@article {pmid41388822,
year = {2025},
author = {Rozenblum, G and Ait-Aissa, K and Zahran, G and Alipour, M and Sahyoun, AM and Munkhsaikhan, U and Kassan, A and Ishrat, T and Wang, Q and Abidi, AH and Kassan, M},
title = {Unraveling the oral microbiome's role in Alzheimer's disease: From pathophysiology to therapeutic potential.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71011},
doi = {10.1002/alz.71011},
pmid = {41388822},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/microbiology/physiopathology ; *Microbiota/physiology ; *Mouth/microbiology ; *Dysbiosis/microbiology/complications ; Fusobacterium nucleatum ; Amyloid beta-Peptides/metabolism ; },
abstract = {Oral dysbiosis contributes to Alzheimer's disease (AD) by promoting neuroinflammation. Pathobionts such as Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum release virulence factors that induce amyloid beta aggregation and tau hyperphosphorylation, while the loss of commensals like Streptococcus salivarius and Neisseria spp. impairs anti-inflammatory protection, worsening neuronal damage. P. gingivalis is strongly linked to an increased risk of AD, especially in individuals with systemic conditions like diabetes, hypertension, and chronic kidney disease. Its presence in brain tissue correlates with a higher likelihood of AD, while salivary Veillonella and periodontal pathogens in gingival crevicular fluid show potential as non-invasive biomarkers for early AD detection. Therapeutic strategies targeting the oral microbiota, such as gingipain inhibitors, antimicrobials, probiotics, and prebiotics, show promise for mitigating AD risk. However, causal mechanisms and clinical efficacy remain to be fully established. Maintaining microbial balance through preventive and targeted modulation represents an innovative approach to reducing AD susceptibility. HIGHLIGHTS: We identified Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum as key oral pathogens driving Alzheimer's disease (AD) via gingipain-induced amyloid beta aggregation, systemic inflammation, and blood-brain barrier disruption. Our study revealed diabetes, hypertension, and chronic kidney disease (CKD) amplify AD risk through shared oral dysbiosis, with uremic toxins (CKD) and hyperglycemia (diabetes) exacerbating neuroinflammation. We propose Veillonella in saliva and Porphyromonas gingivalis in gingival crevicular fluid as non-invasive AD biomarkers, correlating with 6 to 10× higher AD risk when detected in brain tissue. Gingipain inhibitors (e.g., COR388), nitrate-reducing probiotics, and integrated dental-neurology care are promising interventions to disrupt the oral-brain axis. We advocate for oral microbiome screening in high-risk populations (apolipoprotein E ε4 carriers, diabetics) and interdisciplinary approaches to AD prevention.},
}

Humans
*Alzheimer Disease/microbiology/physiopathology
*Microbiota/physiology
*Mouth/microbiology
*Dysbiosis/microbiology/complications
Fusobacterium nucleatum
Amyloid beta-Peptides/metabolism

@article {pmid41388821,
year = {2025},
author = {Castellano, T and Wang, TC and Nolan, E and Wu, Y and Zhang, M and Clifton, M and Janve, VA and Durant, A and Regelson, A and Cody, K and Harrison, T and Engelman, CD and Jagust, W and Albert, M and Johnson, S and Resnick, SM and Sperling, R and Bilgel, M and Saykin, A and Vardarajan, B and Mayeux, R and , and Betthauser, T and Bennett, DA and Schneider, J and De Jager, P and Menon, V and Tosun, D and Mormino, E and Archer, DB and Dumitrescu, L and Hohman, TJ and Koran, ME},
title = {APOE, ABCA7, and RASGEF1C are associated with earlier onset of amyloid deposition from more than 4000 harmonized positron emission tomography images.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71006},
doi = {10.1002/alz.71006},
pmid = {41388821},
issn = {1552-5279},
support = {K76AG088554//Intramural Research Program of the NIA/NIH/ ; P50-AG008702.ROS/MAP//The Columbia University Alzheimer's Disease Research Center/ ; P30AG10161//The Columbia University Alzheimer's Disease Research Center/ ; P30AG72975//The Columbia University Alzheimer's Disease Research Center/ ; R01AG15819//The Columbia University Alzheimer's Disease Research Center/ ; R01AG17917//The Columbia University Alzheimer's Disease Research Center/ ; U01AG46152//The Columbia University Alzheimer's Disease Research Center/ ; U01AG61356//The Columbia University Alzheimer's Disease Research Center/ ; AACSF-22-973008/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; Positron-Emission Tomography ; Male ; Female ; *Alzheimer Disease/genetics/diagnostic imaging ; Aged ; *ATP-Binding Cassette Transporters/genetics ; *Apolipoproteins E/genetics ; *Brain/diagnostic imaging/metabolism ; *ras Guanine Nucleotide Exchange Factors/genetics ; Age of Onset ; Aged, 80 and over ; },
abstract = {INTRODUCTION: New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes.

METHODS: Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA.

RESULTS: Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA.

DISCUSSION: APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD.

HIGHLIGHTS: Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses.},
}

Humans
Positron-Emission Tomography
Male
Female
*Alzheimer Disease/genetics/diagnostic imaging
Aged
*ATP-Binding Cassette Transporters/genetics
*Apolipoproteins E/genetics
*Brain/diagnostic imaging/metabolism
*ras Guanine Nucleotide Exchange Factors/genetics
Age of Onset
Aged, 80 and over

@article {pmid41388809,
year = {2025},
author = {Moreno, N and Shchankin, N and Fung, L and Puangmalai, N and Bhatt, N and Haque, MA and Zhao, Y and Keene, CD and Limon, A and Kayed, R},
title = {APOE isoform-associated tau oligomer polymorphs differ in synaptotoxicity and seeding activity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70965},
doi = {10.1002/alz.70965},
pmid = {41388809},
issn = {1552-5279},
support = {AG06071801/NH/NIH HHS/United States ; AG07245801/NH/NIH HHS/United States ; AG07725301/NH/NIH HHS/United States ; AG05402506/NH/NIH HHS/United States ; AG077484/NH/NIH HHS/United States ; AG070255/NH/NIH HHS/United States ; AG073133/NH/NIH HHS/United States ; AG067952/NH/NIH HHS/United States ; },
mesh = {*tau Proteins/metabolism/genetics ; Humans ; *Apolipoproteins E/genetics/metabolism ; Protein Isoforms/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; Female ; Male ; *Synapses/pathology/metabolism ; Aged ; Animals ; },
abstract = {INTRODUCTION: Pathological tau aggregates form distinct polymorphic species across diseases and even across Alzheimer's disease (AD) patients. However, tau aggregate polymorphism across the apolipoprotein E isoforms (APOE ε2, ε3, ε4), the strongest predictors of late-onset AD development, is unknown.

METHODS: This study assessed the conformational and bioactivity properties of tau oligomers from 14 patients with varying APOE genotypes.

RESULTS: Tau oligomers differ in proteolytic stability and cleavage site profiles across the APOE isoforms, indicating conformationally distinct polymorphs. APOE isoform-associated tau oligomers affect synaptic plasticity differently, with ε4-associated oligomers having the highest potency and strongest impact on synaptic functioning. Bioactivity assays reveal that ε4-associated oligomers demonstrate particularly high seeding activity. Interestingly, tau oligomer synaptotoxicity and seeding activity are independent characteristics.

DISCUSSION: The APOE isoforms are associated with distinct tau oligomer polymorphs with varying bioactivity, underscoring the importance of considering APOE status when generating AD therapies. Polymorph-specific targeting of pathological tau species could provide a novel method of combating AD.

HIGHLIGHTS: Conformational and bioactivity distinctions of tau oligomers have not yet been investigated across the APOE isoforms (ε2, ε3, ε4). Tau oligomers differ in conformational properties across the APOE isoforms. APOE ε4-relevant tau oligomers strongly impair synaptic plasticity and demonstrate high tau seeding activity. APOE ε4-relevant tau oligomers exist as a particularly toxic species, making them an ideal target for tau-based AD therapies.},
}

*tau Proteins/metabolism/genetics
Humans
*Apolipoproteins E/genetics/metabolism
Protein Isoforms/genetics/metabolism
*Alzheimer Disease/genetics/metabolism/pathology
Female
Male
*Synapses/pathology/metabolism
Aged
Animals

@article {pmid41388808,
year = {2025},
author = {Cary, GA and Li, Q and Wiley, JC and Paisie, CA and Du, Y and Zoeller, EL and Duong, D and Fu, H and Seyfried, NT and Levey, AI and Betarbet, R and Carter, GW and , },
title = {Integrated phenotypic and proteomic screening identifies top-tier Alzheimer's disease therapeutic targets.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71008},
doi = {10.1002/alz.71008},
pmid = {41388808},
issn = {1552-5279},
support = {//Sun Health Research Institute Brain and Body Donation Program of Sun City/ ; //Arizona Alzheimer's Disease Core Cente/ ; //Arizona Department of Health Services/ ; U54 AG065187/AG/NIA NIH HHS/United States ; },
mesh = {*Proteomics/methods ; *Alzheimer Disease/metabolism/genetics/drug therapy ; Animals ; Phenotype ; Mice ; *Microglia/metabolism ; Presenilin-2/genetics/metabolism ; Humans ; RNA, Small Interfering ; Cell Line ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder. Hundreds of therapeutic targets have been nominated through genetic and multi-omic studies, but effective prioritization remains a major bottleneck.

METHODS: We applied an integrative screening framework to assess 29 candidate targets from risk-enriched biological domains. Using disease-relevant murine BV2 microglial cell lines with stable Psen2 knockdown, we performed small interfering RNA-mediated perturbations followed by cellular phenotypic assays and quantitative proteomics.

RESULTS: Twenty-five candidate targets significantly altered at least one phenotype, with stronger effects in Psen2 knockdown cells. Integrated proteomic analyses identified several perturbations that reversed AD-associated molecular patterns. Five targets-Ap2a2, Pdhb, Pdha1, Dlat, and Psmc3-impacted both phenotypes and related proteomic responses.

DISCUSSION: We established a scalable platform for target functional validation that bridges unbiased systems-level assessments of AD risk with experimental evidence. The Emory-Sage-Structural Genomics Consortium-Jax Center Target Enablement to Accelerate Therapy Development for Alzheimer's Disease center will prioritize further resource development for these validated targets.

HIGHLIGHTS: A screening platform was created to identify the most potent targets from nominated hypotheses. Integrated analysis of cellular proteomics and assay phenotypes was performed. Targets capable of reversing disease-associated proteomic signal were identified. The most impactful targets were strongly implicated in Alzheimer's disease pathogenesis.},
}

*Proteomics/methods
*Alzheimer Disease/metabolism/genetics/drug therapy
Animals
Phenotype
Mice
*Microglia/metabolism
Presenilin-2/genetics/metabolism
Humans
RNA, Small Interfering
Cell Line

@article {pmid41388803,
year = {2025},
author = {Sundaresh, SN and Vogel, EW and Hue, CD and Zhang, H and Staniszewski, A and Berman, HL and Gill, Z and Asam, K and Liang, S and Shen, L and Gnanaprakash, M and Acquarone, E and Masone, A and Fà, M and Kanaan, NM and Morrison, B and Arancio, O and Nicholls, RE},
title = {PP2A methylesterase, PME-1, and PP2A methyltransferase, LCMT-1, control sensitivity to impairments caused by injury-related oligomeric tau.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70947},
doi = {10.1002/alz.70947},
pmid = {41388803},
issn = {1552-5279},
support = {12347//Paul G. Allen Frontiers Group/ ; W81XWH-12-1-0579//U.S. Department of Defense/ ; W81XWH-15-1-0550//U.S. Department of Defense/ ; HT9425-23-1-0384//U.S. Department of Defense/ ; },
mesh = {Animals ; *tau Proteins/metabolism/toxicity ; *Carboxylic Ester Hydrolases/metabolism/genetics ; Humans ; *Protein O-Methyltransferase/metabolism/genetics ; Mice ; *Brain Injuries, Traumatic/metabolism ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; *Tauopathies ; *Protein Phosphatase 2/metabolism ; },
abstract = {INTRODUCTION: Oligomeric species of tau are a hallmark of Alzheimer's disease (AD). Given the evidence implicating protein phosphatase 2A (PP2A) in the molecular pathogenesis of tauopathies, we sought to determine whether manipulating the expression of enzymes that regulate PP2A activity, such as leucine carboxyl methyltransferase 1 (LCMT-1) and protein methylesterase 1 (PME-1), would alter pathological responses to oligomeric tau.

METHODS: We tested the effect of LCMT-1 and PME-1 overexpression on cognitive and electrophysiological impairments caused by exposure to either recombinant oligomeric human tau or oligomeric tau prepared from mice subjected to blast-induced traumatic brain injury.

RESULTS: We found that LCMT-1 overexpression reduced sensitivity while PME-1 overexpression increased sensitivity to tau-induced impairments. Moreover, shockwave exposure increased the propensity of endogenous tau to form toxic oligomers.

DISCUSSION: These results suggest that manipulating LCMT-1 or PME-1 activity may represent novel therapeutic approaches for disorders involving exposure to pathogenic forms of oligomeric tau.

HIGHLIGHTS: LCMT-1 and PME-1 overexpression alters sensitivity to oligomeric tau-induced impairments. Blast-induced traumatic brain injury increases the propensity of tau to oligomerize. Pathogenic tau-induced cognitive impairments were dependent on its oligomeric form.},
}

Animals
*tau Proteins/metabolism/toxicity
*Carboxylic Ester Hydrolases/metabolism/genetics
Humans
*Protein O-Methyltransferase/metabolism/genetics
Mice
*Brain Injuries, Traumatic/metabolism
Male
Disease Models, Animal
Mice, Inbred C57BL
*Tauopathies
*Protein Phosphatase 2/metabolism

@article {pmid41388643,
year = {2025},
author = {Mason, AC and Fatih, N and Sofat, R and Rentsch, CT and Smeeth, L and Bhaskaran, K and Chaturvedi, N and Garfield, V},
title = {Disentangling the relationship between glucose, insulin and brain health: A UK Biobank study.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70353},
pmid = {41388643},
issn = {1463-1326},
support = {220283/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; SCA/01/NCF/22//Diabetes Research and Wellness Foundation/ ; NIHR303160//NIHR/ ; },
abstract = {BACKGROUND: Glycaemic traits are associated with poorer brain health and dementia risk. Recent advances in genetic instruments for specific glycaemic markers enable an in-depth investigation of the likely nature of associations and underlying mechanisms between diabetes-related mechanisms and brain health and dementia.

METHODS: We used two-sample Mendelian randomisation (MR) in the UK Biobank (UKB) (maximum N = 357 883 White British, mean age 56.9 years, 54% female) applying inverse-variance weighted MR as our main estimator alongside MR-Egger, weighted median estimator (WME) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) as sensitivity tests. Instruments were 53 insulin resistance, 109 fasting glucose, 48 fasting insulin and 15 2-h post-load glucose genetic variants with variant-outcome effects estimated adjusting for 10 PCs. We checked core MR assumptions and sought to replicate results in an independent Alzheimer's dementia genome-wide association study (GWAS).

RESULTS: In UKB, higher 2-h post-load glucose was associated with a 69% increased Alzheimer's dementia risk (odds ratio 1.69 [95% confidence interval 1.38-2.07]), though this did not replicate in an independent GWAS. Fasting insulin, fasting glucose and postprandial glucose did not influence total brain, hippocampal or white-matter hyperintensity volumes.

DISCUSSION: The association between elevated 2-h post-load glucose and increased Alzheimer's risk supports a potential role for postprandial hyperglycaemia in dementia. The lack of associations between fasting or postprandial glucose and hippocampal, total-brain or white matter hyperintensity volumes suggests this risk may operate independently of gross structural atrophy.

CONCLUSION: Genetically proxied postprandial hyperglycaemia contributes to increased Alzheimer's risk in mid-life, warranting replication in other populations and ancestries to confirm and clarify underlying mechanisms.},
}

@article {pmid41388626,
year = {2025},
author = {Stringhi, R and Pelucchi, S and D'Andrea, L and La Greca, F and Zianni, E and Targa, L and Mosconi, C and Vandermeulen, L and Ascagni, M and Speciani, MC and Gardoni, F and Scheggia, D and Edefonti, V and Di Luca, M and Marcello, E},
title = {Cyclase-Associated Protein 2 gene delivery as a potential multi-target approach for preventing synaptic failure in Alzheimer's disease.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2025.12.023},
pmid = {41388626},
issn = {1525-0024},
abstract = {Alzheimer's Disease (AD) is marked by synaptic failure, with actin cytoskeleton alterations playing a key role in its pathogenesis. Cofilin, a regulator of actin dynamics in dendritic spines, forms cofilin-actin rods upon exposure to Amyloid-β (Aβ) oligomers, contributing to synaptic loss. Cyclase-associated protein 2 (CAP2) is crucial for regulating cofilin activity. During long-term potentiation, CAP2 dimerization is relevant for cofilin translocation to spines required for spine remodeling. In AD, CAP2 is downregulated, thus disrupting synaptic CAP2/cofilin complexes. To investigate the neuroprotective potential of CAP2 overexpression in preventing Aβ-induced synaptic dysfunction, we used adeno-associated virus serotype 9 (AAV) gene delivery to elevate CAP2 levels in APP/PS1 mice-a model of amyloid pathology-starting from the asymptomatic stage. APP/PS1 animals received bilateral stereotaxic injection of either AAV expressing CAP2 or a control AAV. This approach preserved synaptic CAP2/cofilin interaction, maintained synaptic plasticity pathways, and sustained cognitive function. CAP2 overexpression reduced cofilin-actin rod formation and mitigated tau abnormalities. Notably, CAP2 is present in cofilin-actin rods, and its dimerization is required to prevent Aβ-driven synaptic loss but not to protect neurons from rod formation. These findings highlight CAP2 upregulation as a promising strategy to enhance neuronal resilience and counteract Aβ synaptic toxicity in AD.},
}

@article {pmid41388533,
year = {2025},
author = {Khan, AR and Makhoul, GW and Raji, MA},
title = {Mirtazapine for gastrointestinal side effects of glucagon-like peptide-1 receptor agonist therapy in older adults.},
journal = {Endocrine regulations},
volume = {59},
number = {1},
pages = {260-264},
doi = {10.2478/enr-2025-0030},
pmid = {41388533},
issn = {1336-0329},
mesh = {Humans ; Aged ; Female ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetes Mellitus, Type 2/drug therapy ; *Mirtazapine/therapeutic use ; *Hypoglycemic Agents/adverse effects ; Glucagon-Like Peptides/adverse effects ; *Gastrointestinal Diseases/chemically induced/drug therapy ; Nausea/chemically induced/drug therapy ; Vomiting/chemically induced/drug therapy ; Glucagon-Like Peptide 1 ; },
abstract = {Objective. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) play a role in management of type 2 diabetes (T2D) and obesity by promoting glycemic control and weight reduction. Beyond these benefits, GLP-1 RAs have demonstrated positive effects on cardiovascular, renal, and neurological health, with emerging evidence supporting their therapeutic potential in conditions such as chronic kidney disease, asthma, obstructive sleep apnea, Parkinson's disease, and Alzheimer's disease. However, their widespread clinical use is often hindered by gastrointestinal side effects including nausea, anorexia, vomiting, and diarrhea that limit adherence and dose titration. Effective management of these adverse effects is essential to optimize treatment outcomes and maintain long-term therapy. Case report. A 72-year-old woman with a history of cognitive impairment, T2D, atrial fibrillation, obesity, and mood disorders presented with persistent gastrointestinal symptoms while receiving semaglutide. Dose escalation was restricted due to severe nausea, vomiting, and diarrhea, which markedly affected her quality of life. To manage these symptoms, mirtazapine was initiated. Following its introduction, the patient reported significant improvement in gastrointestinal tolerance enabling continued semaglutide therapy and successful dose advancement. Additional benefits included enhanced mood, better sleep, and overall well-being. No adverse effects related to mirtazapine were observed throughout the treatment. Conclusion. This case suggests that mirtazapine may be beneficial in mitigating GLP-1 RA-induced gastrointestinal side effects, thereby improving adherence and therapeutic efficacy. Further research is needed to evaluate the safety, mechanism, and generalizability of this approach in broader clinical practice.},
}

Humans
Aged
Female
*Glucagon-Like Peptide-1 Receptor Agonists
*Diabetes Mellitus, Type 2/drug therapy
*Mirtazapine/therapeutic use
*Hypoglycemic Agents/adverse effects
Glucagon-Like Peptides/adverse effects
*Gastrointestinal Diseases/chemically induced/drug therapy
Nausea/chemically induced/drug therapy
Vomiting/chemically induced/drug therapy
Glucagon-Like Peptide 1

