". Dynamic interactions between the complex engrams of all three pillars form the "cogniverse". The "higher-level cognitive constructs" may serve as a protective layer for the foundational "core cognitive constructs", which are incessantly challenged by "the bottom circuit". This could be a critical harbinger of neurocognitive decline. The authors further hypothesize that the derivatives of the miscalibrated social cognition, emerging from "the bottom circuit", serve as "cognitive pollutants". Here, authors introduce the term "social proteopathy" encompassing all social cognitive pollutants as a unified concept, which plays a significant pathological role in neurodegenerative dementias alongside biologically and genetically linked proteopathies. These social proteopathies have a profound deleterious impact on the "higher-level cognitive constructs" either through direct toxic potentials or via epigenetic modulation. Misdirected and maladaptive social cognition progressively erodes the layer of "higher-level cognitive constructs", eventually having a deleterious impact on the fundamental "core cognitive constructs", which, in turn, contribute to neurodegenerative dementias and various psychopathologies. The authors further attempt to classify "social brain" into six subtypes to assess the future "social cognitive debt" and the resulting aberrant behavioral burdens. Finally, the authors propose the way forward including genuine mindfulness-based practice and relentless exercise of the "higher-level cognitive constructs" in activities of daily living. This may act as a primordial preventive strategy against neurodegenerative dementias and various psychopathologies.},
}

@article {pmid40786195,
year = {2025},
author = {Humpel, C},
title = {Three-dimensional organotypic mouse brain slices to study Alzheimer's disease pathologies: a review.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1585124},
pmid = {40786195},
issn = {2813-3919},
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative brain disorder molecularly characterized by extracellular β-amyloid plaques, intraneuronal tau neurofibrillary tangles, cholinergic neuron death, neuroinflammation, vascular damage, and astroglial and microglial activation. AD is a complex disorder, with >99% of all cases being sporadic and typically occuring around the age of 65. Due to this intricate nature of the disorder, in vitro experiments have limitations; however, three-dimensional organotypic brain slices may offer the best alternative for studying the mechanisms involved in the progression of AD. This review provides an overview of how to study the general aspects of AD ex vivo, focusing on (a) β-amyloid plaques in brain slices, (b) tau pathology induced by chemical drugs, (c) cell death of cholinergic neurons and protection by nerve growth factor, (d) activation of astrocytes and microglia, and (e) vascular pathologies, including the role of platelets. Furthermore, we investigated (f) how microcontact printing on brain slices can be used to study the spread of β-amyloid and tau, and (g) how brain slices can help identify novel human AD biomarkers.},
}