@article {pmid41388396,
year = {2025},
author = {Tsagkari, D and Panagiotidou, E and Tavernarakis, N},
title = {The role of lipid metabolism in neuronal senescence.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70181},
pmid = {41388396},
issn = {2211-5463},
support = {GA-101087071//the General Secretariat for Research and Innovation of the Greek Ministry of Development/ ; 15546//Hellenic Foundation for Research and Innovation/ ; HFRI-FM17C3- 0869//Hellenic Foundation for Research and Innovation/ ; },
abstract = {Senescence is a complex cellular state characterised by irreversible growth arrest and metabolic reprogramming. In neurons, senescence has been mainly observed in the context of ageing and age-related neurodegeneration. Lipid metabolism plays a critical role in cellular homeostasis, with emerging evidence suggesting that alterations in lipid species, including fatty acids, cholesterol, sphingolipids and phospholipids, fundamentally drive or contribute to the senescent phenotype in both neuronal and non-neuronal cells in the brain. Namely, changes in lipid species levels result in the accumulation of lipid droplets (LDs), leading to dysregulation of membrane dynamics, and in turn to the production of bioactive lipid mediators, which collectively shape the senescence-associated secretory phenotype (SASP) in the brain. In this review, we describe the cell type-specific patterns of lipid dysregulation in neurons, astrocytes, microglia and other glial cells during senescence, highlighting the role of key lipid species and their association with senescence markers and phenotypes. Furthermore, we discuss the bidirectional relationship between lipid metabolism and mitochondrial dysfunction in cellular senescence. We also examine the molecular mechanisms through which lipid metabolic pathways can orchestrate neural senescence and their contribution to ageing and age-related neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Finally, we review emerging therapeutic strategies targeting lipid metabolic pathways to modulate neural senescence and potentially ameliorate age-associated brain pathology.},
}

@article {pmid41388352,
year = {2025},
author = {Akinluyi, ET and Takahashi-Yamashiro, K and Connolly, MG and Poon, WW and Macauley, MS},
title = {Interplay between CD33 and TREM2 in Alzheimer's Disease: Potential Mechanistic Insights into Microglial Function in Amyloid Pathology.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00805},
pmid = {41388352},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, tau neurofibrillary tangles, and progressive neuronal loss leading to cognitive decline. With millions affected worldwide, there remains an urgent need for innovative treatment strategies to combat this disease. Genome-wide association studies (GWAS) have identified genes expressed in microglia, the resident immune cells of the brain, as key mediators of AD susceptibility. Among microglial risk genes, CD33 and TREM2 stand out for their contrasting roles in AD risk. Accumulating evidence indicates that these receptors converge on overlapping signaling pathways to regulate microglial activation and Aβ clearance. Here, we review the current understanding of CD33 and TREM2 biology in AD, with a focus on their potential crosstalk and functional antagonism. We propose potential mechanistic models by which human CD33 isoforms regulate TREM2 activity in either the absence or presence of Aβ pathology and discuss therapeutic strategies targeting this axis. Together, these insights suggest new avenues for microglia-targeted interventions in AD.},
}

@article {pmid41388319,
year = {2025},
author = {Hwang, J and Moon, SY and Lee, H and Lee, J and Park, YK and Jeong, JH and Hong, CH and Jung, J and Na, HR and Cho, SH and Sung, J and Lee, SJ and Choi, SH},
title = {Polygenicity and APOE ε4 shape response to intervention in mild cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {262},
pmid = {41388319},
issn = {1758-9193},
support = {No. RS-2021-KH112636 and No. RS-2024-00337993//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC) funded by the Korea government (Ministry of Health & Welfare and MSIT)/ ; No. CRC22013-600//National Research Council of Science and Technology (NST) Aging Convergence Research Center funded by the Korea government (MSIT)/ ; No. NRF-2020M3E5D2A01084721//Basic Science Research Program through the National Research Foundation of Korea funded by the Korea government (MSIT)/ ; No. 2023R1A2C2002925//National Research Foundation of Korea grant funded by the Korea government (MSIT)/ ; No. 2022-0-00448/RS-2022-II220448//Institute of Information and Communications Technology Planning and Evaluation (IITP) funded by the Korea government (MSIT)/ ; },
mesh = {Humans ; *Cognitive Dysfunction/genetics/therapy/psychology ; *Apolipoprotein E4/genetics ; Male ; Female ; Aged ; Neuropsychological Tests ; *Multifactorial Inheritance/genetics ; Treatment Outcome ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Multidomain lifestyle interventions have shown effectiveness in preventing dementia, but identifying high-risk groups most likely to benefit remains unclear.

METHODS: We re-evaluated the SUPERBRAIN-MEET multidomain intervention study in mild cognitive impairment (MCI) patients, incorporating polygenic risk scores (PRS) for Alzheimer's disease and APOE ε4 status using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total index as the primary outcome.

RESULTS: Both intervention and control groups showed cognitive improvement over 24 weeks, with greater gains in the intervention arm. Relative intervention efficacy (RIE) increased with higher genetic risk, being most pronounced among APOE ε4 carriers and individuals with high PRS. When both factors were considered jointly, APOE ε4 carriers with high PRS exhibited the largest RIE (β = 7.54, SE = 2.59, p = 0.005), driven by markedly greater improvement in the intervention group. The secondary outcomes did not show as consistent results as RBANS total index.

DISCUSSION: These findings suggest that MCI individuals who are APOE ε4 carriers with high PRS may benefit most from multidomain interventions. These results support the complementary use of PRS and APOE status for identifying high-risk subgroups most likely to benefit from multidomain interventions.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05023057. Registered on 26 August 2021.},
}

Humans
*Cognitive Dysfunction/genetics/therapy/psychology
*Apolipoprotein E4/genetics
Male
Female
Aged
Neuropsychological Tests
*Multifactorial Inheritance/genetics
Treatment Outcome
Aged, 80 and over
Middle Aged

@article {pmid41388301,
year = {2025},
author = {Caceres-Palomo, L and Sanchez-Mejias, E and Trujillo-Estrada, L and Perez-Moreno, JJ and Lopez-Oliva, E and Lim, TE and DeFlitch, L and Chang, SH and Kampman, L and Corces, MR and Blurton-Jones, M and Moreno-Gonzalez, I and Pascual, A and Vitorica, J and Garcia-Leon, JA and Gutierrez, A},
title = {Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03607-z},
pmid = {41388301},
issn = {1742-2094},
support = {UMA20-FEDERJA-048 (to JAGL), PY18-RT-2233 (to AG), SNGJ4-11 (to LCP)//Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía/ ; UMA20-FEDERJA-048 (to JAGL), PY18-RT-2233 (to AG), SNGJ4-11 (to LCP)//Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía/ ; UMA20-FEDERJA-048 (to JAGL), PY18-RT-2233 (to AG), SNGJ4-11 (to LCP)//Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía/ ; P30 AG066519/NH/NIH HHS/United States ; P01AG073082, U01AG072573, and UM1HG012076 to MRC./NH/NIH HHS/United States ; P30 AG066519/NH/NIH HHS/United States ; PI21/00915 and PI24/00274 (to AG) and PI21/00914 and PI24/00308 (to JV)//Instituto de Salud Carlos III/ ; PI21/00915 and PI24/00274 (to AG) and PI21/00914 and PI24/00308 (to JV)//Instituto de Salud Carlos III/ ; PI-0276-2018 (to JAGL)//Consejería de Salud y Familias, Junta de Andalucía/ ; B1-2020_04 (to JAGL)//Universidad de Málaga/ ; },
}

@article {pmid41388214,
year = {2025},
author = {Li, W and Wang, X and Liu, J and Chen, Y},
title = {The Role of c-Abl in Alzheimer's Disease: Guilty or not Guilty?.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-025-01650-1},
pmid = {41388214},
issn = {1573-6830},
support = {81602796//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder. Extracellular senile plaques composed of amyloid-β (Aβ) peptides, intracellular neurofibrillary tangles (NFTs) containing the hyperphosphorylated tau protein, excessive production of reactive oxygen species (ROS) and neuroinflammation are crucial contributing factors to the pathological mechanisms of AD. The nonreceptor tyrosine kinase c-Abl plays a complex dual role in AD through the regulation of signaling pathways such as oxidative stress, DNA repair, and apoptosis. c-Abl mitigates early neuronal damage by activating antioxidant enzymes and potentially promoting homologous recombination (HR) repair. However, its aberrant activation is associated with Aβ plaque formation, tau phosphorylation, neuronal cell death, and synaptic dysfunction. Its synergistic interaction with Aβ and tau exacerbates the neurodegenerative pathology. This article provides a systematic review of the molecular mechanisms of c-Abl in AD, including its dual role in oxidative stress, synergistic regulation of neuronal function with Aβ and the tau protein, involvement in the maintenance of genomic stability, and potential as a therapeutic target.},
}

@article {pmid41388182,
year = {2025},
author = {McCoy, ND and Gawrys, SP and Mackintosh, SG and Byrum, S and Kosari, N and Zhou, A and Mansoor, MAM and Ikeno, Y and Isola, JVV and Stout, MB and Schneider, A and Masternak, MM and Mason, JB},
title = {Ovarian somatic tissue rejuvenates circulating apolipoproteins and promotes cognitive health in postreproductive female mice.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41388182},
issn = {2509-2723},
support = {R15AG061795/NH/NIH HHS/United States ; R56AG074499/NH/NIH HHS/United States ; R01AG069742/NH/NIH HHS/United States ; 24A12//Ed and Ethel Moore Alzheimer's Disease Research Program, Florida Department of Health/ ; P30 AG050911/AG/NIA NIH HHS/United States ; GCRLE-4501//The Global Consortium for Reproductive Longevity and Equality/ ; UTA01159//Utah Agricultural Experiment Station/ ; },
abstract = {Women experience more pronounced lipidomic changes with aging than men, which may contribute to the higher rates of Alzheimer's disease seen in postmenopausal women. Our earlier findings showed that transplantation of young ovarian somatic tissues or cells produced positive health-enhancing results in postreproductive females. In the current experiments, we looked to find key health-enhancing ovarian cells and pathways involved in this phenomenon. We conducted physiological and molecular analysis on animals/samples from old, postreproductive mice that received young ovarian tissue/cell transplants. Our analysis revealed a loss with age and a restoration with ovarian tissue/cell exposure, of serum biomarkers of lipid signaling and histological and behavioral markers of cognitive function. We further found, with single-cell transcriptomics and Raman spectroscopy, two candidate ovarian somatic cell types implicated in the restoration of health through a lipid signaling-based process. These results have identified key factors toward the determination of how germ cell-independent ovarian somatic tissues restore health through regulation of lipid signaling and dementia in postreproductive female mice.},
}

@article {pmid41388145,
year = {2025},
author = {Ehret, F and Doludda, B and Liu, H and Nexhipi, S and Huang, H and Rost, F and Overall, RW and Barde, W and Rünker, AE and Sieweke, M and Dahl, A and Schmidt, MHH and Kempermann, G},
title = {Lifestyle shapes preclinical social and microglial deficits in an Alzheimer's disease mouse model.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41388145},
issn = {1476-5578},
support = {98 597//Volkswagen Foundation (VolkswagenStiftung)/ ; 98 597//Volkswagen Foundation (VolkswagenStiftung)/ ; 19038//Alzheimer Forschung Initiative (Alzheimer Forschung Initiative e.V.)/ ; },
abstract = {Alzheimer's disease has a long preclinical phase, during which no overt signs of the manifest disease are present, but subtle, usually non-specific changes are already detectable. Emerging early biomarkers underscore the importance of this phase for preventive measures including lifestyle interventions. As a reductionistic model for lifestyle factors, we used a novel enrichment paradigm in which App[NL-G-F] knock-in mice were continuously tracked until 7 months of age. Despite minimal plaque burden and no memory impairment at that age, there were early and progressive deficits in social parameters - such as following behavior, social interaction, and exploration - suggesting preclinical behavioral vulnerability. Altered correlations between adult neurogenesis and social parameters linked neural plasticity to preclinical behavior. Plasma profiling at 3 months identified early systemic shifts in markers of inflammation and apoptosis that predicted later cortical pathology. We found increased microglia coverage in more socially active animals. More actively exploring controls, but not App[NL-G-F] mice, exhibited more ramified and less amoeboid microglia, suggesting that AD pathology impairs immune surveillance at a very early stage. Single-cell RNA sequencing of hippocampal microglia revealed that enrichment dampened interferon-responsive microglia, which typically increase as amyloidosis advances. A shifted immune response was also measured by reduced transcripts related to antigen processing and presentation and by increased chemokine signaling. Our study demonstrates that the preclinical phase of AD is not silent, but even in a reductionistic knock-in model characterized by early interwoven preclinical changes in multiple domains, including brain plasticity, behavioral trajectories, sociality and immunity.},
}

@article {pmid41388139,
year = {2025},
author = {Lima, MR and Capstick, A and Geranmayeh, F and Nilforooshan, R and Matarić, M and Vaidyanathan, R and Barnaghi, P},
title = {Evaluating spoken language as a biomarker for automated screening of cognitive impairment.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-025-01263-1},
pmid = {41388139},
issn = {2730-664X},
support = {EP/W031892/1//RCUK | Engineering and Physical Sciences Research Council (EPSRC)/ ; MR/T001402/1//RCUK | Medical Research Council (MRC)/ ; },
abstract = {BACKGROUND: Timely and accurate assessment of cognitive impairment remains a major unmet need. Speech biomarkers offer a scalable, non-invasive, cost-effective solution for automated screening. However, the clinical utility of machine learning (ML) remains limited by interpretability and generalisability to real-world speech datasets.

METHODS: We evaluate explainable ML for screening of Alzheimer's disease and related dementias (ADRD) and severity prediction using benchmark DementiaBank speech (N = 291, 64% female, 69.8 ± 8.6 years). We validate generalisability on pilot data collected in-residence (N = 22, 59% female, 76.2 ± 8.0 years). To enhance clinical utility, we stratify risk for actionable triage and assess linguistic feature importance.

RESULTS: We show that a Random Forest trained on linguistic features for ADRD detection achieves a mean sensitivity of 69.4% (95% confidence interval (CI) = 66.4-72.5) and specificity of 83.3% (78.0-88.7). On pilot data, this model yields a mean sensitivity of 70.0% (58.0-82.0) and specificity of 52.5% (39.3-65.7). For prediction of Mini-Mental State Examination (MMSE) scores, a Random Forest Regressor achieves a mean absolute MMSE error of 3.7 (3.7-3.8), with comparable performance of 3.3 (3.1-3.5) on pilot data. Risk stratification improves specificity by 13% on the test set, offering a pathway for clinical triage. Linguistic features associated with ADRD include increased use of pronouns and adverbs, greater disfluency, reduced analytical thinking, lower lexical diversity, and fewer words that reflect a psychological state of completion.

CONCLUSIONS: Our predictive modelling shows promise for integration with conversational technology at home to monitor cognitive health and triage higher-risk individuals, enabling early screening and intervention.},
}

@article {pmid41387998,
year = {2025},
author = {Yumlembam, S and Singh, K and Gupta, A and Adhikarimayum, P and Kumari, A and Sarangthem, K and Singh, LR},
title = {S-allyl cysteine and alliin enhance catalase activity and prevent aggregation to counter oxidative stress in alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30035-z},
pmid = {41387998},
issn = {2045-2322},
support = {09/476(0100)2020-EMR-I//CSIR/ ; },
abstract = {Oxidative stress is a key driver of Alzheimer's disease (AD), often linked to reduced activity of catalase, a major antioxidant enzyme. In AD, catalase is not only less active but also found as part of harmful protein aggregates with amyloid-β in brain plaques. Finding safe molecules that can boost catalase activity and stop it from aggregating could, therefore, offer a new strategy to lower disease progression. In this study, we examined two natural organosulfur compounds from garlic-S-allyl cysteine (SAC) and Alliin-for their effects on catalase. We found that both compounds significantly increased catalase activity in a concentration-dependent manner by stabilizing its structure and enhancing its thermodynamic stability. Furthermore, Molecular docking and Simulation studies revealed that SAC and Alliin bind at an allosteric site, promoting structural compaction and enhancing stability. Importantly, these compounds also reduced the tendency of catalase to form amyloid-like aggregates, a feature directly relevant to AD pathology. Our findings provide new mechanistic insights into how SAC and Alliin act on catalase-both stabilizing the enzyme and resulting in an increase in its activity along with lowering its aggregation propensity. This suggests that SAC and Alliin may serve as promising, natural candidates for therapeutic intervention in Alzheimer's disease.},
}

@article {pmid41387918,
year = {2025},
author = {Dougnon, G and Matsui, H},
title = {Lipofuscin accumulation in aging and neurodegeneration: a potential "timebomb" overlooked in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {67},
pmid = {41387918},
issn = {2047-9158},
support = {22K20681//Japan Society for the Promotion of Science/ ; 23K14672//Japan Society for the Promotion of Science/ ; JP 22484842//Japan Society for the Promotion of Science/ ; JP 23790744//Japan Society for the Promotion of Science/ ; JP23gm1710010//Japan Agency for Medical Research and Development/ ; P24wm0625506//Japan Agency for Medical Research and Development/ ; JPMJMS2024//Moonshot Research and Development Program/ ; },
mesh = {Humans ; *Lipofuscin/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Aging/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Oxidative Stress/physiology ; Amyloid beta-Peptides/metabolism ; Microglia/metabolism ; Lysosomes/metabolism ; Biomarkers/metabolism ; },
abstract = {Lipofuscin, a marker of aging, is the accumulation of autofluorescent granules within microglia and postmitotic cells such as neurons. Lipofuscin has traditionally been regarded as an inert byproduct of cellular degradation. However, recent findings suggest that lipofuscin may play a role in modulating age-related neurodegenerative processes, and several questions remain unanswered. For instance, why do lipofuscin granules accumulate preferentially in aged neurons and microglia? What happens to these pigments upon neuronal demise? Particularly in neurodegenerative diseases like Alzheimer's disease (AD), why does amyloid β (Aβ) deposition usually begin in late adulthood or during aging? Why do lipofuscin and amyloid plaques appear preferentially in grey matter and rarely in white matter? In this review, we argue that lipofuscin should be revisited not as a simple biomarker of aging, but as a potential modulator of neurodegenerative diseases. We synthesize emerging evidence linking lipofuscin to lysosomal dysfunction, oxidative stress, lipid peroxidation and disease onset-mechanisms critically implicated in neurodegeneration. We also explore the potential interactions of lipofuscin with Aβ and their spatial location, and summarize evidence showing that lipofuscin may influence disease progression via feedback loops affecting cellular clearance and inflammation. Finally, we propose future research directions toward better understanding of the mechanisms of lipofuscin accumulation and improved lysosomal waste clearance in aging.},
}

Humans
*Lipofuscin/metabolism
*Alzheimer Disease/metabolism/pathology
*Aging/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Oxidative Stress/physiology
Amyloid beta-Peptides/metabolism
Microglia/metabolism
Lysosomes/metabolism
Biomarkers/metabolism

@article {pmid41387800,
year = {2025},
author = {Guo, H and Guo, T and Wang, X and Bao, Y and Zhang, Z and Xue, F and Cheng, D},
title = {LAX1 as a core biomarker in Alzheimer's disease and periodontitis via the STAT signaling pathway.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-025-06865-x},
pmid = {41387800},
issn = {1471-2318},
support = {20241084 to Han Guo//the Medical Science Research Project in Hebei Province, PR China/ ; H2025206332//Natural Science Foundation of Hebei Province/ ; },
abstract = {BACKGROUND: The relationship between Alzheimer's disease (AD) and chronic periodontitis (PD) rarely share the medical spotlight, yet epidemiological mirroring hints at a common inflammatory root.

METHODS: Mining four GEO (Gene Expression Omnibus) cohorts (211 AD + 27 controls; 24 PD + 23 controls), batch-corrected and validated by principal component analysis (PCA)/t-distributed stochastic neighbour embedding (t-SNE)/uniform manifold approximation and projection (UMAP), we identified 61 shared differentially expressed genes (DEGs) with lymphocyte transmembrane adaptor 1 (LAX1) ranked first in weighted gene co-expression network analysis (WGCNA), maximum clique centrality (MCC), Degree, edge percolated component (EPC) and Stress algorithms, tightly co-expressed with colony-stimulating factor 3 receptor (CSF3R) and signal transducer and activator of transcription 1/3 (STAT1/3). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) uniquely highlighted the "LAX1/CSF3R/STAT" triad in apoptosis and JAK-STAT cascades. CIBERSORT de-convolution showed LAX1 covaried with plasma-cell, mast-cell and M0-macrophage infiltration.

RESULTS: Plasma from 42 AD and 38 stage-III/IV PD patients showed elevated soluble LAX1 (sLAX1) correlating with Mini-Mental State Examination (MMSE) decline (r =-0.67) and clinical attachment loss (r = 0.71), outperforming Aβ42 and receptor activator of nuclear factor-κB ligand (RANKL) in receiver operating characteristic (ROC) analyses (area under the curve [AUC] = 0.91). We hypothesised that LAX1 orchestrates the dialogue via the STAT axis. In human periodontal-ligament fibroblasts and 5 × FAD glia exposed to Porphyromonas gingivalis LPS or amyloid-β42 (Aβ42), LAX1 overexpression (pCMV6-LAX1) amplified STAT1/3 phosphorylation, elevated interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by 2.3-3.1-fold and escalated p53, cleaved caspase-3 and FAS, whereas LAX1 small interfering RNA (siRNA) abolished these effects. In other words, targeting of the LAX1 validated that the inflammatory/apoptotic signature scales with LAX1 abundance.