@article {pmid40785395,
year = {2025},
author = {Bucci, M and Almkvist, O and Bluma, M and Ashton, NJ and Savitcheva, I and Chiotis, K and Di Molfetta, G and Blennow, K and Zetterberg, H and Nordberg, A},
title = {Profiling Plasma Biomarkers, Particularly pTau217 and pTau217/Aβ42, and Their Relation to Cognition in Memory Clinic Patients.},
journal = {Journal of neurochemistry},
volume = {169},
number = {8},
pages = {e70182},
doi = {10.1111/jnc.70182},
pmid = {40785395},
issn = {1471-4159},
support = {//Hjärnfonden/ ; 2017-06086//Vetenskapsrådet/ ; 2019-02397//Vetenskapsrådet/ ; 2020-4-3018//Vetenskapsrådet/ ; 2022-01018//Vetenskapsrådet/ ; 2023-00356//Vetenskapsrådet/ ; 2023-02649//Vetenskapsrådet/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; //KI private bequest (A Nordberg)/ ; //Fondation pour la Recherche sur Alzheimer/ ; //Family Kaudert donation/ ; //Region Stockholm KI CIMED/ ; //Region Stockholm (ALF grant)/ ; //Alzheimer fonden/ ; },
mesh = {Humans ; Male ; Female ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; Biomarkers/blood ; Aged ; *Cognitive Dysfunction/blood/diagnostic imaging/psychology ; *Peptide Fragments/blood ; Middle Aged ; Alzheimer Disease/blood/psychology/diagnostic imaging ; Aged, 80 and over ; *Cognition/physiology ; Positron-Emission Tomography ; Neuropsychological Tests ; },
abstract = {Alzheimer's disease (AD) is characterized by brain protein depositions, impaired synaptic transmission, and progressive cognitive decline. This clinical study, conducted at the tertiary memory clinic of Karolinska University Hospital in Stockholm, evaluates plasma pTau217 (in comparison to other plasma biomarkers) as a non-invasive marker for predicting brain amyloid load and cognitive impairment. Uniquely, it integrates plasma biomarkers with cognitive profiling and amyloid PET to assess diagnostic utility across disease stages in a real-world memory clinic setting. A total of 122 patients underwent extensive clinical examinations, including CSF analysis (used here for clinical diagnosis only), CT/MRI, neuropsychological (NP) testing (n = 80) and blood biomarker measurements. Prior to PET imaging, 74 patients were diagnosed with MCI among other diagnoses (AD, other dementia, no dementia). Following PET, patients were reclassified into diagnostic groups: MCI Aβ- (n = 29), MCI Aβ+ (n = 19), AD (n = 51), other dementias (n = 11). ROC analysis evaluated the ability of plasma biomarkers to predict Aβ-PET positivity. NP test z-scores were reduced into principal components (PCs) using PCA. Plasma pTau217 and pTau217/Aβ42 ratio were elevated in Aβ+ patients compared to MCI Aβ-patients. The ratio distinguished MCI Aβ+ from AD and, together with pTau217, showed the highest predictive value for Aβ positivity in the MCI group among the biomarkers analyzed (AUC 92.8% and 91.4%). Plasma pTau217/Aβ42 ratio was associated with principal component PC2 ("memory encoding and recall") in MCI Aβ+ (ρ =0.64, p=0.01) and negatively correlated with RAVL retrieval (PC2) in the same group (ρ =-0.57 and -0.6, p=0.028 and 0.017, respectively). Additionally, pTau217 correlated with the "Information" z-score (PC4) in both AD (ρ = -0.50, p = 0.005) and MCI Aβ+ (ρ = 0.53, p = 0.042). Plasma pTau217/Aβ42 might be a valuable predictor of brain amyloid pathology and a potential marker of domain-specific cognitive impairment in AD.},
}

Humans
Male
Female
*tau Proteins/blood
*Amyloid beta-Peptides/blood
Biomarkers/blood
Aged
*Cognitive Dysfunction/blood/diagnostic imaging/psychology
*Peptide Fragments/blood
Middle Aged
Alzheimer Disease/blood/psychology/diagnostic imaging
Aged, 80 and over
*Cognition/physiology
Positron-Emission Tomography
Neuropsychological Tests

@article {pmid40785374,
year = {2025},
author = {Shen, S and Lin, S and Gao, D and Hu, J and Bao, Z},
title = {Fish scale collagen peptide improves neurodegenerative disorders by dual regulation of acetylcholinesterase activity and antioxidant defense system.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70107},
pmid = {40785374},
issn = {1097-0010},
support = {//National Key Research and Development Program of China (2023YFF11052)/ ; },
abstract = {BACKGROUND: Memory impairment, a hallmark manifestation of neurodegenerative disorders exemplified by Alzheimer's disease, constitutes a critical global public health challenge requiring urgent therapeutic innovation. The present study aims to systematically investigate the potential mechanisms of fish scale collagen peptides (FSCP) in enhancing cognitive function through behavioral experiments, detection of hippocampal biochemical indicators and histopathological observation. Concurrently, liquid chromatography-tandem mass spectrometry analysis and in silico methods were utilized to screen active peptide fragments with potential auxiliary effects on memory improvement.