CONCLUSION: LAX1 gates STAT-dependent neuroinflammation and periodontal destruction, offering a druggable checkpoint and blood-based biomarker for these convergent chronic diseases.},
}

@article {pmid41387730,
year = {2025},
author = {Daniel Estrella, L and Sveeggen, TM and de la Guardia, G and Cacho, J and Stauch, KL and Bagher, P},
title = {A systematic review of the cerebrovascular adaptations following exposure to spaceflight or ground-based analogs: lessons from human and animal studies.},
journal = {NPJ microgravity},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41526-025-00540-6},
pmid = {41387730},
issn = {2373-8065},
support = {HL155618/HL/NHLBI NIH HHS/United States ; 80NSSC19K0392/NASA/NASA/United States ; },
abstract = {Human space exploration is rapidly advancing, with long-term expeditions becoming more common. Long-term space missions introduce prolonged exposure to microgravity and ionizing radiation, which elicit stress responses throughout many organ systems. As the cerebrovascular system is responsible for regulating blood flow to the brain, it is imperative to understand the effects of the space environment on the cerebrovascular system. Cerebrovascular alterations are also linked to neurological diseases such as Alzheimer's Disease, Parkinson's Disease, glaucoma, and stroke. This systematic review evaluates the current literature to demonstrate that spaceflight conditions (actual or ground-based analogs) can lead to changes in the cerebrovascular system at the network, cellular, and molecular levels. These findings demonstrate differences and similarities between cerebrovascular alterations due to the space environment and neurological conditions, highlighting that the mechanisms behind the reversibility and readaptation to Earth following spaceflight could inform treatments of neurological disease.},
}

@article {pmid41387393,
year = {2026},
author = {Roberts, SJ and Luckett, T and Ivynian, S and DiGiacomo, M},
title = {Elder Clowning Interventions for Persons With Dementia in Long-Term Care: A Systematic Review and Metasynthesis of Qualitative Research.},
journal = {Dementia (London, England)},
volume = {25},
number = {1},
pages = {192-214},
doi = {10.1177/14713012251366738},
pmid = {41387393},
issn = {1741-2684},
mesh = {Humans ; *Dementia/psychology/therapy ; Qualitative Research ; *Long-Term Care ; Quality of Life/psychology ; Aged ; Interpersonal Relations ; *Laughter Therapy/methods ; },
abstract = {Elder clowning is a psychosocial intervention delivered to persons living with dementia in long-term care. It aims to improve quality of life through interpersonal interaction and connection. This review aimed to synthesise international cross-disciplinary qualitative research regarding elder clowning specialist capabilities, engagement techniques, and potential benefits, for persons living with dementia, their families, and staff. The method was informed by systematic review methodologies. A comprehensive search of major health databases was undertaken. The search identified 198 studies, 15 articles from 10 studies were appraised and included in the review. Three major themes resulted from the synthesis: 1) understanding the elder clown, 2) journeying together to cultivate connection, and 3) promoting wellbeing through connection. Elder clowns were suggested to be perceptive, attuned, empathetic, present, adaptive, and performative. These capabilities supported a wide range of engagement techniques used to prepare for, approach, initiate, sustain, redirect, appeal for, and exit engagement with persons with dementia, which resulted in potential benefits across cognitive, behavioural, emotional, social, and experiential domains. The synthesis offers a common rubric for describing the components of elder clowning interventions for use across disciplines and identifies potential benefits to aid in the design of future trials of effectiveness.},
}

Humans
*Dementia/psychology/therapy
Qualitative Research
*Long-Term Care
Quality of Life/psychology
Aged
Interpersonal Relations
*Laughter Therapy/methods

@article {pmid41387343,
year = {2025},
author = {Park, J and Kim, B and Ha, M and Park, M and Ryu, H and Yu, H and Park, S and Roh, YS and Lim, KH and Hong, JT and Han, SB and Park, CW and Yong, SB and Park, H},
title = {CRISPRa Lipid Nanocomplex-Mediated Mt3 Targeting Enhances Astrocytic Endocytosis of Amyloid-β in an Alzheimer's Disease Mouse Model.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e03725},
doi = {10.1002/advs.202503725},
pmid = {41387343},
issn = {2198-3844},
support = {RS-2025-16068284//Korea government (MSIT)/ ; RS-2025-02273102//Korea government (MSIT)/ ; RS-2024-00440787//Bio & Medical Technology Development Program of the National Research Foundation (NRF)/ ; GTL24021-000//National Research Council of Science & Technology (NST)/ ; },
abstract = {Metallothionein 3 (Mt3) is crucial for cellular homeostasis and neuroprotection, with accumulating evidence linking it to amyloid-beta (Aβ) clearance by astrocytes. This study developed a CRISPR activator (CRISPRa) system using lipid nanoparticles to selectively upregulate Mt3 in astrocytes, aiming to enhance Aβ endocytosis in an Alzheimer's disease (AD) mouse model. To directly assess the therapeutic potential of Mt3 activation in a specific brain region, stereotaxic injection is utilized to deliver the CRISPRa lipid nanocomplexes. This approach enabled precise in vivo brain delivery and Mt3 activation. The findings reveal that CRISPRa lipid nanocomplex-mediated Mt3 upregulation significantly boosts Aβ uptake by astrocytes, leading to a marked reduction in Aβ plaque accumulation in AD mouse brains. These results highlight CRISPRa lipid nanocomplex-mediated Mt3 targeting as a promising strategy to enhance endogenous Aβ clearance, presenting a novel therapeutic avenue for AD.},
}

@article {pmid41387197,
year = {2025},
author = {Fredriksen-Goldsen, KI and Teri, L and Kim, HJ and Jones-Cobb, B and LaFazia, D and McKenzie, G and Petros, R and Jung, H and Oswald, AG and Hoy-Ellis, C and Emlet, C},
title = {Innovations in Dementia Empowerment and Action: RCT for Underserved Communities.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70189},
pmid = {41387197},
issn = {1532-5415},
support = {R01AG055488//National Institute on Aging of the National Institutes of Health/ ; },
abstract = {BACKGROUND: Research has revealed dementia disparities among underserved older adults. Built upon standard-Reducing Disability in Alzheimer's Disease (s-RDAD), Innovations in Dementia Empowerment and Action (IDEA) is designed and culturally tailored for underserved communities through an empowerment stigma-reduction cognitive-behavioral intervention and tested with sexual and gender minority (SGM) adults and care partners.

METHODS: The study is a 2-arm (IDEA and s-RDAD), single-blind, randomized controlled trial (RCT) with a staggered multiple baseline design. With 161 dyads (person living with dementia/care partner), the aim of the study is to compare the two arms via between and within group differences on primary (physical activity) and secondary outcomes (e.g., quality of life, physical functioning, and resource literacy) at post-treatment, and 30 and 56 week follow-up.

RESULTS: When comparing the two arm between-group differences, the IDEA care partners' community resource literacy was significantly higher at 30-week follow-up than for s-RDAD (contrast = 0.10, p = 0.005). While both intervention arms demonstrated efficacy with significant improvement in physical activity (contrastIDEA = 0.10, p = 0.010; contrasts-RDAD = 0.14, p < 0.001) and quality of life (contrastIDEA = 0.06, p < 0.001; contrasts-RDAD = 0.03, p = 0.035) for the person with dementia at post-treatment, positive treatment effects on physical activity (contrastIDEA = 0.09, p = 0.032) and quality of life (contrastIDEA = 0.03, p = 0.040) persisted at 30 weeks for IDEA but not for s-RDAD.

CONCLUSION: While both intervention arms were efficacious, IDEA demonstrated sustained efficacy. The cultural tailoring of interventions is promising to address disparities in dementia care and interventions in underserved communities. Future research is needed for the translation of this efficacious intervention to the larger community.

CLINICALTRIALS: gov identifier: NCT03550131.},
}

@article {pmid41386992,
year = {2025},
author = {Myers, AK and Sakheim, M and Rivell, C and Fengler, C and Festa, LK and Guerra, KM and Jarrahy, L and Shin, R and Case, M and Chapman, C and Basel, L and Springer, S and Kern, N and Gidicsin, J and Cho, G and Kim, S and Tighiouart, M and Golden, JA},
title = {Anxiety-associated behaviors following ablation of Miro1 from cortical excitatory neurons.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0436-25.2025},
pmid = {41386992},
issn = {2373-2822},
abstract = {Autism spectrum disorder, schizophrenia, and bipolar disorder are neuropsychiatric conditions that manifest early in life with a wide range of phenotypes, including repetitive behavior, agitation, and anxiety (American Psychological Association, 2013). While the etiology of these disorders is incompletely understood, recent data implicate a role for mitochondrial dysfunction (Norkett et al., 2017; Khaliulin et al., 2025). Mitochondria dynamically translocate to intracellular compartments to support energetics and free-radical buffering; failure to achieve this localization results in cellular dysfunction (Picard et al., 2016). Mitochondrial Rho-GTPase 1 (Miro1) resides on the outer mitochondrial membrane and facilitates microtubule-mediated mitochondrial motility and homeostasis (Fransson et al., 2003). The loss of MIRO1 is reported to contribute to the onset/progression of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease (Kay et al., 2018). We have hypothesized that MIRO1 also has a role in nervous system development and function (Lin-Hendel et al., 2016). To test this, we ablated Miro1 from cortical excitatory progenitors by crossing floxed Miro1 mice with Emx1-Cre mice and used mice of either sex for experiments. We found that mitochondrial mis-localization in migrating excitatory neurons was associated with reduced brain weight, decreased cortical volume, and subtle cortical disorganization. Adult Miro1 conditional mutants exhibit agitative-like behaviors, including decreased nesting behavior and abnormal home cage activity. The mice exhibited anxiety-like behavior and avoided confined spaces, features that have been linked to several human behavioral disorders. Our data link MIRO1 function with mitochondrial dynamics in the pathogenesis of several neuropsychiatric disorders and implicate intracellular mitochondrial dynamics to some anxiety-like behaviors.Significance Statement Neuropsychological disorders such as autism spectrum disorder, schizophrenia, and bipolar disorder have overlapping endophenotypes. While the mechanisms underlying these disorders are poorly understood, recent evidence implicates mitochondrial dysfunction and cellular mis-localization playing a role. Mitochondria support energy requirements and other physiological functions in cells. Previous research from our lab has shown distinct dynamic localization patterns within migrating excitatory and inhibitory neurons during development. To further examine the importance of mitochondrial localization, we ablated MIRO1, a protein important for coupling mitochondria to motor proteins, in excitatory neurons. The mis-localization of mitochondria in migrating excitatory neurons is associated with diminished motor skills and anxiety-like behavior in post-natal mice.},
}

@article {pmid41386518,
year = {2025},
author = {Contreras, PR and Henriquez, F and Gonzalez-Campo, C and Altschuler, F and Fraile-Vazquez, M and Ferreira, PC and Bellaver, B and Karikari, T and Pascoal, TA and Okuma, C and Gonzalez-Billault, C and Court, F and Cerda, M and Lillo, P and Khondoker, M and Hornberger, M and Slachevsky, A},
title = {Impact of cardiometabolic factors and AD plasma biomarkers on white matter hyperintensities volume in individuals with cognitive complaints from the global south.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.013},
pmid = {41386518},
issn = {1873-7544},
abstract = {White matter hyperintensities (WMH) are a magnetic resonance imaging (MRI) sign associated with cognitive complaints in the Alzheimer's Disease (AD) continuum, including the pre-dementia steps. Cardiovascular and neurodegenerative pathophysiology have been postulated as relevant factors in the origin of WMH in AD. However, this evidence comes mainly from northern global populations, where the epidemiological profile differs from other geographical regions. This study explores the relationship between WMH, cardiometabolic and plasma neurodegeneration biomarkers in individuals with cognitive complaints from a developing country in the global south, where cardiometabolic risk factors are highly prevalent. We analyzed 112 individuals with cognitive complaints, assessing plasma pTau217, Aβ42/Aβ40 ratio, blood pressure, and glycemia levels while quantifying and segmenting WMH volumes. Multiple regression analyses revealed that diastolic blood pressure was significantly associated with WMH in specific white matter tracts, including the anterior thalamic radiation, cingulum, forceps minor, and subcortical regions. In contrast, no associations were found with glycemia, pTau217, Aβ42/40, or systolic blood pressure. These findings suggest that cardiovascular factors could be more critical in WMH development than neurodegeneration markers in this population. Our study, in addition to reflecting, in part, the associations between cardiovascular risk factors and WMH, highlights the need for further research on neurovascular contributions to dementia pathophysiology in these populations, emphasizing the role of neurovascular integrity, blood-brain barrier function, and cerebrospinal fluid circulation in underrepresented geographical contexts.},
}

@article {pmid41386339,
year = {2025},
author = {Baviskar, PS and Mahajan, HS},
title = {"Unveiling Alzheimer's Disease (1901-2025): Historical Insights, Global Burden, Biological Mechanisms, Diagnostics, And Therapeutic Strategies".},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102990},
doi = {10.1016/j.arr.2025.102990},
pmid = {41386339},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), first identified by Dr. Alois Alzheimer in 1906, has evolved from a rare presenile dementia to a global health crisis affecting over 58 million people as of 2020, with projections reaching 152 million by 2050. Manuscript offers a comprehensive overview of AD, tracing its historical origins, epidemiological trends, pathophysiological mechanisms, diagnostic advancements, and therapeutic strategies. The pathogenesis of AD is multifactorial, involving amyloid-β plaque accumulation, tau protein hyperphosphorylation, cholinergic deficits, oxidative stress, and metal ion dyshomeostasis. These mechanisms converge to cause progressive neurodegeneration, cognitive decline, and behavioral disturbances. Clinically, AD manifests through a spectrum of neuropsychiatric symptoms, progressing from mild cognitive impairment to severe dementia, with distinct phenotypes and overlapping features with other dementias like DLB and VaD. Diagnostic approaches have advanced from clinical observation to biomarker-based precision, incorporating CSF and plasma tau assays, neuroimaging modalities (MRI, PET, SPECT), and AI-driven models for early detection. Despite these innovations, definitive diagnosis remains challenging due to symptom heterogeneity and overlap with other conditions. Therapeutically, the landscape has shifted from symptomatic treatments (e.g., cholinesterase inhibitors, memantine) to disease-modifying agents. Recent FDA approvals of monoclonal antibodies like Aducanumab, Lecanemab, and Donanemab mark a new era in targeted immunotherapy. However, many candidates targeting amyloid and tau pathways have failed in trials, underscoring the complexity of AD. Emerging drug delivery systems, including nanocarriers and intranasal formulations, aim to overcome the BBB and enhance therapeutic efficacy. The manuscript emphasizes the urgent need for integrative, personalized, and scalable solutions to manage AD's growing burden.},
}

@article {pmid41386298,
year = {2025},
author = {Ealy, A and Serapiglia, AM and Panicker, N},
title = {Sterile Innate Immune Mechanisms in Neurodegenerative diseases.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {111039},
doi = {10.1016/j.jbc.2025.111039},
pmid = {41386298},
issn = {1083-351X},
abstract = {Neurodegenerative diseases are characterized by the dysfunction and death of susceptible neuronal populations. Increasing evidence has demonstrated that sustained neuroinflammation and activation of innate immune complexes underlie neurodegeneration, worsening disease progression and outcomes. Sterile inflammation (which occurs in the absence of infection) can be triggered by neurodegenerative disease-associated misfolded proteins. These studies highlight the need to decipher the complexities of innate immune signaling mechanisms and their contribution to neuropathology. In this review, we focus on major neurodegenerative diseases that have a well-documented neuroinflammatory component: Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS) and Frontotemporal Dementia (FTD). In the context of these diseases, we discuss recent advances in innate-immune mechanisms that have been demonstrated to partake in disease progression and neurodegeneration. These include evolutionarily conserved innate-immune signaling complexes whose uncontrolled activation amplifies neurodegeneration, damaging lipid droplets that accumulate within myeloid cells and prevent their ability to clear toxic protein aggregates, as well as genome-wide studies implicated genes/proteins. The individual and/or concerted actions of these pathways could be leveraged to rationally target the pathogenesis or progression of neurodegenerative diseases.},
}

@article {pmid41386198,
year = {2025},
author = {Iqbal, S and Liu, L and Marshall, GA and Sarkis, RA},
title = {Plasma p-Tau217 and p-Tau181 levels in Well-Controlled versus Drug-Resistant focal epilepsy.},
journal = {Epilepsy & behavior : E&B},
volume = {175},
number = {},
pages = {110855},
doi = {10.1016/j.yebeh.2025.110855},
pmid = {41386198},
issn = {1525-5069},
abstract = {BACKGROUND: Compared to patients with well-controlled epilepsy, those with drug-resistant epilepsy often experience greater morbidity, mortality, and accelerated aging. Plasma biomarkers pTau217 and pTau181 align with cerebrospinal fluid tau values and amyloid PET imaging, correlating with Alzheimer's disease (AD) pathology. These minimally invasive markers may help explore links between neurodegeneration and epilepsy. This study assessed plasma pTau217 and pTau181 levels in patients with drug-resistant (DR) and well-controlled (C) epilepsy to determine whether poor seizure control correlates with elevated biomarkers.

METHODS: Adults aged 18-65 with focal epilepsy were prospectively recruited from the Brigham and Women's Hospital Epilepsy Clinic. Clinical data, including time since last seizure, were obtained from electronic health records. Plasma pTau181 and pTau217 levels were measured and analyzed in relation to seizure control, MRI lesion presence, antiseizure medication use, and time since last seizure.

RESULTS: Plasma was collected from 103 patients: 48 well-controlled (C, 31.3 % female) and 55 drug-resistant (DR, 50.9 % female). Mean ages were 38.7 ± 12.3 years (C) and 37.0 ± 11.6 years (DR). Log-transformed mean plasma levels were not significantly different: pTau181 (DR: 2.17 ± 0.99 vs. C: 2.33 ± 0.87, p = 0.35) and pTau217 (DR: 3.87 ± 0.97 vs. C: 4.10 ± 0.95, p = 0.23). No correlation was observed between plasma tau and time since last seizure: pTau181 (ρ = +0.001, p = 0.99), pTau217 (ρ = +0.13, p = 0.18). Tau levels did not differ based on use of synaptic vesicle protein 2A inhibitors or sodium channel blockers.

DISCUSSION: Interictal plasma biomarkers of neurodegeneration are not elevated in adults with poorly controlled epilepsy and do not correlate with time since last seizure or specific antiseizure medications. Future studies should explore whether subpopulations exist with increased risk or early markers of accelerated aging.},
}

@article {pmid41385865,
year = {2025},
author = {Kim, S and Kumar, V and Shin, SJ and Nam, Y and Park, YH and Jang, S and Park, JY and Kim, DH and Moon, M},
title = {In silico virtual screening of natural small molecules for dual inhibition of Aβ and tau aggregation in Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118876},
doi = {10.1016/j.biopha.2025.118876},
pmid = {41385865},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is defined by the accumulation of amyloid beta (Aβ) plaques and twisted fibers of hyperphosphorylated tau, with their aggregation driving neurodegeneration and cognitive decline. Presently, the majority of therapies in development are largely single-targeted, focusing either on Aβ or tau aggregation. This highlights a significant gap in strategies that can simultaneously modulate aggregation of both proteins in AD. This study employed an integrated in silico approach to identify phenolic small molecules capable of modulating both Aβ and tau aggregation. From a library of 160 natural compounds, fifteen phenolic-structured compounds inhibited Aβ aggregation by more than 50 %, and subsequent in silico screening identified baicalein, genkwanin, 2-hydroxycinnamaldehyde, and gallic acid as potential dual inhibitors. To further evaluate their dual-modulating potential, we conducted molecular docking, molecular dynamics simulations, and pharmacokinetic predictions. First, molecular docking with multiple conformers of Aβ and tau showed that all four compounds bound strongly to key aggregation-prone residues. Second, molecular dynamics simulations further demonstrated stable interactions with dimeric Aβ and tau. Third, pharmacokinetic predictions supported drug-likeness, including favorable blood-brain barrier permeability and systemic clearance. Finally, Thioflavin T assays were subsequently conducted to examine whether the computationally predicted anti-aggregation potential was reflected in biological outcomes, and the results confirmed that the predicted interactions were partially recapitulated under in vitro conditions. Together, our findings provide mechanistic and pharmacokinetic support for the further development of these phenolic compounds as Aβ and tau-targeting agents in early-stage AD therapy.},
}

@article {pmid41385796,
year = {2025},
author = {Castilla Bolanos, MA},
title = {3D Bioprinting cell-laden bioinks for engineering neural tissues and potential models for Parkinson's disease.},
journal = {Progress in biomedical engineering (Bristol, England)},
volume = {},
number = {},
pages = {},
doi = {10.1088/2516-1091/ae2c2a},
pmid = {41385796},
issn = {2516-1091},
abstract = {Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer's disease, affecting over ten million people worldwide. It is characterized by motor symptoms such as tremors, rigidity, and gait disturbances. Current treatments focus on alleviating symptoms and slowing down brain degeneration, but no cure exists, leading to a progressive decline in patients' quality of life. Three-dimensional (3D) bioprinting has emerged as a powerful technique for developing constructs that engineer neural tissues with complexities mimicking physiological conditions. These constructs can serve as vehicles for controlled drug delivery and potential substitutes for neurodegeneration. This article aims to compile new research data and review the current state of PD models engineered by 3D bioprinting, focusing on the desired biochemical features of bioinks for cell protection during printing, cell behavior, and differentiation into 3D constructs. Additionally, it discusses the physical, mechanical, and chemical characterization of bioprinted scaffolds and the importance of post-printing assessment to ensure printability, shape fidelity, appropriate construct degradation, and extracellular matrix production rates for developing complex 3D bioprinted constructs. Finally, it proposes opportunities for models that can be used to study novel therapeutics and immunomodulatory responses in tissues engineered for PD and other neurodegenerative diseases. .},
}