RESULTS: The results of our study demonstrated that mice treated with a medium dose of FSCP via gavage exhibited optimal behavioral performance. Moreover, the number of Nissl bodies in the CA1 and CA3 regions increased to (114.83 ± 8.74) and (71.67 ± 5.79), respectively. Hippocampal pathology was improved, Acetylcholine levels were elevated, Acetylcholinesterase ctivity was decreased and hippocampal oxidative stress was reduced in the mice. Among the digested products of FSCP, the tripeptides PPP, GGL, GLL and MAP were found to exhibit higher relative abundance and activity scores.

CONCLUSION: These results demonstrate that mice treated with a medium dose of FSCP via gavage exhibited the most substantial improvement in memory function. Bioactive peptides such as PPP and GGL are promising to provide a new source for the development of drugs for assisted memory improvement. © 2025 Society of Chemical Industry.},
}

@article {pmid40785310,
year = {2025},
author = {Kim, B and Shin, J and Lee, KH},
title = {Determinants of burden among family caregivers of persons with dementia: Observational study using multiple monitoring methods.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251365642},
doi = {10.1177/13872877251365642},
pmid = {40785310},
issn = {1875-8908},
abstract = {BackgroundSupporting persons with dementia and their caregivers is a global public health priority. However, current research typically relies on subjective caregiver reports, lacking the integration of objective physiological indicators.ObjectiveTo identify the determinants of caregiver burden among family caregivers of persons with dementia, guided by a biopsychosocial framework.MethodsSeventy-five dyads of persons with dementia and their caregivers participated in this study. The determinants of caregiver burden, including biological, psychological, and social factors, were assessed using sweat patches, actigraphy, and surveys, and analyzed using hierarchical multiple regression analysis.ResultsThe mean caregiver burden score was 42.32. Hierarchical multiple regression analysis showed that psychological factors explained 39.3% of the variance in caregiver burden. A 17.5% increase was observed by the addition of biological factors, accounting for 56.8% of the variance. Among the biological factors, high level of pro-inflammatory cytokine tumor necrosis factor-α in persons with dementia was significantly associated with increased caregiver burden. In contrast, long total sleep time was associated with decreased caregiver burden. Amidst psychological factors, not only increased depressive symptoms but also severe behavioral and psychological symptoms of dementia in individuals with dementia were significantly associated with increased caregiver burden.ConclusionsThese findings highlight the importance of tailored interventions that address both biological and psychological factors to reduce caregiver burden and improve care outcomes. Additionally, by alleviating caregiver burden, these interventions may also support ageing-in-place, allowing persons with dementia to remain in familiar environments within their communities.},
}

@article {pmid40785309,
year = {2025},
author = {Singh, RK and Bekena, S and Damera, N and Zhu, Y and Trani, JF and Babulal, GM},
title = {The relationships between cerebrospinal fluid neurofilament light chain and hippocampal atrophy with cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251365219},
doi = {10.1177/13872877251365219},
pmid = {40785309},
issn = {1875-8908},
abstract = {BackgroundIdentifying predictive biomarkers of cognitive decline is critical for timely intervention in early Alzheimer's disease and related dementia. Biomarkers such as cerebrospinal fluid (CSF) neurofilament light (NfL), and MRI-based hippocampal atrophy are potential indicators of neurodegeneration, but their long-term predictive value remains unclear.ObjectiveThis study examined 20-year longitudinal associations between CSF NfL, MRI-based hippocampal atrophy, and cognitive decline in cognitively normal older adults.MethodsA cohort of 279 cognitively normal adults aged ≥55 years was followed from 2003 to 2023 at the Knight ADRC. Participants underwent annual cognitive and neurological assessments, including Clinical Dementia Rating (CDR), CSF NfL quantification, and MRI-based hippocampal volumetry. Cognitive decline was defined as: (1) first progression (CDR ≥ 0.5) and (2) sustained progression (two consecutive CDRs ≥ 0.5). Analyses included Kaplan-Meier survival, Cox proportional hazards models, and linear mixed-effects (LME) models.ResultsParticipants had a mean age of 66.5 years (SD = 6.08); 58.4% were female. Mean follow-up was 11.41 years (SD = 3.5). First progression occurred in 71 participants (25.4%), and sustained progression in 35 (13%). Higher CSF NfL levels were associated with faster time to first (95% CI:0.2-1; p < 0.001) and sustained progression (95% CI:0.46-1; p = 0.008). Cox models showed increased risk of first progression (HR = 1.83; 95% CI: 1.11-3.01; p = 0.018) but not sustained (p = 0.093). LME models showed CSF NfL increase and hippocampal volume decline (p < 0.001) in both outcomes.ConclusionsCSF NfL is a strong predictor of cognitive decline and may serve as a screening biomarker for early dementia risk.},
}

@article {pmid40785308,
year = {2025},
author = {Motaghi, M and Potvin, O and Duchesne, S and , },
title = {Commonalities in cortical neurodegeneration between type 2 diabetes and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251365671},
doi = {10.1177/13872877251365671},
pmid = {40785308},
issn = {1875-8908},
abstract = {BackgroundType 2 diabetes (T2D) is a prevalent metabolic condition associated with increased risk of cognitive decline and dementia, including Alzheimer's disease (AD). While both T2D and AD are linked to neurodegeneration, the extent to which their patterns of brain atrophy overlap remain unclear.ObjectiveTo assess the similarities and differences in cortical atrophy patterns among individuals with controlled and uncontrolled T2D, mild cognitive impairment (MCI), and AD.MethodsStructural magnetic resonance imaging data from the UK Biobank (UKBB) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed. Participants aged 55 and older were selected. Linear regression models were applied to generate cortical thickness maps for each group, controlling for age and sex. Group comparisons were conducted using permutation-based tests accounting for spatial autocorrelation.ResultsThe study included 175 individuals with T2D (86 uncontrolled, 89 controlled) and 127 healthy controls without diabetes (HC) from UKBB, 334 individuals with MCI, 119 with AD and 315 cognitively healthy (CH) from ADNI. Uncontrolled T2D was associated with significant cortical atrophy in specific brain regions, with partial overlap in neurodegeneration patterns observed in MCI and AD. However, correlations between the cortical thinning patterns were weak and non-significant, suggesting distinct trajectories. Controlled T2D showed no significant cortical thinning, supporting the potential neuroprotective effects of glycemic control.ConclusionsUncontrolled T2D is linked to region-specific cortical atrophy that partially overlaps with MCI and AD but follows an independent neurodegenerative trajectory. Effective diabetes management may help preserve brain structure and reduce dementia risk, highlighting the importance of early metabolic intervention.},
}

@article {pmid40785278,
year = {2025},
author = {Karakaya, A and Acar Çevik, U and Kaya, B and Çiftçi, B and Necip, A and Işık, M and Beydemir, Ş and Özkay, Y and Kaplancıklı, ZA},
title = {Design, Synthesis, In Silico Absorption, Distribution, Metabolism, and Elimination and Molecular Docking Studies of Thiazole-Based Furan Derivatives, and Their Biological Evaluation for Alzheimer Disease Therapy.},
journal = {ChemistryOpen},
volume = {},
number = {},
pages = {e202500305},
doi = {10.1002/open.202500305},
pmid = {40785278},
issn = {2191-1363},
support = {//The Scientific and Technological Research Council of Türkiye (TÜBİTAK)/ ; },
abstract = {Herein, a series of novel 5-hydroxymethylfuran incorporated thiazole-based furan derivatives are synthesized and characterized. The in vitro inhibitory potentials of the derivatives against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are evaluated. In addition, the inhibitory potential of the thiazole-based furan derivatives against AChE (4EY7) and BChE (4BDS) proteins is examined as in silico. For this purpose, the effects of the compounds on human metabolism are evaluated with absorption, distribution, metabolism, excretion, and toxicity programming. Furthermore, their antioxidant potential is assessed through 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging assays. The enzymatic inhibition studies reveal that all compounds exhibit inhibitory effects on both AChE and BChE. Among them, compound 2b demonstrates the most potent inhibition against AChE, with a KI value of 14.887 ± 1.054 μM, whereas compound 2f exhibits the highest inhibitory activity against BChE, with a KI value of 4.763 ± 0.321 μM. Compounds 2a (12.202% for DPPH and 56.842% for ABTS) and 2i (13.309% for DPPH and 31.842% for ABTS) are among the most active compounds for both radical scavenging tests. These findings highlight that the synthesized derivatives possess promising dual cholinesterase (ChE) inhibitory activity as well as radical scavenging potential. These activities emphasize their potential as therapeutic candidates for neurodegenerative disorders such as Alzheimer's disease.},
}