@article {pmid41385611,
year = {2025},
author = {Yin, Q and Yuan, M and Que, F and Huang, S and Wang, F},
title = {Research on secondary metabolites of the oyster endophytic fungus Penicillium griseofulvum QDYM-3 and their anti-Alzheimer's disease activity.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/14786419.2025.2591176},
pmid = {41385611},
issn = {1478-6427},
abstract = {Five compounds were isolated from the fermentation broth of the oyster endophytic fungus Penicillium griseofulvum QDYM-3, including 1,6-dihydroxy-3-methoxy-8-methylxanthone (1), (+)-griseofulvin (2), (4 R,5R,6R)-4,5-dihydroxy-6-(6'-methylsalicyloxy)-2-methyl-2-cyclohexen-1-one (3), 3-hydroxybenzyl alcohol (4), and epigriseofulvin (5). Compounds (1), (3), and (4) significantly inhibited Aβ aggregation, with compound (3) being the most effective, after the compound (3) was incubated with Aβ for 9 h, the THT fluorescence was detected to be 1089.67 AU, close to the 1044.33 AU of the positive control. Its neuroprotective effects were evaluated using an Aβ1-42 induced SH-SY5Y cell injury model, showing no cytotoxicity at concentrations of 1 to 25 µg/mL. Notably, 1 µg/mL of compound (3) reduced ROS levels by 26.87%, the enzymatic activities of SOD, CAT, and GSH were elevated by 13.97%, 20.74%, and 82.27% respectively, while the level of MDA was reduced by 20.42%. Additionally, the expression of intracellular proteins p-Akt, p-GSK-3β and β-catenin were up-regulated by 57.9%, 50.8% and 40.4%, respectively, at a sample concentration of 5 μg/ml compared with the injury group.},
}

@article {pmid41385529,
year = {2025},
author = {Ahmed, TF and Ahmed, A and Haque, Z and Azmi, MB and Salam, JU and Hanif, F},
title = {Mapping the microRNA-mediated crosstalk between insulin resistance and Alzheimer's disease: A computational genomic insight.},
journal = {PloS one},
volume = {20},
number = {12},
pages = {e0329056},
pmid = {41385529},
issn = {1932-6203},
mesh = {*Alzheimer Disease/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; *Insulin Resistance/genetics ; Humans ; *Computational Biology/methods ; Protein Interaction Maps ; Gene Regulatory Networks ; *Genomics/methods ; Gene Expression Regulation ; Signal Transduction ; },
abstract = {Insulin resistance (IR) and Alzheimer's disease (AD) share overlapping molecular mechanisms, but the precise link between these conditions remains unclear. MicroRNAs, as post-transcriptional regulators of gene expression, may mediate this connection by targeting genes involved in both pathways. In this study, we employed a multi-step bioinformatics approach to identify microRNAs that simultaneously regulate genes associated with IR and AD. Twenty key IR-related genes were selected from the literature, and their microRNA regulators were predicted using five computational tools. These predictions were validated using experimentally supported databases (TarBase and miRTarBase), and each miRNA-gene interaction was scored. Sixteen high-confidence microRNAs were shortlisted based on cumulative prediction and validation scores. These microRNAs were then analyzed for their interactions with AD pathway genes via KEGG pathway analysis. The AD-related target genes were further processed through protein-protein interaction network analysis using STRING and hub gene identification via Cytoscape. Functional enrichment of these hub genes using Gene Ontology and KEGG analysis revealed their involvement in shared biological processes, including apoptosis, insulin signaling, glucose metabolism, and neuroinflammation. Prominent candidates such as miR-7-5p, miR-106b, miR-424-5p, and miR-15a were identified. These results suggest that a subset of microRNAs may serve as critical molecular links between IR and AD, offering potential targets for early diagnosis and intervention.},
}

*Alzheimer Disease/genetics/metabolism
*MicroRNAs/genetics/metabolism
*Insulin Resistance/genetics
Humans
*Computational Biology/methods
Protein Interaction Maps
Gene Regulatory Networks
*Genomics/methods
Gene Expression Regulation
Signal Transduction

@article {pmid41385492,
year = {2025},
author = {, },
title = {Correction: Integration of wearable devices and artificial intelligence in Alzheimer's disease: A scoping review protocol.},
journal = {PloS one},
volume = {20},
number = {12},
pages = {e0339031},
pmid = {41385492},
issn = {1932-6203},
abstract = {[This corrects the article DOI: 10.1371/journal.pone.0331129.].},
}

@article {pmid41385426,
year = {2025},
author = {Chen, S and Wu, W and Zhang, X and Xu, J and Xiong, T and Yang, C and Xu, X},
title = {T2AgeNet: A Text-Guided Framework with Tissue Features for Brain Age Estimation.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2025.3643900},
pmid = {41385426},
issn = {1558-2531},
abstract = {Brain age estimation from structural MRI is an effective approach for detecting abnormal neurodevel opment and neurodegeneration. However, most existing methods produce global biomarkers that lack tissue-level specificity and fail to leverage medical prior knowledge. To address these limitations, we propose T2AgeNet, a dual-path image-text framework for tissue-level brain age estimation that integrates anatomical features with clinical semantics. The framework first segments brain MRI to generate tissue-specific masks, forming the basis for localized age prediction. To further incorporate medical prior knowledge, the model first aligns visual features with personalized clinical descriptions to guide semantic understanding of tissue-level variation. In parallel, it transforms handcrafted aging-related features into textual representations through an auxiliary branch using a large language model, enabling enriched interpretation and representation. We evaluate T2AgeNet on five datasets spanning fetal development, preterm infants, Alzheimer's disease, and autism spectrum disorder. Results demonstrate accurate age estimation across diverse populations. On the OASIS-3 and ABIDE-I datasets, the model further identifies tissue specific structural abnormalities consistent with known neurological patterns.},
}

@article {pmid41385352,
year = {2025},
author = {Sachdev, P},
title = {Alzheimer's & Dementia: The Journal of the Alzheimer's Association.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.12924},
pmid = {41385352},
issn = {1552-5279},
}

@article {pmid41385296,
year = {2025},
author = {Sha, L and Li, H and Peng, A and Yang, H and Liu, X and Zhao, H and Ma, W and Hong, Q and Tang, Y and Zhang, M and Chen, L},
title = {Diagnostic value of saccades in mild cognitive impairment (MCI): a community-based study.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaf264},
pmid = {41385296},
issn = {1758-535X},
abstract = {BACKGROUND: Accurate diagnosis and assessment of mild cognitive impairment (MCI) are essential. The efficacy of saccades in the detection of MCI lacks validation through large-scale clinical trials.

METHODS: All eligible participants underwent saccadic assessment in four tasks and cognitive assessment. MCI diagnoses were made on the basis of clinical indicators and MRI by experienced physicians. The physicians were blinded to the saccade experiments and the operators of saccade experiments were blind to the diagnosis of physicians. The classification models based on machine learning was constructed for assessing the diagnostic accuracy of MCI based on saccadic parameters.

RESULTS: Of the 559 residents who consented to participate, 383 (153 with MCI and 230 controls) were completely assessed. The classification model trained by saccadic parameters achieved high accuracy in dissociating MCI and control with AUROC of 0.945 (95% CI, 0.924-0.964), sensitivity of 0.824 (95% CI, 0.769-0.886) and specificity of 0.904 (95% CI, 0.867-0.935). The parameters of the memory-guided and antisaccade tasks demonstrated better diagnostic efficacy. The saccade model also exhibited a good diagnostic value in patients with borderline cognition being defined by the score of MoCA. When the borderline cognition was defined as 23-27 of MoCA score, the diagnosing accuracy of MCI based on saccadic parameters resulted with AUROC of 0.911 (95% CI: 0.836-0.972), sensitivity of 0.929 (95% CI, 0.762-1.000) and specificity of 0.796 (95% CI, 0.718-0.863).

CONCLUSIONS: Saccades can distinguish MCI from controls with great accuracy, offering a sensitive and objective diagnostic aid of MCI, especially in participants with borderline cognition.},
}

@article {pmid41385058,
year = {2025},
author = {Jiang, H and Escamilla, S and Beestrum, M and Salas-Lucia, F},
title = {Cost-effectiveness of testing biofluid biomarkers to diagnose Alzheimer's disease: a systematic review.},
journal = {The European journal of health economics : HEPAC : health economics in prevention and care},
volume = {},
number = {},
pages = {},
pmid = {41385058},
issn = {1618-7601},
abstract = {BACKGROUND: Alzheimer's disease (AD) affects tens of millions of individuals and their families in the world. As AD progresses, the effectiveness of treatment declines, making a timely diagnosis crucial. One promising approach for timely diagnosis is testing biofluid biomarkers in patients' blood and cerebrospinal fluid (CSF). However, a comprehensive evaluation of whether these tests are cost-effective is missing. Here, we conducted a systematic review to assess the cost-effectiveness of testing biofluid biomarkers to diagnose AD.

METHOD: We searched PubMed, Embase, Cochrane Library, and Web of Science for studies published until October 2024. Studies were included if published in English, conducted an economic evaluation of CSF or blood biomarker testing to diagnose AD, and provided economic outcomes. We assessed the quality of studies using the CHEERS 2022 criteria.

RESULTS: Nine studies were included: six evaluated CSF biomarker tests and three on blood biomarker tests. All studies used model-based simulations (decision trees or Markov models) rather than trial-based evaluations. CSF biomarker tests were mostly cost-effective compared to neurocognitive assessments or neuroimaging, while blood biomarker tests showed mixed results. Key cost-effectiveness contributors included AD prevalence, diagnostic accuracy, and treatment effectiveness. Studies met ~ 80% of the CHEERS criteria, with missing information on patient engagement.

CONCLUSION: Our review supports that biofluid biomarker testing could be cost-effective to diagnose AD. Given the lack of trial-based economic evaluations, model-based studies are a valuable starting point. Future evaluations should incorporate patient-centered outcomes and consider the emotional value and other socio-economic factors that affect patients and families suffering from AD.},
}

@article {pmid41384939,
year = {2025},
author = {Wang, W and Wei, X and Sun, Z and Zhang, X and Pan, D and Hong, X and Li, X and Yang, D},
title = {Uncovering the toxicological impact of benzo[a]pyrene on Alzheimer's disease via network toxicology, machine learning, and single-cell transcriptomics.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251405468},
doi = {10.1177/13872877251405468},
pmid = {41384939},
issn = {1875-8908},
abstract = {BackgroundBenzo[a]pyrene (BaP), a common environmental neurotoxicant, has been linked to neurodegenerative diseases, yet its role in Alzheimer's disease (AD) remains unclear.ObjectiveThis study integrated network toxicology, machine learning, single-cell transcriptomics, and bibliometric analysis to explore BaP's mechanistic role in AD.MethodsA total of 253 BaP-AD common targets were identified and analyzed via GO/KEGG enrichment and PPI network construction. Key genes were screened using GEO-based AD differential expression data and machine learning (LASSO and SVM). Molecular docking assessed BaP-target interactions. Cell-type-specific expression was analyzed using single-cell RNA-seq (GSE157827). ROC curves evaluated diagnostic value, and bibliometrics explored research trends.ResultsTargets were enriched in oxidative stress and MAPK/PI3K-Akt pathways. EGFR and HSP90AB1 were identified as core targets, with strong BaP binding affinities (-8.4 and -11.7 kcal/mol, respectively). EGFR was highly expressed in astrocytes and OPCs; HSP90AB1 in astrocytes and neurons. EGFR had better diagnostic performance (AUC = 0.781). Bibliometric analysis showed increasing attention on EGFR's role in AD.ConclusionsBaP may promote AD by targeting EGFR and HSP90AB1, affecting inflammation, proteostasis, and survival pathways. Notably, EGFR may serve emerge a promising biomarker for early diagnosis and therapeutic intervention in AD. This study revealed the underlying molecular mechanisms linking environmental toxicants to AD pathogenesis.},
}

@article {pmid41384929,
year = {2025},
author = {Tsai, A and Gunn-Sandell, LB and Wyman-Chick, KA and Wang, Y and Bayram, E},
title = {Sex differences for symptoms prior to dementia onset in people with Lewy body pathology compared to pure Alzheimer's disease pathology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251405437},
doi = {10.1177/13872877251405437},
pmid = {41384929},
issn = {1875-8908},
abstract = {BackgroundEarly diagnosis of Lewy body dementia (LBD) is challenging, largely due to clinical heterogeneity and features overlapping with Alzheimer's disease (AD). Clinical differentiation is particularly challenging in females, who are more likely to have a mis- and delayed diagnosis than males with LBD.ObjectiveTo investigate whether there are sex differences in the prodromal symptoms and rate of change preceding dementia in people with Lewy body (LB) and pure AD pathologies.MethodsWe used data from National Alzheimer's Coordinating Center for people with dementia and LB (n = 196; 89 females, 107 males; including mostly people with AD co-pathology) or pure AD pathology (n = 308, 167 females, 141 males, without LB co-pathology). Prevalence of cognitive, behavioral, and parkinsonism symptoms were assessed annually starting with two-years prior to dementia. Changes over time for prevalences were compared between pathology groups and sexes.ResultsCognitive fluctuation prevalence was higher for males with LB than other groups. Compared to males with LB, females with LB had faster increase in judgment, language, visuospatial deficit prevalence and dementia severity. Relative to females with AD, affective symptom prevalence increased slower for females with LB. Relative to males with AD, males with LB had higher prevalence of parkinsonism and attention deficit, with slower increase in attention deficit prevalence.ConclusionsCognition can decline faster for females than males during prodromal LBD. Presence of parkinsonism and cognitive fluctuation can help differentiate LB from AD pathology for males. Such prominent differences may not occur for females, suggesting the need for sex-specific diagnostic approaches.},
}

@article {pmid41384926,
year = {2025},
author = {Akaike, S and Ogata, A and Nakagawa, Y and Ura, S and Kondo, K and Imashiro, R and Hashimoto, S and Yabe, I and Otsuki, M},
title = {The Visual Image Simple Recognition Test, a language-minimized recognition test: Psychometric and clinical evaluation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251405433},
doi = {10.1177/13872877251405433},
pmid = {41384926},
issn = {1875-8908},
abstract = {BackgroundEpisodic memory tests in Alzheimer's disease (AD) often depend on verbal recall or drawing.ObjectiveTo develop Visual Image Simple Recognition Test (VISRET) and evaluate its psychometric and clinical performance.MethodsWe studied 149 individuals (healthy participants [HP] = 62; AD = 53; patients with aphasia [AP] = 34). We assessed reliability (split-half Spearman-Brown [SB]), known-groups validity with age-adjusted models and age-stratified analyses, and a Bayesian logistic model (AD versus HP). A Bayesian linear model produced a composite Memory Score and highest posterior density (HPD)-based cut-offs using HP alone, subsequently evaluated by five-fold cross-validation. Convergent and discriminant validity were assessed by correlating VISRET with established neuropsychological tests in non-aphasic AD.ResultsInternal consistency was good in AD (SB = 0.87) and acceptable when pooled within-group (SB = 0.84). AD-HP discrimination was large, persisting after age adjustment, within age strata, and following aphasic AD exclusion. The Bayesian model showed excellent discrimination (posterior-mean AUC = 0.99, 95% HPD = 0.97-0.99). AP differed from HP but with trivial absolute differences (total 39.6 versus 39.4; false recognitions 0.1 versus 0.3). In non-aphasic AD, VISRET total correlated with an established episodic memory test (ρ=0.60) but demonstrated weak or near-zero correlations with non-memory domains (e.g., nonverbal reasoning, ρ=0.02). Cross-validated, HP-derived Memory-Score cut-offs achieved mean AUC = 0.98; at the 95%-HPD threshold, sensitivity = 0.87 and specificity = 0.95; at 99%-HPD, sensitivity = 0.74 and specificity = 0.98.ConclusionsVISRET is a brief, language-minimized recognition test facilitating AD-related memory impairment detection, with minimal practical impact of aphasia. The HP-derived Memory Score and cut-offs demonstrated stable cross-validation, suggesting potential clinical utility pending replication and external validation.},
}

@article {pmid41384925,
year = {2025},
author = {Wang, S and Xi, G and Hang, J and Deng, J and Wang, P and Li, Y and Hu, K and Li, L and Shi, Y and Wang, X},
title = {Hsa_circ_0015335 as a potential biomarker for cognitive decline in type 2 diabetes mellitus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251405447},
doi = {10.1177/13872877251405447},
pmid = {41384925},
issn = {1875-8908},
abstract = {BackgroundType 2 diabetes (T2DM) is an independent risk factor for accelerated cognitive decline, creating a need for non-invasive biomarkers to diagnose T2DM-related mild cognitive impairment (T2DM-MCI). Circular RNAs (circRNAs), known to regulate T2DM pathophysiology, represent promising candidate biomarkers.ObjectiveWe aimed to assess the relationship between circRNAs levels and cognitive decline in T2DM patients.MethodThis study included 64 patients with T2DM-MCI and 75 patients with T2DM and normal cognition (T2DM-NC). All T2DM-MCI participants completed a 1.5-year follow-up period. Neuropsychological assessments were performed for all participants. Blood levels of circRNA were quantified using real-time quantitative polymerase chain reaction.Results(1) Whole-blood expression of hsa_circ_0015335 was significantly reduced in T2DM-MCI patients compared to T2DM-NC controls. (2) Receiver operating characteristic (ROC) curve analysis demonstrated that hsa_circ_0015335 could differentiate T2DM-MCI from T2DM-NC with an Area Under ROC Curve of 0.722. (3) Lower hsa_circ_0015335 levels showed significant negative correlations with global cognitive function, episodic memory, and executive function scores in T2DM-MCI patients. (4) A significant interaction was observed between reduced hsa_circ_0015335 expression and elevated triglyceride glucose (TyG) index, collectively contributing to global cognitive impairment in T2DM-MCI patients. (5) Mediation analysis revealed that the TyG index significantly mediated the association between baseline hsa_circ_0015335 levels and the rate of global cognitive decline during follow-up.ConclusionsPeripheral blood hsa_circ_0015335 shows potential as a biomarker for T2DM-MCI identification and cognitive decline progression in affected patients. This circRNA may contribute to cognitive impairment pathogenesis in T2DM, potentially through mechanisms involving glucose metabolism dysregulation.},
}

@article {pmid41384840,
year = {2025},
author = {Sołtys, A and Wnuk, M},
title = {Types of caregivers for people with Alzheimer's disease in the context of their value system and personality traits.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406616},
doi = {10.1177/13872877251406616},
pmid = {41384840},
issn = {1875-8908},
abstract = {BackgroundAssuming the role of a caregiver for a person with Alzheimer's disease entails significant physical and psychological burden. This role is rarely taken on by choice, emerges as the disease progresses in a close family member. The caregiver's values and cultural context may play an important role in the decision to continue providing care. The duration of care and the severity of the disease's symptoms are direct factors contributing to burden, and depression. A caregiver's personality may determine how they respond to stressful situations, while knowledge of their system of values may influence their interpretation of the caregiving role and their psychological well-being. Understanding personality types and value hierarchies may support caregivers in adapting to the situation and alleviating burden.ObjectiveThe aim of our study was to identify caregiver profiles based on their personality traits and preferred value system.MethodsTo distinguish groups of caregivers based on selected psychological characteristics (personality traits, personal values, caregiving involvement, perceived stress, levels of depression), a cluster analysis using the k-means method was conducted.ResultsAnalysis of the results enabled the identification of distinct caregiver profiles, with two predominant patterns emerging in this sample, which differed in their personality traits and value systems.ConclusionsCaregivers with a Balanced-Task-Oriented profile exhibited lower levels of stress and depressive symptoms than those with an Unbalanced-Supportive profile. The results suggest that caregivers guided by a strong value system and higher levels of neuroticism are more susceptible to stress and depression than those with a more stable personality.},
}

@article {pmid41384838,
year = {2025},
author = {Batlle, P and Darcy, M and Levine, M and Hamzi, B and Owhadi, H and Bastani, M and Zhang, Y and Sarsour, K and Talamas, F and , },
title = {Benchmarking Gaussian processes for prediction and data assimilation of Alzheimer's disease progression.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404082},
doi = {10.1177/13872877251404082},
pmid = {41384838},
issn = {1875-8908},
abstract = {The ability to predict the trajectory of disease progression with high resolution for individual patients can enhance clinical trial design, enabling personalized, data-driven medical approaches. In this study, we deployed a kernel/Gaussian process-based dynamic model to predict Alzheimer's disease progression. Our numerical results demonstrate that the dynamic method outperforms static linear regression, improving the prediction of ADAS-Cog 11 subscores over extended periods by effectively incorporating intermediate data observations. This approach highlights the potential of computational models in enhancing clinical trial design and advancing personalized medicine for Alzheimer's disease.},
}

@article {pmid41384835,
year = {2025},
author = {An, B and Auger, SA and Lutsey, PL and Mielke, MM and Yu, F and Hoogeveen, RC and Gottesman, RF and Zhang, L and Meyer, M and Sullivan, KJ and Zantek, ND and Alonso, A and Walker, KA and Li, D},
title = {Association of LDL cargo proteins with white matter hyperintensity volume in older adults from the atherosclerosis risk in communities study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401480},
doi = {10.1177/13872877251401480},
pmid = {41384835},
issn = {1875-8908},
abstract = {BackgroundLow-density lipoprotein cholesterol (LDL-C) has been associated with Alzheimer's disease (AD) pathology and other neuroimaging measures, such as brain volume and white matter hyperintensity (WMH) volume.ObjectiveIn this exploratory study, we examined cross-sectional associations between LDL cargo proteins and AD-related outcomes.MethodsWe randomly selected 65 participants without dementia with amyloid PET and brain MRI data available in the Atherosclerosis Risk in Communities. We used a mass spectrometry-based technique to quantify proteins in LDL isolated from plasma collected at the ARIC Visit 5. Linear or logistic regression was applied to evaluate the associations between individual LDL protein or LDL-C and (1) brain amyloid deposition (yes or no), (2) temporal-parietal meta-ROI brain volume (a biomarker of AD-related neurodegeneration), or (3) WMH volume, adjusting for covariates.ResultsParticipants' average age was 76.3 years with a standard deviation of 5.4, and females comprised 53.8% (35 out of 65). The estimated effect sizes of many LDL protein's associations with these neuroimaging measures were larger than that of LDL-C. The strongest association was higher LDL apolipoprotein C1 (apoC1) and lower WMH volume. Each SD increment of LDL apoC1 LDL was associated with a lower WMH volume of 7243.1 mm[3] (95% CI [-10482.0, -4004.1]; a BH-adjusted p = 0.002). In comparison, each SD increment of LDL-C (in mg/dL) was associated with a lower WMH volume of 1676.1 mm[3] (95% CI [-5425.9, 2073.7]; a BH-adjusted p of 0.90).ConclusionsThis study suggests that increased LDL apoC1 was linked to decreased WMH volume in older adults without dementia.},
}

@article {pmid41384834,
year = {2025},
author = {Wang, J and Li, H and Wang, Y and Meng, F and Liu, Z and Zhao, T and Xu, P and Guo, C and Zhu, Y},
title = {Effects of virtual reality-based therapy on cognitive and psychological outcomes in older adults with predementia: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404046},
doi = {10.1177/13872877251404046},
pmid = {41384834},
issn = {1875-8908},
abstract = {BackgroundPredementia, encompassing subjective cognitive decline (SCD) and mild cognitive impairment (MCI), represents an early phase of neurodegeneration with a heightened risk of progression to dementia. This stage offers a critical window for intervention. Virtual reality (VR) enhances neuroplasticity in predementia via multisensory stimulation, addressing research gaps. ObjectiveTo assess the impact of VR-based interventions on cognitive abilities, emotional well-being, and instrumental activities of daily living (IADL) in individuals with predementia conditions.MethodsA search of seven databases identified studies involving seniors aged ≥65 with SCD or MCI. Eligible studies compared conventional cognitive training or usual care as controls. Quality was assessed using the Cochrane Risk of Bias Tool, and evidence certainty was graded using the GRADE framework.ResultsTwelve randomized controlled trials were included. The meta-analysis revealed that, in comparison to control groups, VR-based cognitive interventions had superior effects on subjective cognitive complaints (SMD = -4.06, 95% CI [-4.86, -3.25]), learning and memory (SMD = 0.41, 95% CI [0.02, 0.80]), working memory (SMD = -0.06, 95% CI [-0.08, -0.03]), verbal fluency (SMD = 0.49, 95% CI [0.03, 0.94]), spatial cognition (SMD = 1.43, 95% CI [0.77, 2.10]), and IADL (SMD = 0.77, 95% CI [0.14, 1.40]).ConclusionsVR-based cognitive interventions could improve objective cognitive performance, subjective cognitive complaints, and IADL in predementia. Future research should prioritize optimizing the intervention protocols and enhancing the geriatric-specific VR-based cognitive intervention.},
}

@article {pmid41384832,
year = {2025},
author = {Villarejo Galende, A and González-Sánchez, M and Hilario, A and Llamas-Velasco, S and Morenas-Rodríguez, E and Muñoz-García, MI and Ramos-González, A and Pérez-Martínez, DA and Blanco-Palmero, VA},
title = {Severe symptomatic amyloid-related imaging abnormalities in Alzheimer's disease: Two case reports and systematic review of reported cases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404505},
doi = {10.1177/13872877251404505},
pmid = {41384832},
issn = {1875-8908},
abstract = {BackgroundAmyloid-related imaging abnormalities (ARIA) are a recognized complication of anti-amyloid monoclonal antibodies for Alzheimer's disease (AD). While typically asymptomatic, a subset of patients develops severe clinical symptoms and radiological findings requiring intensive management. Data on their presentation, treatment, and outcomes remain limited.ObjectiveWe report two cases and analyze the clinical features of all published cases of severe symptomatic ARIA, with a focus on associated risk factors, therapeutic approaches, and patient outcomes.MethodsWe report two cases of severe symptomatic ARIA in patients treated with gantenerumab. A systematic review was conducted following PRISMA guidelines using MEDLINE, Web of Science, and manual reference screening. We included case reports and series providing individual-level data on symptomatic ARIA episodes classified as severe by clinical criteria. Demographic, genetic, clinical, radiological, therapeutic, and outcome data were extracted.ResultsThirty-six cases were included (2 new and 34 from 21 publications). Fifteen cases were associated with lecanemab, 10 with gantenerumab, 6 with donanemab, and 5 with other antibodies. APOE ε4 was present in 62.5%, including 10 ε4/ε4 homozygotes. Baseline MRI showed hemorrhagic markers in 10 cases, including superficial siderosis in 2 of the 5 patients with isolated macrohemorrhages. Most episodes occurred within 6 months of treatment. Symptoms included altered consciousness (75%), focal deficits (66.7%), seizures (38.9%), and headache (36.1%). ARIA-E resolved in all non-fatal cases. Corticosteroids were used in 72%. Among the patients whose outcome data were available, 15 patients recovered completely, 10 had persistent deficits, and 10 died.ConclusionsSevere symptomatic ARIA is a rare but serious adverse effect of anti-amyloid therapy. Standardized diagnostic and therapeutic guidelines are needed to minimize ARIA-related morbidity and mortality.PROSPERO registration no. CRD420251055067.},
}

@article {pmid41384831,
year = {2025},
author = {Choi, YH and Kim, H and Hong, S and Baek, C and Wang, B and Shim, Y and Hong, YJ and Byun, S and Song, IU and Na, S and Won, WY and Park, SK and Ryu, SY and Hahn, C and Shin, HE and Cho, AH and Lim, E and Lim, HK and Kang, DW and Kim, HJ and Choi, H and Yoon, B and Kim, W and Lim, JS and Yang, DW},
title = {Deep-learning analysis of speech using mel-spectrograms for the assessment of mild cognitive impairment and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401202},
doi = {10.1177/13872877251401202},
pmid = {41384831},
issn = {1875-8908},
abstract = {BackgroundSpeech abnormalities are recognized as early indicators of Alzheimer's disease (AD) and mild cognitive impairment (MCI).ObjectiveTo determine whether deep-learning models trained on mel-spectrograms of brief speech tasks can (i) discriminate individuals with MCI and AD from cognitively normal controls (NC) and (ii) estimate cognitive status with clinically useful accuracy.MethodsSpeech from 594 participants (185 NC, 231 MCI, 178 AD) was recorded through a mobile application that included 11 cognitive-linguistic tasks. Audio was converted into mel-spectrogram images and processed using a VGG16-based deep-learning model with transfer learning and fine-tuning of block 5. Task-specific feature vectors were extracted, concatenated, and used to train a deep neural network. The dataset was split into training, validation, and test sets (3:1:1), and five-split cross-validation was performed.ResultsThe model demonstrated an overall accuracy of 72.4% in classifying NC from the abnormal group (MCI and AD), with sensitivity and specificity of 72.5% and 72.2%, respectively, a balanced accuracy of 72.4%, and an AUC of 0.997. In binary classifications, the model achieved 82.9% accuracy (balanced accuracy 82.9%, AUC 0.992) for NC versus AD, 70.7% accuracy (balanced accuracy 70.3%, AUC 0.956) for NC versus MCI, and 77.5% accuracy (balanced accuracy 78.9%, AUC 0.889) for MCI versus AD. Tasks such as serial subtraction, storytelling, and picture description contributed most to classification performance, indicating their effectiveness in capturing cognitive deficits.ConclusionsMel-spectrogram-based deep-learning analysis of speech shows promise as a rapid, non-invasive, and language-independent screening tool for early cognitive impairment, with potential advantages over traditional assessments such as the Mini-Mental State Examination.},
}

@article {pmid41384830,
year = {2025},
author = {Caldichoury, N and Morales-Asencio, B and Coronado, JC and Ripoll-Córdoba, D and Mendoza-Ruvalcaba, N and Quispe-Ayala, C and Camargo, L and Boza-Calvo, C and Quincho-Apumayta, R and Castellanos, C and Cárdenas, J and García de la Cadena, C and Martínez, J and Florez, Y and Mori, N and Castillo-Tamara, E and Calle, U and Bada, W and Varón, C and Porto, MF and Ramos-Henderson, M and Miranda-Pacheco, J and Salazar, D and Alcos-Flores, K and Palomino-Torres, E and Ardila-Duarte, C and Patiño-Rivera, AR and Gargiulo, PA and López, N},
title = {Subjective memory complaints in Latin American older adults: Prevalence and risk factors.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251400666},
doi = {10.1177/13872877251400666},
pmid = {41384830},
issn = {1875-8908},
abstract = {BackgroundSubjective memory complaints (SMC) are linked to an increased risk of neurocognitive disorders (NCD).ObjectiveTo estimate the prevalence of SMC and their association with sociodemographic and clinical factors in 3285 older adults (OA) from ten Latin American and Caribbean (LAC) countries.MethodThis population-based analysis used secondary data from an international multicenter study on NCD prevalence during the COVID-19 pandemic. Cognitively healthy participants were identified based on clinical criteria, cognitive assessments, and expert consensus. Participants were categorized as with (WSMC; n = 602) or without SMC (NSMC; n = 2683). Sociodemographic and clinical variables were recorded. Cognitive performance was assessed using the Montreal Cognitive Assessment-Short Version (MoCA-T), depressive symptoms with the 15-item Geriatric Depression Scale (GDS-15), and functional decline with the Eight-Item Informant Interview (AD8). Mean difference analyses and logistic regressions were performed.ResultsThe regional prevalence of SMC was 18.33%, ranging from 11.59% in Guatemala to 26.30% in Peru. OA with SMC showed lower education, poorer cognitive performance, and higher rates of anxiety, falls, and fractures. Regression models revealed significant associations between SMC and lower education (p < 0.001), emotional distress (p < 0.001), age (p = 0.024), anxiety (p = 0.017), infrequent and occasional falls (p = 0.017; p = 0.002), and fractures (p = 0.028).ConclusionsSMC are prevalent among LAC older adults and are associated with multiple risk factors, highlighting their public health relevance and potential as early indicators of NCD risk.},
}

@article {pmid41384827,
year = {2025},
author = {Farsi, DN and Abadalkareem, R and Linden, GJ and McKay, GJ and McEvoy, CT and McAlinden, M and Winning, L and Hurley, M and Kelly, J and Passmore, PA and Holmes, C and Patterson, CC and Teeling, JL and McGuinness, B},
title = {Periodontitis and incident cognitive decline and dementia: A 15-year prospective cohort study of older men residing in Northern Ireland.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401563},
doi = {10.1177/13872877251401563},
pmid = {41384827},
issn = {1875-8908},
abstract = {BackgroundPeriodontitis is a chronic bacterial infection that elicits systemic inflammation. While retrospective studies have linked periodontal pathogens with Alzheimer's disease (AD) and dementia, few have combined cognitive assessments, pathogen exposure, and inflammatory markers.ObjectiveTo investigate the longitudinal risk between periodontitis, cognitive impairment and dementia.MethodsWe examined the relationship between periodontitis and onset of mild cognitive impairment (MCI) and dementia over 15.6 years (SD 1.6) in older men from Northern Ireland enrolled in the PRIME-COG cohort, using logistic regression. We also assessed associations between exposure to periodontal pathogens and blood inflammatory markers.ResultsAmong 642 men, baseline periodontitis was not significantly associated with later onset of dementia and/or MCI (severe versus mild/none, OR 0.83, 95% CI 0.45-1.50, p = 0.923). However, having more teeth predicted lower risk (OR 0.95, 95% CI 0.91-0.99, p = 0.023). Dementia and/or MCI was associated with higher serum IL-6, IL-8, and IFN-γ at baseline, and IL-8 and TGF-β at follow-up. IgG levels to periodontal pathogens remained stable in men who developed dementia and/or MCI but declined in cognitively normal men. A positive correlation between IgG to periodontal pathogens and proinflammatory cytokines was observed in men who developed dementia and/or MCI.ConclusionsClinical periodontitis was not associated with dementia or MCI onset, but tooth retention was protective. Elevated inflammatory markers in affected men suggest systemic inflammation may contribute to cognitive decline. Larger, more diverse cohort studies are needed to clarify the role of periodontal disease in dementia and AD risk.},
}

@article {pmid41384825,
year = {2025},
author = {Hreha, K and Ashner, MC and Peskoe, S and Downer, B and Reistetter, T and Palta, P and Wruck, L and Gottesman, RF and Windham, BG and Whitson, HE},
title = {Prevalence of pre-stroke and stroke-related vision impairments and their association with mild cognitive impairment and dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404018},
doi = {10.1177/13872877251404018},
pmid = {41384825},
issn = {1875-8908},
abstract = {BackgroundVision impairment is a risk factor for mild cognitive impairment (MCI) among stroke survivors, but it is unclear if this association is driven by vision impairment present before or due to the stroke, and if similar associations exist with dementia.ObjectiveTo (1) characterize the prevalence of pre-stroke and stroke-related vision impairment(s) among stroke survivors, and (2) quantify associations of vision impairment with dementia and cognitive impairment (MCI/dementia).MethodsUsing participants from the Atherosclerosis Risk in Communities (ARIC) dataset with adjudicated incident strokes, we gathered descriptive statistics on the cohort, assessed if vision impairment was present at the time of incident stroke, and classified the impairments as pre-stroke or stroke-related. Multivariable logistic regression was used to estimate the association between these types of vision impairment and post-stroke cognitive impairment.ResultsAmong 233 incident stroke survivors (mean = 69 years old and 50.2% female sex), 23.2% with pre-stroke vision impairment and 18.9% with stroke-related vision impairment, there were 124 (53%) cases of cognitive impairment (n = 76 MCI, n = 48 dementia). Stroke-related vision impairment was significantly associated with higher odds of dementia (ref = normal/MCI) (adjusted odds ratio (aOR) = 2.32, 95% confidence interval (CI) = 1.08-4.92, p = 0.029), but not any cognitive impairment (ref = normal) (aOR = 1.33 95% CI = 0.67-2.70, p = 0.425). Further adjusting for stroke severity score attenuated the association of stroke-related vision impairment with dementia (aOR = 2.0, 95% CI = 0.90, 4.32, p = 0.08).ConclusionsStroke-related vision impairment, but not pre-stroke vision impairment, was associated with higher odds of dementia. There is evidence that stroke severity could, at least partially, explain the observed association.},
}

@article {pmid41384822,
year = {2025},
author = {Guy, TO and Ghanem, A and Berry, DS and Hernandez, NC and Sharma, VD and Chapman, S and Cosentino, S and Louis, ED},
title = {Blood-based Alzheimer's disease biomarkers and cognitive decline in essential tremor.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404035},
doi = {10.1177/13872877251404035},
pmid = {41384822},
issn = {1875-8908},
abstract = {BackgroundTwo epidemiological studies demonstrated an association between essential tremor (ET) and prevalent dementia as well as substantially elevated risks of incident dementia among ET cases. At this early point, the underlying pathophysiology of ET-dementia is not known. In vivo biomarkers of Alzheimer's disease (AD) and neurodegeneration could help bridge the gap between the pathophysiological processes that present in the context of ET-dementia.ObjectiveExamine blood concentrations of t-tau, p-tau181, p-tau217, Aβ42/40, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in ET with a range of cognitive diagnoses.Methods40 ET cases (mean age = 81.5 ± 7.3; including 20 normal cognition (NC), 12 cognitively normal with some weaknesses, 4 mild cognitive impairment, and 4 dementia) were enrolled in a study of cognitive performance in ET, during which phlebotomy was performed.ResultsGreater cognitive difficulty was associated with higher blood concentrations of p-tau217, p-tau181, GFAP, and NfL, and a lower Aβ42/40 ratio (p tests for trend < 0.05). Cases with dementia had marginally higher concentrations of p-tau217 (p = 0.06) and higher concentrations of GFAP and NfL (p < 0.05) than cases with NC. Furthermore, higher concentrations of p-tau217, GFAP, and NfL were associated with lower cognitive test scores across multiple cognitive domains (p < 0.05).ConclusionsAlbeit based on a small sample of cases, our findings suggest a potential role of blood-based biomarkers as markers for cognitive function in ET patients. Cognitive decline in ET may be due to underlying neurodegenerative processes involving tau and perhaps Aβ pathology.},
}

@article {pmid41384508,
year = {2025},
author = {Karahan, H and Hartigan, K and Al-Amin, MM and John, SK and McCord, B and Wijeratne, HRS and Acri, DJ and Smith, DC and Dabin, LC and Cordero, HMR and Kim, B and Lee, DH and Kim, J},
title = {Deletion of neuronal Idol ameliorates Alzheimer's disease-related pathologies via APOE receptors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70949},
doi = {10.1002/alz.70949},
pmid = {41384508},
issn = {1552-5279},
support = {R01AG053242/AG/NIA NIH HHS/United States ; NIRG-12-240682/ALZ/Alzheimer's Association/United States ; //Indiana University Strategic Research Initiative/ ; //Indiana University Precision Health Initiative/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; Mice ; *Neurons/metabolism/pathology ; *Apolipoproteins E/metabolism ; Mice, Knockout ; Reelin Protein ; *Receptors, LDL/metabolism ; *Brain/metabolism/pathology ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Microglia/metabolism ; *Ubiquitin-Protein Ligases/genetics/metabolism ; },
abstract = {INTRODUCTION: Overexpression of the low-density lipoprotein receptor (LDLR) is known to decrease apolipoprotein E (APOE) levels and alleviate amyloid beta (Aβ) pathology. We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL), an enzyme that ubiquitinates LDLR for degradation, would increase endogenous LDLR levels and attenuate amyloid pathology.

METHODS: To investigate the cell-type-specific role of IDOL, we generated Idol conditional knockout mice on an Aβ-amyloidosis mouse model and performed biochemical, histological, and multi-omics analyses.

RESULTS: We demonstrated that neuronal, but not microglial, Idol deletion reduced amyloid accumulation and altered brain LDLR and APOE levels, indicating the critical role of neuronal IDOL-LDLR in amyloid pathology. In addition, neuronal Idol deletion increased the levels of Reelin receptors important for synaptic function, and single-nuclei RNA sequencing revealed significant changes associated with synaptic organization.

DISCUSSION: Neuronal IDOL, but not microglial IDOL, plays a key role in Alzheimer's disease pathogenesis by regulating the levels of brain APOE receptors.

HIGHLIGHTS: Neuronal, but not microglial, Idol deletion reduces amyloid burden and modulates brain APOE and LDLR levels. Deletion of neuronal Idol increases the levels of APOER2 and VLDLR, the Reelin receptors, in the brain. Single-nuclei RNA sequencing highlights the neuronal IDOL's impact on inhibitory neurons and synaptic organization. Targeting neuronal IDOL may provide multiple therapeutic benefits in Alzheimer's disease by modulating APOE receptors.},
}

Animals
*Alzheimer Disease/pathology/metabolism/genetics
Mice
*Neurons/metabolism/pathology
*Apolipoproteins E/metabolism
Mice, Knockout
Reelin Protein
*Receptors, LDL/metabolism
*Brain/metabolism/pathology
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Microglia/metabolism
*Ubiquitin-Protein Ligases/genetics/metabolism

@article {pmid41384297,
year = {2026},
author = {Zhou, B and Li, L and Qiu, X and Wu, J and Xu, L and Shao, W},
title = {[Retracted] Long non‑coding RNA ANRIL knockdown suppresses apoptosis and pro‑inflammatory cytokines while enhancing neurite outgrowth via binding microRNA‑125a in a cellular model of Alzheimer's disease.},
journal = {Molecular medicine reports},
volume = {33},
number = {2},
pages = {},
doi = {10.3892/mmr.2025.13772},
pmid = {41384297},
issn = {1791-3004},
abstract = {Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the cell apoptotic data shown in Fig. 5A were strikingly similar to data appearing in different form in another article written by different authors at different research institutes that had already been published in the journal Cell Cycle; moreover, the lens smudging patterns underlying the neurite outgrowth experimental data shown in Figs. 2D and 5C matched that of data shown in other figures of the same article published in journal Cell Cycle, suggesting these data may have been derived from the same original source. Owing to the fact that the contentious data mentioned above had already apparently been published previously, the Editor of Molecular Medicine Reports has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 22: 1489‑1497, 2020; DOI: 10.3892/mmr.2020.11203].},
}

@article {pmid41384038,
year = {2025},
author = {Zainal Abidin, S and Razali, NN and Cheah, PS and Ling, KH},
title = {Biogenesis and function of circular RNAs and their implications in the Down syndrome brain.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1708015},
pmid = {41384038},
issn = {1664-8021},
abstract = {Circular RNAs (circRNAs), a class of covalently closed, non-coding RNAs, have recently emerged as crucial regulators of gene expression. They exert their roles through microRNA (miRNA) sponging, transcriptional regulation, and interactions with RNA-binding proteins (RBPs). Increasing evidence suggests that circRNAs play important roles in neurodevelopmental disorders, including Down syndrome (DS). DS is a condition caused by trisomy of chromosome 21 and characterised by intellectual disability (ID), neuroinflammation, and increased risk of early-onset Alzheimer's disease (AD). Aberrant circRNA expression in DS may contribute to pathogenesis by disrupting competing endogenous RNA (ceRNA) networks, modulating synaptic plasticity, and influencing key molecular pathways, including EZH2-mediated chromatin remodelling, immune response regulation, and neuronal differentiation. Despite these emerging insights, the role of circRNAs in DS remains largely underexplored compared to their well-recognised functions in cancer and other neurological disorders. Most current studies have focused on transcriptomic analyses, identifying differentially expressed circRNAs and predicting their interactions with miRNAs and mRNAs. However, these findings require further experimental validation to uncover the precise mechanisms through which circRNAs contribute to DS pathophysiology. This review highlights the association of circRNAs with DS, emphasising their dysregulation and mechanistic interactions with miRNAs and mRNAs. It further explores how these circRNA-mediated mechanisms may contribute to intellectual disability and impaired neurodevelopment, based on current evidence.},
}

@article {pmid41383962,
year = {2025},
author = {Li, X and Zhang, C and Liu, D and Shang, H and Wang, K and Lin, X and Zheng, J},
title = {Causal Relationships Between Neuropathic Pain and Alzheimer's Disease: A Multi-Omics Mendelian Randomization Study with Exploratory Evidence of a Potential Protective Role of Diabetic Neuropathy.},
journal = {Journal of pain research},
volume = {18},
number = {},
pages = {6527-6544},
pmid = {41383962},
issn = {1178-7090},
abstract = {BACKGROUND: Neuropathic pain (NP) frequently co-occurs with Alzheimer's disease (AD), yet the causal relationship and underlying molecular mechanisms between the two remain unclear, necessitating further investigation to elucidate their intrinsic connection.