@article {pmid40785271,
year = {2025},
author = {Canan, F and Wick, N and Raisanen, JM and Burns, DK and Hatanpaa, KJ and Richardson, TE and White, CL and Daoud, EV},
title = {Characterization of neurodegenerative pathologies in adult and pediatric subjects with Down syndrome.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251362762},
doi = {10.1177/13872877251362762},
pmid = {40785271},
issn = {1875-8908},
abstract = {BackgroundDown syndrome (DS) is frequently associated with Alzheimer's disease neuropathologic change (ADNC). However, studies assessing the full spectrum of neurodegenerative pathologies using modern consensus and staging criteria remain limited.ObjectiveWe aimed to elucidate the progression of neurodegenerative pathologies in DS and to explore the prevalence of comorbid pathologies across a broad age range (0-76 years), using comprehensive neuropathological assessments.MethodsWe conducted a two-phase analysis. First, we investigated an institutional dataset, followed by a pooled analysis incorporating data from the National Alzheimer's Coordinating Center and four published studies. Pathologies assessed included amyloid-β (Aβ), tau, α-synuclein, TDP-43, cerebral amyloid angiopathy (CAA), other cerebrovascular diseases (CVD), hippocampal sclerosis (HS), and basal ganglia mineralizations (BGM).ResultsDiffuse Aβ plaques appeared by age 11, with neuritic plaques emerging in the mid-thirties. Mild tau pathology, including pre-tangles and neuropil threads, first emerged in the second decade, with neurofibrillary tangles fully present in the fourth decade, always concurrent with Aβ plaques. All individuals over 30 exhibited ADNC. α-Synuclein pathology was observed in 27% of cases, while aging-related tau astrogliopathy (ARTAG), HS, and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) were rare. CVD was present in approximately 60%, CAA was nearly universal (98%) after age 50, and 18% had BGM. Brain weight was consistently below the 25th percentile, even in younger individuals without ADNC.ConclusionsDS shows a distinct neurodegenerative trajectory with early Aβ deposition. CAA, arteriolosclerosis, BGM, and α-synuclein pathology were highly prevalent, while ARTAG and LATE-NC were infrequently observed.},
}

@article {pmid40785178,
year = {2025},
author = {Amine, JM and Mourad, M},
title = {Multimodal Deep Learning Approaches for Early Detection of Alzheimer's Disease: A Comprehensive Systematic Review of Image Processing Techniques.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050401817250721190509},
pmid = {40785178},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia, and it is important to diagnose the disease at an early stage to help people with the condition and their families. Recently, artificial intelligence, especially deep learning approaches applied to medical imaging, has shown potential in enhancing AD diagnosis. This comprehensive review investigates the current state of the art in multimodal deep learning for the early diagnosis of Alzheimer's disease using image processing.