METHODS: This study employed a bidirectional two-sample Mendelian randomisation (MR) approach to systematically analyse the association between six NP subtypes and AD. Concurrently, functional annotation and transcriptomic analysis were conducted using the GTEx v10 and GEO GSE156184 databases to explore potential molecular mechanisms.

RESULTS: The study revealed a significant inverse causal effect of diabetic neuropathy (DN) on AD risk (OR=0.86, 95% CI: 0.77~0.95, P IVW=0.0043), with sensitivity analyses confirming the robustness of this finding. Further analysis indicated that DN-associated SNPs regulate four tissue-specific genes including FAM200A and GPC2. These genes exhibit differential expression in the DN transcriptome and are significantly enriched in key pathways such as mitochondrial function and autophagy.

CONCLUSION: This study provides the first evidence that DN may exert a protective effect against AD by regulating the aforementioned tissue-specific genes and associated pathways. This finding challenges the conventional understanding that chronic pain exacerbates AD and offers novel potential targets for developing therapeutic strategies. However, due to population limitations in the study, further experimental validation remains necessary.},
}

@article {pmid41383957,
year = {2025},
author = {Brown, CA and Das, SR and Detre, JA and Nasrallah, IM and Yushkevich, PA and McMillan, CT and Wolk, DA},
title = {Fully individualized models for cross-sectional and longitudinal network-based tau spread.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
pmid = {41383957},
issn = {2837-6056},
abstract = {Heterogeneity in regional tau burden limits evaluation of disease progression using one-size-fits-all approaches. Prior work using tau positron emission tomography (PET) has highlighted the important role of connectivity to epicenters of tau pathology in explaining this heterogeneity. However, previous studies using population-based epicenters or connectomes fall short of a fully individualized approach to predicting regional tau burden. We use diffusion MRI-derived structural connectomes to assess the prediction of regional tau burden using distance along individual structural connectomes from individualized epicenters of tau pathology both cross-sectionally and longitudinally. Fully individualized models of connectivity and epicenters outperformed models using either population-based connectomes or epicenters in explanation of cross-sectional and longitudinal regional tau burden, improved prediction in validation datasets, and produced stronger single-subject level prediction. Together, these findings demonstrate the power of a fully individualized approach to explain regional tau heterogeneity and provide the strongest in vivo evidence to date for network-based spread of tau pathology.},
}

@article {pmid41383949,
year = {2025},
author = {Zhang, N and Zhao, Z and Chen, X and Yao, H and Zhu, M and Ma, S and Wang, H and Yin, X and Zhou, Y and Zheng, C and Li, J and Pan, J and Wang, K and Yang, B and Wang, Y and Fan, J and Gong, Y and Liu, R and Zeng, J and Fan, X and Shentu, Y},
title = {Downregulation of forkhead box O1 (FOXO1) acetylation ameliorates cognitive dysfunction by inhibiting endoplasmic reticulum stress-regulated neuronal apoptosis in APP/PS1 transgenic mice.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {183-201},
pmid = {41383949},
issn = {2770-730X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that affects the central nervous system. Silent information regulator sirtuin 1 (SIRT1) may deacetylate and suppress forkhead box O (FOXO) activities to promote neuronal survival. FOXO1 is involved in the regulation of metabolism, senescence, stress response, and apoptosis. Moreover, endoplasmic reticulum stress (ERS) mediates cell apoptosis. Therefore, this study aimed to determine whether the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice.

METHODS: We used APP/PS1 transgenic mice to construct an in vivo AD model. Additionally, we used β-amyloid (Aβ)-incubated HT22 cells and primary neurons (PNs) for in vitro analyses. Cognitive function was assessed using novel object recognition, the Morris water maze, and fear conditioning. Discrepancies between wild-type (WT) and APP/PS1 transgenic mice were evaluated using an unpaired t test. In addition, one-way analysis of variance was conducted for behavioral assessments and other tests involving four distinct groups, followed by a Tukey's honestly significant difference test for post hoc pairwise comparisons.

RESULTS: The expression of SIRT1 was downregulated (in animal experiments, WT mice vs. APP/PS1 mice, n = 3, p = 0.002; in cell experiments, HT22 cells vs. HT22 cells + Aβ1-42, n = 3, p = 0.001; primary neurons vs. primary neurons + Aβ1-42, n = 3, p < 0.001), whereas FOXO1 acetylation was upregulated both in vivo and in vitro (in animal experiments, WT mice vs. APP/PS1 mice, n = 3, p < 0.001; in cell experiments, HT22 cells vs. HT22 cells + Aβ1-42, n = 3, p = 0.004; primary neurons vs. primary neurons + Aβ1-42, n = 3, p < 0.001), leading to cognitive dysfunction, Aβ plaque deposition, and neuronal apoptosis. Quercetin, a SIRT1 agonist, reversed these changes (For SIRT1, APP/PS1 mice vs. Quercetin-treated APP/PS1 mice, n = 3, p = 0.014; HT22 cells + Aβ1-42 vs. HT22 cells + Aβ1- 42 + Quercetin, n = 3, p = 0.003; primary neurons + Aβ1-42 vs. primary neurons + Aβ1-42 + Quercetin, n = 3, p = 0.014. For ac-FOXO1, APP/PS1 mice vs. Quercetin-treated APP/PS1 mice, n = 3, p < 0.001; HT22 cells+ Aβ1-42 vs. HT22 cells + Aβ1-42 + Quercetin, n = 3, p = 0.023; primary neurons + Aβ1- 42 vs. primary neurons + Aβ1-42 + Quercetin, n = 3, p = 0.003). However, the FOXO1 antagonist AS1842856 invalidated the positive effects of quercetin in APP/PS1 transgenic mice (ac-FOXO1: Quercetin-treated APP/PS1 mice vs. AS1842856-treated APP/PS1 mice, n = 3, p < 0.001). Quercetin counteracted FOXO1 acetylation and ERS-mediated apoptosis. In contrast, AS1842856 promoted these processes in vivo and in vitro.

CONCLUSION: Our findings demonstrate that the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis.},
}

@article {pmid41383948,
year = {2025},
author = {Mu, L and Wang, Y},
title = {The role of gut microbiota-derived metabolites in neuroinflammation.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {131-144},
pmid = {41383948},
issn = {2770-730X},
abstract = {Neuroinflammation, a key defense mechanism of the nervous system, is associated with changes in inflammatory markers and stimulation of neuroimmune cells such as microglia and astrocytes. Growing evidence indicates that the gut microbiota and its metabolites directly or indirectly regulate host health. According to recent studies, bacterial dysbiosis in the gut is closely linked to several central nervous system disorders that cause neuroinflammation, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, sepsis-associated encephalopathy, and ischemic stroke. Recent findings indicate a bidirectional communication network between the gut microbiota and central nervous system that influences neuroinflammation and cognitive function. Dysregulation of this system can affect the generation of cytotoxic metabolites, promote neuroinflammation, and impair cognition. This review explores the lesser-studied microbiota-derived metabolites involved in neuroinflammation-bile acids, trimethylamine-N-oxide, and indole derivatives-as targets for creating new treatment tools for neuroinflammatory illnesses, as well as possible biomarkers for early diagnosis and prognosis.},
}

@article {pmid41383947,
year = {2025},
author = {Schwartz, SS and Rhea, EM and Banks, WA and Herman, ME},
title = {Beta cells to brain cells: The pivotal role of insulin and glucose metabolism in Alzheimer's disease.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {145-164},
pmid = {41383947},
issn = {2770-730X},
abstract = {The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that has emerged is glucose dysmetabolism. It is now understood that energy imbalances or excess nutrient intake sit in the crosshairs of neurodegeneration. Within the brain, the regulation of glucose operates semiautonomously from the periphery to ensure a defended, uninterrupted supply of glucose for neuronal processes. In this localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and insulin resistance constitute independent risk factors for AD. Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are two newly understood insults connecting glucose metabolism with AD. This dysglycemia waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques. In parallel, studies in the clinical setting demonstrate that glucose-lowering in patients with type 2 diabetes (T2D) reduces the risk of AD. The American Diabetes Association (ADA) elevated its guidelines to include cognitive issues (or risk) as a comorbidity in T2D patient treatment plans. Choice of antidiabetes therapy is imperative: evidence supports the use of metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor analogs, and sodium glucose cotransporter 2 inhibitors to help prevent and mitigate cognitive outcomes and AD. Sulfonylureas, on the other hand, may actually worsen cognitive deficits and integrity. We are at a fascinating juncture: preclinical research is at a stage to inform the development of rational previously unexplored targets. Simultaneously, current clinical evidence is translatable now into real-world strategies to reduce the incidence and severity of comorbid AD in our aging population.},
}

@article {pmid41383945,
year = {2025},
author = {Li, S and Walczak, P and Ji, X and Boltze, J},
title = {Targeting peripheral processes to protect the central nervous system.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {117-119},
pmid = {41383945},
issn = {2770-730X},
}

@article {pmid41383898,
year = {2025},
author = {Çankaya, Ş and İpek, L and Ayyıldız, S and Sayman, D and Karaca, R and Ayyıldız, B and Velioğlu, HA and Öktem, EÖ and Hanoğlu, L and Yuluğ, B},
title = {The Adaptive Role of Entorhinal Cortical Thickness in Post-COVID 19 Cognitive Impairment.},
journal = {Noro psikiyatri arsivi},
volume = {62},
number = {4},
pages = {310-314},
pmid = {41383898},
issn = {1300-0667},
abstract = {INTRODUCTION: Only limited information is still available concerning cognitive dysfunctions and cortical thickness in individuals who recovered from mild COVID-19 infections and did not require hospitalization. Our aim was to evaluate if the highly adaptive potential of cortical thickness might play a critical role in COVID-19-related cognitive disorder in a compensatory manner.

METHODS: Fifteen individuals with no history of medical, neurological, or psychiatric disease and with positive COVID-19 test results, and sixteen healthy age and education-matched healthy controls identified from the official hospital health system were evaluated in terms of cognitive scores using Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-Cog) and brain MRI cortical thickness measurements using FreeSurfer, Version 7.4.0.

RESULTS: An increased cortical thickness in the right entorhinal cortex (EC) and impaired cognition (increased ADAS score) were observed in the post-COVID 19 group as compared to the controls confirmed by the student's t test (respectively, p=0.006, p<0.001).The apparent correlation observed between cognitive impairment and increased entorhinal cortical thickness in our COVID-19 patients might suggest a continuum pathophysiology between healthy and COVID-19 affected brains that was not evident in previous COVID-19 cases with cognitive impairment.

CONCLUSION: Our findings of increased entorhinal cortical thickness, together with impaired cognitive scores, may indicate a flexible role of EC thickness in compensatory mechanisms of cognition.},
}

@article {pmid41383893,
year = {2025},
author = {Güleç, ZN and Ercan, M and Erdoğan, Y and Oğuz, K and Uyar, A and Burhanoğlu, BB and Uslu, Ö and Erata, MC and Eker, MÇ and Gönül, AS},
title = {The Effects of Late-Onset Depression on Brain Activity During an Episodic Memory Task.},
journal = {Noro psikiyatri arsivi},
volume = {62},
number = {4},
pages = {302-309},
pmid = {41383893},
issn = {1300-0667},
abstract = {INTRODUCTION: Late-onset depression (LOD) has been implicated in irreversible cognitive decline, potentially mirroring early Alzheimer's Disease (AD) pathology. This study aimed to investigate brain activity differences during an episodic memory (EM) task in LOD patients compared to healthy controls (HC).

METHODS: We recruited 15 LOD patients and 13 HC matched for age and gender. Participants completed a face-name association task during functional magnetic resonance imaging (fMRI) focusing on both the encoding and retrieval phases of EM.

RESULTS: The statistical contrast between the groups revealed that the HC group showed increased activity in the left visual association cortex (VAC) and left caudate compared to the LOD group during the encoding task. During the face recognition task, the HC group showed increased activity in the right caudate, and during the name recognition task, they showed increased activity in the right frontal eye field (FEF) compared to the LOD group.

CONCLUSION: The differences observed between the HC and LOD groups in the VAC, caudate, and FEF suggest early changes in maintaining attention, goal-directed learning, EM formation, and coordination of information from storage to retrieval before apparent impairment develops in LOD. Although we did not find statistically significant activations in areas linked to increased vulnerability to AD, our findings of hypoactivation in regions responsible for visual processing and attentional orienting in LOD patients are consistent with hypoactivation patterns observed in AD patients in previous research. These results enhance our understanding of the neural mechanisms underlying memory impairments in LOD and their potential overlap with AD pathology.},
}

@article {pmid41383880,
year = {2025},
author = {Falasca, NW and Ferretti, A and Granzotto, A and Sensi, SL and Franciotti, R and , },
title = {Machine learning models of Alzheimer's disease spectrum using blood tests.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70228},
pmid = {41383880},
issn = {2352-8729},
abstract = {INTRODUCTION: The diagnosis of Alzheimer's disease (AD) traditionally relies on cerebrospinal fluid and plasma levels of amyloid beta and phosphorylated tau. Although informative, these biomarkers represent a narrow, hypothesis-driven approach to intercept the disease.

METHODS: Data-driven analysis was applied on demographic data, apolipoprotein E (APOE) ε4 allele, and 82 biomarkers obtained from blood tests of healthy controls (HC), mild cognitive impairment that remained stable within 36 months following blood collection (sMCI), and patients with AD.

RESULTS: Statistical analyses revealed differences among groups in many cholesterol-related analytes. APOE ε4 and analytes such as amino acids, lipoproteins, and fatty acids emerged as the most influential features in machine learning (ML) classification algorithms. Glycolysis-related metabolites and amino and fatty acids were predictive for distinguishing sMCI and AD from HC.

DISCUSSION: These findings support the hypothesis that systemic alterations also occur during the preclinical stages of dementia, which can be detected by ML models on blood biomarkers.

HIGHLIGHTS: Machine learning on blood tests detects preclinical cognitive decline.Glycolysis metabolites are predictive for distinguishing stable MCI and AD from HC.Amino acids, lipoproteins, and fatty acids are the most predictive features.Inflammatory and metabolic biomarkers represent a biosignature of cognitive health.},
}

@article {pmid41383879,
year = {2025},
author = {Rubio-Guerra, S and Sánchez-Saudinós, MB and Sala, I and Videla, L and Bejanin, A and Estanga, A and Ecay-Torres, M and de Luis, CL and Rami, L and Tort-Merino, A and Castellví, M and Pozueta, A and García-Martínez, M and Gómez-Andrés, D and Lage, C and López-García, S and Sánchez-Juan, P and Balasa, M and Lladó, A and Altuna, M and Tainta, M and Arranz, J and Zhu, N and Alcolea, D and Lleó, A and Fortea, J and Rodríguez, ER and Sánchez-Valle, R and Martínez-Lage, P and Illán-Gala, I},
title = {Development of amyloid-negative neuropsychological norms using GAMLSS.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70224},
pmid = {41383879},
issn = {2352-8729},
abstract = {INTRODUCTION: Recent research has suggested increased sensitivity of Alzheimer's disease (AD)-negative neuropsychological norms; concurrently, generalized additive models for location, scale, and shape (GAMLSS) have emerged as a promising alternative to traditional norming approaches. Here, we developed amyloid β-negative (Aβ-) next-generation norms (NGN) for a comprehensive neuropsychological battery using GAMLSS.

METHODS: We included N = 987 cognitively normal (CN) individuals from a Spanish multicenter study with extensive neuropsychological data and cerebrospinal fluid AD biomarker assessment. NGN were developed using GAMLSS based on the performance of n = 774 Aβ- CN individuals aged 30-90 years.

RESULTS: Age-, education-, and sex-adjusted z-scores were obtained for 14 measures covering the main cognitive domains (memory, language, attention/executive, and visuospatial functions). A user-friendly calculator for the z-scores was made available in an open-access ShinyApp to facilitate their application.

DISCUSSION: NGN may improve the detection of objective cognitive impairment in clinical and research settings.

HIGHLIGHTS: Brain amyloid β (Aβ) is associated with poorer performance in cognitively normal individuals.We provide GAMLSS-based Aβ-negative norms for 14 neuropsychological measures.Age, education, and often sex significantly influence cognitive performance.An online calculator for the demographically adjusted z-scores is freely available.},
}

@article {pmid41383878,
year = {2025},
author = {Rubio-Guerra, S and Sala, I and Sánchez-Saudinós, MB and Videla, L and Bejanin, A and Estanga, A and Ecay-Torres, M and de Luis, CL and Rami, L and Tort-Merino, A and Castellví, M and Pozueta, A and García-Martínez, M and Gómez-Andrés, D and Lage, C and López-García, S and Sánchez-Juan, P and Balasa, M and Lladó, A and Altuna, M and Tainta, M and Arranz, J and Zhu, N and Alcolea, D and Lleó, A and Fortea, J and Rodríguez, ER and Sánchez-Valle, R and Martínez-Lage, P and Illán-Gala, I},
title = {Amyloid-negative neuropsychological norms: Added value in the era of biomarkers and disease-modifying therapies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70223},
pmid = {41383878},
issn = {2352-8729},
abstract = {INTRODUCTION: We previously applied generalized additive models for location, scale, and shape to derive amyloid β-negative next-generation norms (NGN) for a comprehensive neuropsychological battery. Here, we evaluated the accuracy of NGN in detecting cognitive impairment compared to traditional norms (TN).

METHODS: This multicenter study included N = 2405 participants classified as cognitively normal (CN, n = 987) or with mild cognitive impairment (MCI, n = 1418) using conventional criteria. All participants underwent neuropsychological testing and cerebrospinal fluid Alzheimer's disease (AD) biomarker assessment. We used actuarial neuropsychological criteria to reclassify all participants using TN and NGN. Diagnostic groups were compared on cognitive performance, AD biomarker positivity, and longitudinal cognitive trajectories.

RESULTS: Nineteen percent of TN-classified CN participants were diagnosed with MCI by NGN, whereas 3% of TN-classified MCI were identified as CN by NGN. NGN demonstrated stronger associations with neuropsychological performance, AD biomarkers, and progression than TN.

DISCUSSION: NGN enhance the detection of objective cognitive impairment, with direct implications for clinical practice and research.

HIGHLIGHTS: Next-generation norms (NGN) reclassify one of every five cases from cognitively normal (CN) to mild cognitive impairment (MCI).This group shows poor cognitive performance and a high prevalence of amyloid β positivity.NGN-based diagnosis of MCI predicts cognitive progression on follow-up.Results indicate that NGN improve the detection of objective cognitive impairment.NGN can inform biomarker use, therapy indication, and clinical trial design.},
}

@article {pmid41383817,
year = {2025},
author = {Villino-Rodríguez, R and Ríos-Rivera, MM and Montoya-Murillo, G and Patricio Baldera, J and Salazar-Londoño, S and Rodríguez-Oroz, MC and Borda, MG and Jiménez-Huete, A and Riverol, M},
title = {Clinical and neuropsychological features associated with progression in subjective cognitive decline.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1680762},
pmid = {41383817},
issn = {1663-4365},
abstract = {BACKGROUND AND OBJECTIVES: Subjective Cognitive Decline (SCD) is recognized as an early indicator of neurodegeneration, yet factors that predict its progression to mild cognitive impairment (MCI) or dementia remains not fully understood. In this study, we aim to identify clinical and neuropsychological features associated with the progression of SCD.

METHODS: 450 persons with SCD were included, consisting in 319 non progressors (SCDnp) and 131 progressors (SCDp) to MCI or dementia due to AD. The study was conducted at the Clínica Universidad de Navarra Memory Clinic between 2001 and 2017. We included data on medical interviews and neuropsychological evaluations. Differences between SCDnp and SCDp were assessed and, to evaluate the association between exposure variables and progression in time, proportional-hazards Cox models were applied. In addition to the exposure variables, the models were adjusted for age, sex, and years of education.

RESULTS: At baseline, SCDp were older, had a higher prevalence of hypertension and hypercholesterolemia and had worst performance on tests related to processing speed, verbal fluency, visual memory, verbal memory, and executive functioning. Factors associated with progression at follow-up were lower scores in some cognitive tests: MMSE, TMT-B, and the CERAD regarding trial 1 of immediate recall, trial 2 of immediate recall, trial 3 of immediate recall and the delay recall score.

DISCUSSION: Lower scores on global cognition, executive functioning and verbal memory tests were predictors of progression to MCI or dementia in patients with SCD. These findings underscore the importance of nuances in neuropsychological evaluation, even with a normal score, for detecting high-risk individuals for early intervention.},
}

@article {pmid41383815,
year = {2025},
author = {Zhang, R and Liu, YY and Xia, X and Li, X},
title = {Unvalidated efficacy and significant risks hinder clinical use of deep cervical lymphatic-venous anastomosis for Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1671741},
pmid = {41383815},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and the pathological accumulation of amyloid-beta (Aβ) plaques and tau tangles. Recent studies suggest that dysfunction of the cerebral lymphatic clearance system may contribute to the progression of AD. This review critically examines the potential of deep cervical lymphatic-venous anastomosis (LVA) as a treatment for enhancing brain protein clearance and reducing cognitive decline in AD patients. Although animal models indicate that improving lymphatic drainage could facilitate Aβ clearance, clinical evidence is still insufficient. Current studies often have small sample sizes, short follow-up periods, and methodological weaknesses. Despite preliminary reports of cognitive improvements in small-scale clinical trials, the efficacy of LVA remains unproven, making widespread clinical adoption premature. Ethical concerns and technical challenges also pose significant barriers to clinical implementation. Rigorous randomized controlled trials (RCTs) are necessary to assess the long-term safety and efficacy of LVA for treating AD. Furthermore, the establishment of clear ethical and regulatory frameworks is essential before clinical use.},
}

@article {pmid41383776,
year = {2025},
author = {Pirhanov, A and Rodriguez, C and Tashakori-Asfestani, F and Gonsoulin, R and Santiago, R and Tobunluepop, K and Erhunmwunsee, E and Puri, S and Arbaciauskaite, M and He, W and Wolozin, B and Cho, Y},
title = {Nanobodies targeting hnRNPA2/B1 and tau.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.21.689763},
pmid = {41383776},
issn = {2692-8205},
abstract = {Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) is an RNA-binding protein that mislocalizes to the cytoplasm and forms stress-induced granules in tauopathy and multisystem proteinopathy. It also preferentially interacts with oligomeric tau and is required for tau-mediated neurodegeneration in a mouse model of Alzheimer's disease. To study endogenous hnRNPA2/B1 and tau, we generated nanobodies that specifically recognize these proteins. We screened yeast surface display nanobody libraries using an avidity-enhanced screening strategy that enabled selection of binders against short peptide ligands. This led to isolation of anti-hnRNPA2/B1 and anti-tau nanobodies with defined epitopes. Directed evolution of the anti-hnRNPA2/B1 nanobody improved binding affinity by over 20-fold but caused cytoplasmic aggregation, demonstrating a tradeoff between affinity and intracellular behavior. Although the final nanobodies retained modest affinities, they showed robust intracellular colocalization with their targets. Furthermore, fusion to ubiquitin ligase adaptor domains significantly decreased hnRNPA2/B1 and tau levels. Collectively, these nanobodies provide valuable tools for studying hnRNPA2/B1 and tau dynamics in their native cellular context.},
}

@article {pmid41383762,
year = {2025},
author = {Ku, TS and Mullett, SJ and Sui, Z and Zeng, L and Ding, Y and Yocum, AK and MacDonald, M and Gelhaus, SL and Kofler, J and Sweet, RA},
title = {Proteomic Analysis in Alzheimer's Disease with Psychosis Reveals Separate Molecular Signatures for Core AD Proteinopathy and Postsynaptic Density Disruption.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.26.690872},
pmid = {41383762},
issn = {2692-8205},
abstract = {BACKGROUND AND HYPOTHESIS: Alzheimer's disease with psychosis (AD+P) is a subgroup of AD patients with more rapid cognitive deterioration. While our previous study showed that AD+P is associated with loss of prefrontal cortex postsynaptic density (PSD) proteins, identifying proteins in the broader cellular environment that influence PSD loss addresses a critical knowledge gap about synaptic dysfunction mechanisms in early disease stages.

STUDY DESIGN: We conducted a proteomic analysis comparing prefrontal grey matter cortex tissue homogenates from elderly normal controls (n=18), individuals with AD+P (n=61), and individuals with AD-P (n=48), all with Braak stages 3-5.

STUDY RESULTS: AD+P showed the most pronounced alterations relative to controls (178 proteins with q<0.05), although alterations in AD-P and AD+P relative to controls were highly similar (R²=0.965, p<0.001). Weighted-gene correlation network analysis (WGCNA) identified four modules significantly associated with disease status comparing AD subjects to controls, but none differed significantly between AD+P and AD-P. We identified 15 proteins significantly correlated with PSD yield across all samples, including ENPP6, linked to AD+P by GWAS. Additionally, PSD yield-associated proteins showed minimal overlap with altered AD proteins (1 of 137). WGCNA revealed one module significantly correlated with PSD yield across all samples, enriched for inflammatory terms.

CONCLUSIONS: Our findings suggest a model in which AD+P arises from the combination of quantitative alterations within a shared AD proteome profile and a superimposed set of protein alterations correlated with PSD yield that are largely independent of the shared AD proteome, conferring distinct mechanisms of synaptic vulnerability and psychosis risk.},
}

@article {pmid41383524,
year = {2025},
author = {Zhang, X and Zhong, M and Li, Y and Wang, H and Xi, G and Wang, F and Cheng, C and Shi, Y},
title = {Oral microbiota and central nervous system diseases: A review.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {1},
pages = {79-94},
pmid = {41383524},
issn = {2770-730X},
abstract = {Oral microbiota is the second largest microbial colony in the body and forms a complex ecological community that influences oral and brain health. Impaired homeostasis of the oral microbiota can lead to pathological changes, resulting in central nervous system (CNS) diseases. However, the mechanisms and clinical value of how the oral microbiome influences the brain remain unclear. This review summarizes recent clinical findings on the role of the oral microbiota in CNS diseases and proposes potential approaches to understand the way the oral microbiota and brain communicate. We propose three underlying patterns involving neuroinflammation, neuroendocrine regulation, and CNS signaling between oral microbiota and CNS diseases. We also summarize the clinical characteristics and potential utilization of the oral microbiota in ischemic stroke, Alzheimer's and Parkinson's disease, intracranial aneurysms, and mental disorders. Although the current findings are preliminary and clinical evidence is incomplete, oral microbiota is a potential biomarker for the clinical diagnosis and treatment of CNS diseases.},
}

@article {pmid41383520,
year = {2025},
author = {Saxena, SK and Sharma, D and Kumar, S and Maurya, VK and Ansari, S and Malhotra, HS and Singh, A},
title = {Decoding the role of large heat shock proteins in the progression of neuroinflammation-mediated neurodegenerative disorders.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {1},
pages = {48-62},
pmid = {41383520},
issn = {2770-730X},
abstract = {Chronic neuroinflammation and protein aggregation are the fundamental events mainly responsible for the progression of neurodegenerative diseases (NDs). Potential neurotoxic changes in the intra- and extracellular environment are typical hallmarks of many NDs. Treatment of ND is challenging, as the symptoms in these patients arises when a significant numbers of neurons have already been destroyed. Heat shock proteins (HSPs) can bind to recipient cells that are susceptible to stress, such as neurons, in the extracellular environment, therefore enhancing stress resistance. Among all, HSP60, HSP70, and HSP90 are highly conserved molecular chaperones involved in protein folding and assembly, maintaining cellular homeostasis in the central nervous system. Notably, α-synuclein accumulation is a major pathophysiology in Parkinson's disease, where HSP90 modulates the assembly of α-synuclein in vesicles to prevent its accumulation. Moreover, HSP90 regulates the activity of the glycogen synthase kinase-3β protein, which is crucial in diabetes mellitus-associated neurocognitive disorder. Therefore, understanding the molecular mechanism by which HSPs facilitate protein aggregation and respond to inflammatory stimuli, including metabolic disease such as diabetes, is essential for understanding the significance of HSPs in NDs. This review emphasizes the role of various HSPs in the progression of NDs such as Alzheimer's, Parkinson's, multiple sclerosis, and Huntington's disease, including diabetes, which is one of the major risk factors for neurodegeneration.},
}

@article {pmid41383377,
year = {2024},
author = {Hanumanthappa, R and Parthasarathy, A and Heggannavar, GB and Pc, K and Nanjaiah, H and Kumbhar, R and Devaraju, KS},
title = {Recent advances in therapeutic strategies for Alzheimer's and Parkinson's disease using protein/peptide co-modified polymer nanoparticles.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {4},
pages = {255-275},
pmid = {41383377},
issn = {2770-730X},
abstract = {The blood-brain barrier (BBB), which protects the brain from foreign molecules, makes delivery of drugs to the central nervous system is challenging. Nanoparticles (NPs) have been used over the past decade as drug delivery systems for the treatment of many disorders with great results. However, the effectiveness of NPs in delivering drugs to the brain for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD) is limited by the BBB. A recent breakthrough in nanotechnology delivery systems involves the use of surface-modified polymer NPs that enhance drug absorption and transport across the BBB; however, the technology still has some limitations. Studies conducted over the past few years have demonstrated that NPs modified with peptides or proteins can effectively cross the BBB via specific receptors, thus enhancing their delivery efficiency. In this review, we explore the use of polymer NPs combined with peptides and proteins for the treatment of AD and PD. This discussion focuses on the pathophysiology of these diseases, the BBB, and the potential of therapeutics based on co-modifying NPs with peptides and proteins. Additionally, we outline future directions for the use of polymer NPs conjugated with these biomolecules.},
}

@article {pmid41383373,
year = {2024},
author = {Chen, J and Chen, J and Liang, C and Liu, C and Jie, L and Liu, B and Yang, X},
title = {Liver enzyme and risk of vascular dementia: A univariable and multivariable Mendelian randomization of European descent.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {4},
pages = {310-317},
pmid = {41383373},
issn = {2770-730X},
abstract = {BACKGROUND: Observational studies have indicated a link between liver enzymes and dementia, but the causal relationship remains uncertain. We conducted a two-sample Mendelian randomization (MR) study to investigate potential causal links between liver function markers (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyltransferase [GGT]) and various forms of dementia (all-cause dementia, Alzheimer's disease [AD], vascular dementia [VaD], and frontotemporal dementia [FTD]).

METHODS: Genome-wide association study (GWAS) data of liver enzyme levels with 517 single nucleotide polymorphisms from 315,572 individuals of European descent were considered as exposures. Additional GWAS data on dementia from the FinnGen consortium and the UK Biobank were used as outcomes. The causal relationship was evaluated using univariable MR (UVMR) and multivariable MR (MVMR) methods. UVMR approaches such as inverse variance weighting (IVW), MR-Egger, weighted median, simple mode, and weighted mode were used, with IVW as primary. MVMR techniques, such as extended versions of IVW, MR-Egger, and Q-minimization methods, were used to assess causal effects. The robustness of the MR analysis findings was verified through heterogeneity, horizontal pleiotropy, and leave-one-out analyses.

RESULTS: MVMR analysis demonstrated that a genetically determined one standard deviation rise in blood GGT levels was associated with an increased risk of VaD (IVW: odds ratio = 1.007, 95% confidence interval = 1.002-1.011, p = 0.010). These findings remained consistent after adjusting for confounding variables in MVMR analysis. Sensitivity analyses further supported the causal relationship. However, no significant links were observed between ALT, AST, ALP, and all-cause dementia, VaD, AD, or FTD.

CONCLUSIONS: Our study suggests clinical implications, demonstrating that high blood GGT concentrations are potential causal risk factors for VaD in European populations. Further research is needed to uncover the underlying biological mechanisms between GGT and VaD and validate the clinical relevance of early prevention and intervention strategies.},
}

@article {pmid41383223,
year = {2025},
author = {Hirano, S and Zhou, L and Ouchi, M and Suwa, S},
title = {Daily life experiences of an older woman with Alzheimer's disease residing alone as recorded in her diaries.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251396055},
pmid = {41383223},
issn = {2542-4823},
abstract = {BACKGROUND: In Japan, the aging population is rapidly increasing, with more older persons residing alone. Among them, individuals with dementia face unique challenges in maintaining daily life and self-identity.

OBJECTIVE: This study aimed to clarify what an older woman living with Alzheimer's disease, who resided alone, experienced in her daily life based on the diaries she kept.

METHODS: The contents of 13 diary books belonging to Aki (a pseudonym), an older woman with dementia who lived alone at home, were quantitatively analyzed using KH Coder, and a co-occurrence network was created. In addition, qualitative content analysis of the diary contents was performed for each subgraph obtained from this network.

RESULTS: Across all years, most days with entries had only 1 entry. However, as the years passed, the number of days with multiple entries increased. The co-occurrence network consisted of 8 subgraphs. According to the content in each subgraph, Aki experienced "sorrow and loneliness due to forgetfulness". However, Aki made efforts such as "recording the current time," "writing in a notebook to maintain my proper character". The analyses also revealed her experience of trying to live positively, as reflected in statements such as "I will live positively even though my siblings passed away, leaving me all alone."

CONCLUSIONS: Keeping a diary may have been an important means to complement her memory function and orientation, and to inspire motivation to live positively even after the loss of her family members, moreover as well as maintaining her self-esteem.},
}

@article {pmid41383118,
year = {2025},
author = {Peeples, LB and Chrzanowski, L and Mast, BT},
title = {Preparedness as a Bridge: How Religious Coping Shapes Acceptance of Death in Dementia Caregiving.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/07317115.2025.2601447},
pmid = {41383118},
issn = {1545-2301},
abstract = {OBJECTIVES: This study examined the role of religious coping and preparedness in shaping caregivers' acceptance of death following the loss of a care recipient with Alzheimer's disease or related dementias. Two competing path models were tested to determine whether preparedness serves as a mediator or an outcome in the relationship between religious coping and acceptance.

METHODS: Data were drawn from the bereavement battery of the Resources for Enhancing Alzheimer's Caregiver Health (REACH II) study. The analytic sample included 41 bereaved caregivers who completed measures of positive and negative religious coping, preparedness for death, and acceptance of death. Path analyses were conducted in R using the lavaan package.

RESULTS: Bivariate analyses indicated that both positive and negative religious coping were significantly associated with greater preparedness, and preparedness was strongly related to acceptance. The first path model, where preparedness predicted coping and acceptance, showed poor global fit. In contrast, the second model, where coping predicted preparedness, which in turn predicted acceptance, showed excellent fit.

CONCLUSIONS: Preparedness emerged as a mechanism linking religious coping with acceptance, highlight an important pathway for supporting caregivers in bereavement.

CLINICAL IMPLICATIONS: Findings suggest that interventions focused on religious coping enhance preparedness which improves caregivers' acceptance in the bereavement process.},
}

@article {pmid41383055,
year = {2025},
author = {Brodman, ST and Heaton, N and Triana-Baltzer, G and Zeng, X and Gogola, A and Kamboh, MI and Villemagne, VL and Lopez, OL and Kolb, H and Deek, RA and Cohen, AD and Karikari, TK},
title = {Plasma biomarkers, brain amyloid-beta pathology, and cortical thickness in a non-Hispanic White and Black/African American middle-aged community cohort: The HCP-CoBRA study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70985},
doi = {10.1002/alz.70985},
pmid = {41383055},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; R01AG083874//NIH/NIA)/ ; //Karikari Laboratory/ ; U24AG082930 P30 AG066468 RF1 AG077474 R01 AG083156 R37 AG023651 R01 AG025516 R01 AG073267 R01 AG075336 R01 AG072641 P01 AG025204//NIH/NIA/ ; U01 NS131740 U01 NS141777//NIH/NINDS/ ; R01 MH108509/MH/NIMH NIH HHS/United States ; DAF2255207//Aging Mind Foundation/ ; HT94252320064//DoD/ ; //Anbridge Charitable Fund/ ; //University of Pittsburgh/ ; },
mesh = {Humans ; Female ; Male ; *Amyloid beta-Peptides/metabolism/blood ; Biomarkers/blood ; Black or African American ; Middle Aged ; Positron-Emission Tomography ; Aged ; tau Proteins/blood ; White People ; Magnetic Resonance Imaging ; Cohort Studies ; *Brain/pathology/diagnostic imaging/metabolism ; *Brain Cortical Thickness ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; *Cerebral Cortex/pathology/diagnostic imaging ; Alzheimer Disease/pathology ; White ; },
abstract = {INTRODUCTION: We evaluated plasma biomarker association with, and classification accuracies for, amyloid beta-positron emission tomography (Aβ-PET) and cortical thickness in the biracial Human Connectome Project-Connectomics in Brain Aging (HCP-CoBRA) cohort (53% Black/African American [B/AA] and 47% non-Hispanic White [NHW]).

METHODS: In n = 218 participants (median age 62, range: 57-71] years, 65% female and 15% Aβ-PET positive), plasma biomarkers (phosphorylated tau-181 [p-tau181], p-tau217, p-tau231, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], and Aβ42/Aβ40) were compared to Aβ-PET and magnetic resonance imaging (MRI) neuroimaging indicators.

RESULTS: Plasma p-tau217 (Johnson & Johnson and ALZpath [areas under the curve [AUCs] = 0.915 vs. 0.919]) had high sensitivity and specificity (>85%) for Aβ-PET status. All plasma biomarkers except p-tau231 effectively ruled out Aβ pathology (negative predictive value [NPV] >95%) but only Johnson & Johnson p-tau217+ was good for confirmation (covariate-adjusted positive predictive value [PPV] = 0.909). The plasma biomarkers performed poorly for identifying cortical thickness status but were elevated according to joint Aβ-PET and neurodegeneration profiles. Plasma biomarker accuracies for Aβ-PET positivity were unaffected by self-identified race, except for ALZpath p-tau217 (p = 0.024). However, correlations with Aβ-PET standardized uptake value ratio varied by self-identified race.

DISCUSSION: Plasma p-tau217 is a promising tool for Alzheimer's disease-associated Aβ pathology in older/middle-aged individuals. However, apparent race-related performances should be further studied.

HIGHLIGHTS: Plasma phosphorylated tau-217 (p-tau217) and glial fibrillary acidic protein (GFAP) best predicted abnormal brain amyloid beta-positron emission tomography (Aβ-PET). Plasma p-tau217 accurately identified abnormal Aβ-PET (Johnson & Johnson p-tau217: area under the curve [AUC] = 0.9145, 95% confidence interval [CI] = 0.8367-0.9923; ALZpath p-tau217: AUC = 0.9198, 95% CI = 0.8585-0.981) followed by GFAP and Aβ42/40 ratio (GFAP: AUC = 0.8529, 95% CI = 0.7485-0.9573; Aβ42/40:AUC = 0.7962, 95% CI = 0.6581-0.9346). All plasma biomarkers performed poorly in identifying cortical thickness, despite being higher according to combined Aβ-PET and neurodegeneration profiles. Correlations of p-tau217 (Johnson & Johnson p < 0.001), p-tau181 (p = 0.005), and Aβ42/40 (p = 0.004) with Aβ-PET in predicting amyloid burden were stronger in self-identified non-Hispanic Whites vs Black/African Americans. Biomarker accuracies for Aβ-PET positivity were unaffected by self-identified race, except ALZpath p-tau217 (p = 0.024).},
}

Humans
Female
Male
*Amyloid beta-Peptides/metabolism/blood
Biomarkers/blood
Black or African American
Middle Aged
Positron-Emission Tomography
Aged
tau Proteins/blood
White People
Magnetic Resonance Imaging
Cohort Studies
*Brain/pathology/diagnostic imaging/metabolism
*Brain Cortical Thickness
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
*Cerebral Cortex/pathology/diagnostic imaging
Alzheimer Disease/pathology
White

@article {pmid41383049,
year = {2025},
author = {Pyun, JM and Park, YH and Kim, S and Nho, K and , },
title = {Polygenic risk score predicts pathologically confirmed cerebral amyloid angiopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70958},
doi = {10.1002/alz.70958},
pmid = {41383049},
issn = {1552-5279},
support = {RS-2024-00461936//National Research Foundation of Korea (Ministry of Science and ICT)/ ; P30 AG010133/NH/NIH HHS/United States ; P30 AG072976/NH/NIH HHS/United States ; R01 AG081951/NH/NIH HHS/United States ; R01 LM012535/NH/NIH HHS/United States ; U01 AG072177/NH/NIH HHS/United States ; U19 AG074879/NH/NIH HHS/United States ; AACSFD-24-1310485/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/genetics/pathology/diagnostic imaging ; Female ; Male ; Magnetic Resonance Imaging ; Aged ; Biomarkers ; *Multifactorial Inheritance ; *Alzheimer Disease/pathology/genetics ; Risk Factors ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Genetic Risk Score ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) both involve amyloid beta (Aβ) accumulation in vessels and brain parenchyma, respectively. As Aβ-targeting therapies emerge, CAA draws attention due to its link with amyloid-related imaging abnormalities (ARIA), underscoring the need for biomarkers beyond magnetic resonance imaging (MRI).