METHODS: The research underpinning this review spanned several months. Numerous deep learning architectures are examined, including CNNs, transfer learning methods, and combined models that use different imaging modalities, such as structural MRI, functional MRI, and amyloid PET. The latest work on explainable AI (XAI) is also reviewed to improve the understandability of the models and identify the particular regions of the brain related to AD pathology.

RESULTS: The results indicate that multimodal approaches generally outperform single-modality methods, and three-dimensional (volumetric) data provides a better form of representation compared to two-dimensional images.

DISCUSSION: Current challenges are also discussed, including insufficient and/or poorly prepared datasets, computational expense, and the lack of integration with clinical practice. The findings highlight the potential of applying deep learning approaches for early AD diagnosis and for directing future research pathways.

CONCLUSION: The integration of multimodal imaging with deep learning techniques presents an exciting direction for developing improved AD diagnostic tools. However, significant challenges remain in achieving accurate, reliable, and understandable clinical applications.},
}

@article {pmid40785177,
year = {2025},
author = {Varshney, H and Gaur, K and Subhan, I and Fatima, J and Jyoti, S and I, M and Shahid, M and -, R and Siddique, YH},
title = {Neuroprotective Effects of Fenugreek Leaf Extract in a Drosophila Model of Alzheimer's Disease Expressing Human Aβ-42.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050385870250721072643},
pmid = {40785177},
issn = {1875-5828},
abstract = {INTRODUCTION: Much emphasis has been given to the biological activities of Fenugreek against various diseased conditions. This study investigated the effect of fenugreek leaf extract on behavioural and cognitive function of transgenic Drosophila having human Aβ-42 expression in the neurons, herein referred to as Alzheimer's disease model flies (AD flies).

MATERIALS AND METHODS: AD flies were exposed to four different doses of fenugreek leaf extract (FE) containing i.e., 0.005, 0.010, 0.015 and 0.02 g/ml for 30 days. Thereafter, behavioural and cognitive assessment was done using climbing ability, activity pattern, aversive phototaxis and odour choice indexes. The life span of different groups of flies was also recorded. The effect of FE on the oxidative stress markers, acetylcholinesterase, monoamine oxidase (MAO) and caspase 3 and 9 activities was determined. The deposition of Aβ-42 aggregates in the brain tissue of the flies was studied by performing immunostaining. Also, the metabolic profile of different groups of flies was studied by performing LC-MS/MS. Compared with control flies, 22 selected metabolites were found to be upregulated and downregulated among transgenic AD flies and FE exposed AD flies compared to control.

RESULTS: The findings of this study showed the neuroprotective role of fenugreek extract, which could be employed for the treatment of Alzheimer's disease. The AD flies exposed to FE showed a dose-dependent postponement in the decline of climbing ability, activity and cognitive impairments. A significant dose dependent increase in the life span was also noticed in the AD flies exposed to FE. A significant reduction in the oxidative stress, acetylcholinesterase, monoamine oxidase, and caspase-3&9 activities was also observed in a dose dependent manner. The results obtained from the immunostaining suggest the reduction in the deposition of Aβ-42 fibril, which was also confirmed by the docking studies showing the energetically favoured interaction useful for inhibiting the acetylcholinesterase and Aβ-42 aggregates.

DISCUSSION: This study demonstrates the neurological potency of fenugreek leaf extract (FE) in a Drosophila model of AD due to its antioxidantive, anti-cholinesterase, and neuroprotective properties. Using a combination of behavioral, biochemical, histological, and metabolomic approaches, we evaluated the therapeutic potential of FE in mitigating AD-like symptoms in transgenic flies expressing Aβ-42.

CONCLUSION: Fenugreek leaf extract may serve as a potential natural remedy for slowing down or alleviating the progression of AD.},
}

@article {pmid40785029,
year = {2025},
author = {C, SK and Yegnaswamy, S and Dasgupta, D and Johari, P and Harish, M},
title = {Exploring the impact of serine phosphorylation flanking the KxGS motif in the repeat 3 domain of human tau on tubulin detachment.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/07391102.2025.2543373},
pmid = {40785029},
issn = {1538-0254},
abstract = {Tau, a highly disordered protein, comprises four repeat domains (R1-R4) essential for tubulin binding and structural stability. Post-translational modifications, such as the phosphorylation of serine residues within these repeat domains, regulate the tau protein's association and dissociation with tubulin protein. Notably, the detachment of tau from tubulin following phosphorylation contributes to neurofibrillary tangle formation within neurons, a hallmark of Alzheimer's disease. Despite its significance, the structural alterations induced by phosphorylation and their impact on these domains remain poorly understood. The present in silico study investigates the structural effects of phosphorylation at Ser305 (R2 domain), adjacent to the PGGG motif, and Ser320 (R3 domain), near the regulatory KxGS motif, through docking and simulation studies. The findings indicate that phosphorylation at Ser305 enhances tubulin binding more effectively than phosphorylation at Ser320. Alternatively, this finding was validated by binding the aggregator inducer, heparin, to tau. The results confirmed that Ser320-phosphorylated tau exhibited stronger binding than Ser305-phosphorylated tau protein. Altogether, these results suggest that Ser320-phosphorylated tau enhances the tau protein's propensity to aggregate more by strongly binding to heparin and activating the detachment process through weakly binding to tubulin. Thus, this study suggests that structural changes following phosphorylation at Ser305 might be non-pathogenic, whereas phosphorylation at Ser320 could be pathogenic, contributing to adverse effects. A deeper understanding of the role of phosphorylation in the tau-tubulin detachment mechanism could aid in the development of novel inhibitors to regulate tau aggregation and prevent neurofibrillary tangle formation.},
}

@article {pmid40784967,
year = {2025},
author = {Şener, B and Açıcı, K and Sümer, E},
title = {Improving early detection of Alzheimer's disease through MRI slice selection and deep learning techniques.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {29260},
pmid = {40784967},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Early Diagnosis ; Cognitive Dysfunction/diagnostic imaging/diagnosis ; Aged ; Brain/diagnostic imaging/pathology ; Male ; Female ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and behavioral changes. Early diagnosis, particularly identifying Early Mild Cognitive Impairment (EMCI), is vital for managing the disease and improving patient outcomes. Detecting EMCI is challenging due to the subtle structural changes in the brain, making precise slice selection from MRI scans essential for accurate diagnosis. In this context, the careful selection of specific MRI slices that provide distinct anatomical details significantly enhances the ability to identify these early changes. The chief novelty of the study is that instead of selecting all slices, an approach for identifying the important slices is developed. The ADNI-3 dataset was used as the dataset when running the models for early detection of Alzheimer's disease. Satisfactory results have been obtained by classifying with deep learning models, vision transformers (ViT) and by adding new structures to them, together with the model proposal. In the results obtained, while an accuracy of 99.45% was achieved with EfficientNetB2 + FPN in AD vs. LMCI classification from the slices selected with SSIM, an accuracy of 99.19% was achieved in AD vs. EMCI classification, in fact, the study significantly advances early detection by demonstrating improved diagnostic accuracy of the disease at the EMCI stage. The results obtained with these methods emphasize the importance of developing deep learning models with slice selection integrated with the Vision Transformers architecture. Focusing on accurate slice selection enables early detection of Alzheimer's at the EMCI stage, allowing for timely interventions and preventive measures before the disease progresses to more advanced stages. This approach not only facilitates early and accurate diagnosis, but also lays the groundwork for timely intervention and treatment, offering hope for better patient outcomes in Alzheimer's disease. The study is finally evaluated by a statistical significance test.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Deep Learning
*Magnetic Resonance Imaging/methods
Early Diagnosis
Cognitive Dysfunction/diagnostic imaging/diagnosis
Aged
Brain/diagnostic imaging/pathology
Male
Female