METHODS: CAA polygenic risk scores (CAA-PRS) were generated in 105 ADNI participants, and their predictive ability for pathological CAA was evaluated, including in subgroups with high amyloid burden or without MRI-visible CAA markers.

RESULTS: CAA-PRS was significantly associated with pathological CAA (OR = 1.766, p < 0.001), with an AUC of 0.783 overall and 0.766 (OR = 1.780, p = 0.002) in those with high amyloid burden. A marginal association was observed in MRI-negative individuals.

DISCUSSION: CAA-PRS may serve as a complementary biomarker to imaging for identifying high-risk individuals with CAA, particularly in the context of Aβ-targeting therapies and ARIA risk.

HIGHLIGHTS: CAA-PRS is generated. CAA-PRS is associated with pathologically confirmed CAA. CAA-PRS is associated with CAA in individuals with high amyloid burden.},
}

Humans
*Cerebral Amyloid Angiopathy/genetics/pathology/diagnostic imaging
Female
Male
Magnetic Resonance Imaging
Aged
Biomarkers
*Multifactorial Inheritance
*Alzheimer Disease/pathology/genetics
Risk Factors
Aged, 80 and over
Brain/pathology/diagnostic imaging
Amyloid beta-Peptides/metabolism
Genetic Risk Score

@article {pmid41382294,
year = {2025},
author = {Su, X and Takayanagi, R and Maeda, H and Saido, TC and Ohshima, T},
title = {Sex-related upregulation of bone morphogenetic protein signaling inhibits adult neurogenesis in APP[NL-G-F] alzheimer's disease model mice.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {103},
pmid = {41382294},
issn = {2042-6410},
support = {JP22K06464//Japan Society for the Promotion of Science/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Neurogenesis/physiology ; Female ; Male ; Up-Regulation ; Mice, Transgenic ; Disease Models, Animal ; Signal Transduction ; Mice, Inbred C57BL ; *Bone Morphogenetic Proteins/metabolism ; *Sex Characteristics ; Hippocampus/metabolism ; Mice ; Neural Stem Cells ; Estrogens/pharmacology ; },
abstract = {BACKGROUND: Bone morphogenetic proteins (BMPs) have been reported in many studies to be related to adult neurogenesis. Neurogenic impairment is a hallmark of Alzheimer's disease (AD), while the involvement of BMPs remains unclear.

METHODS: AD models were established using APP[NL-G-F] transgenic mice and C57BL/6 mice subjected to intracerebral injection of Aβ(25-35) peptide. Female APP[NL-G-F] mice received pharmacological inhibitor treatment, whereas Neuro2a cells were exposed to estrogen stimulation in vitro. Immunofluorescence staining was conducted to evaluate hippocampal neural stem cell proliferation. The hippocampus and cellular pellets were isolated, and quantitative PCR (qPCR) was employed to determine mRNA expression levels.

RESULTS: Our study revealed that APP[NL-G-F] mice and Aβ-injected mice exhibited impaired neurogenesis in the brain, with a clear sex-dependent difference only in APP mice. Several BMPs were markedly upregulated in the hippocampus of AD model mice, with significantly higher expression in females than in males. BMP inhibitor attenuated neural stem cell proliferation deficits in female APP[NL-G-F] mice. Estrogen stimulation robustly enhanced BMP6 expression in Neuro2a cells.

CONCLUSIONS: Our findings reveal a sex-dependent impairment of neurogenesis in APP[NL-G-F] mice driven by BMP signaling. Blocking BMP signaling enhances adult neural stem cell proliferation in female APP[NL-G-F] mice, providing a potential therapeutic target for AD.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Neurogenesis/physiology
Female
Male
Up-Regulation
Mice, Transgenic
Disease Models, Animal
Signal Transduction
Mice, Inbred C57BL
*Bone Morphogenetic Proteins/metabolism
*Sex Characteristics
Hippocampus/metabolism
Mice
Neural Stem Cells
Estrogens/pharmacology

@article {pmid41382275,
year = {2025},
author = {Nolt, GL and Golden, LR and Thorpe, SP and Funnell, JL and Stephens, IO and Hernandez, G and MacLean, SM and Lucido, CC and Brock, CR and Pallerla, AV and Adreon, DR and Williams, HC and Morganti, JM and Johnson, LA},
title = {Microglia-derived APOE2 improves remyelination even in the presence of endogenous APOE4.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03639-5},
pmid = {41382275},
issn = {1742-2094},
support = {T32 AG078110/NH/NIH HHS/United States ; RF1NS118558/NH/NIH HHS/United States ; R01AG081421/NH/NIH HHS/United States ; P20 GM148326/GM/NIGMS NIH HHS/United States ; },
abstract = {Demyelination occurs with aging and is exacerbated in neurodegenerative diseases. During demyelination, microglia upregulate expression of APOE, the gene encoding for the brain's primary lipid transport protein apolipoprotein E (ApoE), which also mediates microglial engulfment and elimination of myelin debris. Compared to the E3 allele of APOE, the E2 allele decreases risk for Alzheimer's disease (AD), while the E4 allele increases AD risk and is associated with an increased severity and progression of multiple sclerosis. Previous work shows that mice expressing E2 exhibit improved microglial function and remyelination compared to mice expressing E4. However, whether microglial-derived APOE is responsible for driving these differences following demyelination, and if microglia-selective expression of E2 is sufficient to provide protection, is unknown. We sought to determine if microglia-specific replacement of the E4 allele with E2 can rescue myelin loss and promote remyelination, even in the presence of continued E4 expression by other central nervous system (CNS) cells. Using a novel APOE allelic "switch" model in which we can induce a replacement of E4 with E2 exclusively in microglia, we characterize the glial cell response and lipid profile of mice that underwent either lysophosphatidylcholine (LPC) or cuprizone (CPZ)-induced demyelination and subsequent remyelination. We found that although alterations to the brain lipid profile were subtle, microglial E2 replacement significantly improved remyelination, lessened microgliosis, and decreased astrocytic lipid droplet load following CPZ-remyelination. Our results indicate that microglia-specific E2 expression, in the presence of continued E4 expression, may provide protection against myelin loss via both cell-autonomous and non-autonomous immunometabolic mechanisms.},
}

@article {pmid41382170,
year = {2025},
author = {Jannati, A and Thompson, K and Toro-Serey, C and Gomes-Osman, J and Banks, RE and Higgins, C and Showalter, J and Bates, D and Tobyne, S and Pascual-Leone, A},
title = {Concurrent detection of cognitive impairment and amyloid positivity with a multimodal machine learning-enabled digital cognitive assessment.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {261},
pmid = {41382170},
issn = {1758-9193},
mesh = {Humans ; *Machine Learning ; *Cognitive Dysfunction/diagnosis/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; Aged ; Neuropsychological Tests ; *Alzheimer Disease/diagnosis ; Biomarkers/blood ; Aged, 80 and over ; tau Proteins/metabolism ; Brain/metabolism/diagnostic imaging ; Middle Aged ; },
abstract = {BACKGROUND: Early identification of cognitive impairment and brain pathology associated with Alzheimer's disease (AD) is essential to maximize benefits from lifestyle interventions and emerging pharmacologic disease-modifying treatments (DMT). Digital cognitive assessments (DCAs) can quickly capture an array of metrics that can be used to train machine-learning (ML) models to concurrently evaluate different outcomes. DCAs have the potential to optimize clinical workflows and enable efficient assessment of cognitive function and the likelihood of a given underlying pathology.

METHODS: We assessed the ability of a multimodal ML-enabled DCA, the Digital Clock and Recall (DCR), to concurrently estimate brain amyloid-beta (Aβ) status and detect cognitive impairment, as compared with traditional cognitive assessments, including the MMSE, RAVLT, a DCA, Cognivue[®], and blood-based biomarkers in 930 participants from the Bio-Hermes-001 clinical study.

RESULTS: Aβ42/40, p-tau181, APS, and p-tau217 poorly classified cognitive impairment (AUCs: 0.61; 0.63; 0.63; 0.70, respectively), but accurately classified Aβ status (AUCs: 0.81; 0.78; 0.85, 0.89, respectively). MMSE, RAVLT, and Cognivue poorly classified Aβ status (AUCs: 0.70, 0.73, 0.70, respectively). However, separate multimodal, DCR-based ML classification models, run in parallel, accurately classified both cognitive impairment (AUC = 0.83) and Aβ-PET status (AUC = 0.81).

CONCLUSIONS: DCAs that leverage digital technologies to generate advanced metrics, such as the DCR, enable accurate and efficient detection of cognitive impairment associated with AD pathology. They have the potential to empower health systems and primary care providers to help their patients make timely treatment decisions.},
}

Humans
*Machine Learning
*Cognitive Dysfunction/diagnosis/metabolism
*Amyloid beta-Peptides/metabolism
Male
Female
Aged
Neuropsychological Tests
*Alzheimer Disease/diagnosis
Biomarkers/blood
Aged, 80 and over
tau Proteins/metabolism
Brain/metabolism/diagnostic imaging
Middle Aged

@article {pmid41381974,
year = {2025},
author = {Kim, NJ and Mishra, A and Chowdhury, NF and Anderson, SD and Vega, OM and Chaudhari, NN and Buetow, KH and Thompson, PM and Irimia, A},
title = {Deep neural networks and genome-wide associations reveal the polygenic architecture of local brain aging.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41381974},
issn = {2509-2723},
support = {R01 AG 079957/AG/NIA NIH HHS/United States ; },
abstract = {Local brain age (LBA) is a regional metric of brain aging that offers a spatially resolved alternative to global brain age, but whose genetic basis is unexplored. This study reports the first genome-wide association study of cortical LBA, as estimated by a deep neural network from the T1-weighted magnetic resonance images of 41,708 cognitively normal adults in the UK Biobank. We identified 1,212 single-nucleotide polymorphisms (SNPs) significantly associated with LBA in at least one brain region. Genes mapped to these SNPs are involved in developmental, metabolic, immune, and cytoskeletal pathways. Dimensionality reduction of SNP association profiles uncovered three clusters linked to morphogenetic, cytoskeletal, and immuno-epigenetic processes, helping to relate neuroanatomic, immunosenescent and epigenetic mechanisms of brain aging. Top variants are mapped to KCNK2, NUAK1, GMNC, MSL2, and to other genes implicated in neurodevelopment and neurodegeneration. Spatial clustering of LBA-associated variants in default mode, limbic, and motor network regions parallel regional vulnerability to Alzheimer's disease and frontotemporal dementia. These findings establish a polygenic architecture for regional brain aging and support LBA as a genetically informed phenotype for studying aging-related neurodegeneration. Our results suggest that cortical aging is not governed by isolated loci but by coordinated genetic programs-rooted in development, metabolism, and cellular structure-that confer lifelong patterns of regional brain vulnerability and resilience. This first genetic dissection of spatially specific brain aging reveals a polygenic landscape of coordinated genetic programs, developmentally encoded and metabolically maintained during senescence. This study reframes aging as an anatomically specific genetic process reflecting the varying structural vulnerabilities observed across neurodegenerative diseases.},
}

@article {pmid41381867,
year = {2025},
author = {Yao, XQ and Jiao, SS and Saadipour, K and Zeng, F and Wang, QH and Zhu, C and Shen, LL and Zeng, GH and Liang, CR and Wang, J and Liu, YH and Hou, HY and Xu, X and Su, YP and Fan, XT and Xiao, HL and Lue, LF and Zeng, YQ and Giunta, B and Zhong, JH and Walker, DG and Zhou, HD and Tan, J and Zhou, XF and Wang, YJ},
title = {Correction: p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41380-025-03375-5},
pmid = {41381867},
issn = {1476-5578},
}

@article {pmid41381752,
year = {2025},
author = {Tang, Y and Nishimura, Y and Li, N and Li, H and Salimi, A and Ishida, K and Sakti, AW and Nakai, H and Parida, R and Lee, JY},
title = {Insights into proton transfer dynamics in histidine tautomers of amyloid-β (1-40).},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-025-01790-x},
pmid = {41381752},
issn = {2399-3669},
support = {2022R1A2C1092044//National Research Foundation of Korea (NRF)/ ; },
abstract = {Histidine tautomerization within amyloid beta (Aβ) peptides is crucial in understanding the molecular mechanisms underlying Alzheimer's disease and its potential therapeutic strategies. Despite its significance, the proton transfer dynamics between histidine residues in Aβ-40 at the protein level remain insufficiently explored due to the complexity of solvent effects and the computational challenges of large-scale simulations. This study conducted fully quantum mechanical molecular dynamics (QM-MD) simulations coupled with metadynamics (MTD) to investigate the tautomerization process between histidine tautomers in Aβ-40 within an aqueous environment. Using the divide-and-conquer density-functional tight-binding (DC-DFTB) method, a system of ~3000 atoms was modeled to capture the atomic-scale interactions. MTD simulations revealed that water molecules mediate the tautomerization of histidine residues, HIS 13 and HIS 14, stabilizing specific tautomeric forms. The two-dimensional well-tempered MTD (2D WTMTD) results identified a reaction barrier of approximately 3.51 kcal mol[-1] for tautomerization. This study represents the first comprehensive QM-MD/MTD investigation of histidine tautomerization in amyloid beta peptides, offering insights into the tautomerization process.},
}

@article {pmid41381656,
year = {2025},
author = {Riley, S and Nguyen, V and Bhattacharjee, R and Ng, PQ and Ritchie, T and Kamath, KS and Fisk, I and Gecz, J and Kumar, R and Searle, IR},
title = {TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30121-2},
pmid = {41381656},
issn = {2045-2322},
support = {BB/V018108/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; LP200200957//Australian Research Council/ ; LP200200957//Australian Research Council/ ; LP200200957//Australian Research Council/ ; UA720//South Australian Grains and Industry Trust/ ; },
abstract = {β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.},
}

@article {pmid41381599,
year = {2025},
author = {Yun, J and Chun, MY and Zetterberg, H and Blennow, K and Gonzalez-Ortiz, F and Ashton, NJ and Shin, D and Yoon, S and Yoo, H and Kim, JP and Ham, H and Gu, Y and Kim, HJ and Moon, SH and Cho, H and Choi, JY and Byun, BH and Park, SY and Ha, JH and Na, DL and Seo, SW and Jang, H},
title = {Integrative analysis of AT classification, plasma biomarkers, and cognitive trajectories across diverse dementia syndromes.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30117-y},
pmid = {41381599},
issn = {2045-2322},
support = {#2023-00356//the Swedish Research Council/ ; #2017-00915//the Swedish Research Council/ ; No. 101053962//the European Union's Horizon Europe research and innovation program/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//the Alzheimer Drug Discovery Foundation (ADDF), USA/ ; #ADSF-21-831376-C//the AD Strategic Fund and the Alzheimer's Association/ ; #FO2022-0270//the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, the Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden/ ; No. 860197//the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie/ ; JPND2021-00694//the European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL/ ; #AF-930351//the Swedish Alzheimer Foundation/ ; #FO2017-0243//Hjärnfonden, Sweden/ ; #ALFGBG-715986//the Swedish state under the agreement between the Swedish government and the County Councils/ ; JPND2019-466-236//the European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//the Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC//the Alzheimer's Association 2022-2025 Grant/ ; RS-2020-KH106434//the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2020-KH107436//the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; #SMX1250081//Future Medicine 20*30 Project of the Samsung Medical Center/ ; 2024-ER1003-01//the "Korea National Institute of Health" research project/ ; RS-2019-NR040057//the Korea government (MSIT)/ ; RS-2025-02223212//the Ministry of Health & Welfare, Republic of Korea/ ; RS-2022-KH125667//the Ministry of Health & Welfare and Ministry of science and ICT, Republic of Korea/ ; },
abstract = {This study aimed to examine amyloid-β (Aβ) and tau (AT) biological stages, plasma biomarkers, and cognitive trajectories according to AT stages in Alzheimer's disease-related cognitive impairment (ADCI), subcortical vascular cognitive impairment (SVCI), and frontotemporal dementia (FTD). A total of 275 participants (42 cognitively unimpaired [CU], 132 ADCI, 73 SVCI, and 28 FTD) underwent Aβ and tau positron emission tomography for assessment of AT stages. Participants with cognitive impairment (ADCI, SVCI, and FTD) were classified according to clinical stages of mild cognitive impairment or dementia. Plasma biomarkers were analysed, and cognitive trajectories were assessed using mixed-effects models over 6.1 years. SVCI and FTD showed more advanced clinical stages than ADCI at equivalent AT stages. SVCI participants had higher plasma glial fibrillary acidic protein (P = 0.012) and neurofilament light chain (P = 0.025) than CU participants in the A - T- stage. In the A - T- stage, SVCI (β = -0.738, P = 0.002) and FTD (β = -4.016, P < 0.001) showed faster cognitive decline than CU, but not ADCI. In the A + T - stage, ADCI (β = -0.634, P = 0.005) and SVCI (β = -0.690, P = 0.006) showed faster decline than CU. In the A + T + stage, only ADCI exhibited significantly faster decline than CU (β = -1.856, P = 0.008). Distinct plasma biomarker profiles and cognitive trajectories characterise ADCI, SVCI, and FTD across AT classification, highlighting the heterogeneity in pathophysiological mechanisms across dementia types.},
}

@article {pmid41381446,
year = {2025},
author = {Malakhov, MM and Pan, W},
title = {Co-expression-wide association studies link genetically regulated interactions with complex traits.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {11061},
pmid = {41381446},
issn = {2041-1723},
support = {R01 AG065636/AG/NIA NIH HHS/United States ; RF1 AG067924/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Genome-Wide Association Study/methods ; Alzheimer Disease/genetics/blood ; Parkinson Disease/genetics/blood ; *Multifactorial Inheritance/genetics ; Proteomics/methods ; Transcriptome/genetics ; Cholesterol/blood ; Proteome/genetics ; *Gene Expression Regulation ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Genetic Predisposition to Disease ; Male ; },
abstract = {Transcriptome- and proteome-wide association studies (TWAS/PWAS) have proven successful in prioritizing genes and proteins whose genetically regulated expression modulates disease risk, but they ignore potential co-expression and interaction effects. To address this limitation, we introduce the co-expression-wide association study (COWAS) method, which can identify pairs of genes or proteins whose genetically regulated co-expression is associated with complex traits. COWAS first trains models to predict expression and co-expression from genetic variation, and then tests for association between imputed co-expression and the trait of interest while also accounting for direct effects from each exposure. We applied our method to plasma proteomic concentrations from the UK Biobank, identifying dozens of interacting protein pairs associated with cholesterol levels, Alzheimer's disease, and Parkinson's disease. Notably, our results demonstrate that co-expression between proteins may affect complex traits even if neither protein is detected to influence the trait when considered on its own. We also show how COWAS can help to disentangle direct and interaction effects, providing a richer picture of the molecular networks that mediate genetic effects on disease outcomes.},
}

Humans
*Genome-Wide Association Study/methods
Alzheimer Disease/genetics/blood
Parkinson Disease/genetics/blood
*Multifactorial Inheritance/genetics
Proteomics/methods
Transcriptome/genetics
Cholesterol/blood
Proteome/genetics
*Gene Expression Regulation
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Genetic Predisposition to Disease
Male

@article {pmid41381439,
year = {2025},
author = {Ang, S and Zhang, X and Hong, J and Xue, K and Li, J and Du, X and Gao, Y and Wang, X and Li, X and Chen, B and Li, Y and Zhang, J and Liu, S},
title = {The safety and efficacy of gamma frequency auditory and visual stimulation in the treatment of alzheimer's disease: a systematic review and meta-analysis.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {523},
pmid = {41381439},
issn = {2158-3188},
support = {82271546//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2025-ZZ-004//National Clinical Key Specialty Construction Program - Independent Research Project/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and significant global health burden. Current treatments offer limited benefits, highlighting the need for novel therapies. Gamma-frequency auditory and visual stimulation (GFAVS), utilizing 40 Hz neuromodulation, has gained attention as a non-invasive treatment for cognitive deficits and underlying pathophysiology in AD.

OBJECTIVE: This systematic review and meta-analysis aimed to assess the safety and efficacy of GFAVS in treating Alzheimer's disease (AD) and mild cognitive impairment (MCI).

METHODS: A comprehensive literature search across multiple databases (PubMed, Cochrane Library, MEDLINE, Web of Science, and Embase) was performed up to November 2025. Controlled trials involving adults (≥50 years) with AD or MCI, using GFAVS, were included. Meta-analyses assessed adverse events, cognitive function, and brain changes.

RESULTS: Eleven studies (341 participants) were included. GFAVS was safe, with no significant increase in overall adverse events (RR = 0.99, P = 0.93; RD = -0.01, P = 0.93). However, GFAVS significantly increased the risk of tinnitus (RR = 6.46, P = 0.08; RD = 0.16, P = 0.01). GFAVS significantly improved structural brain changes (SMD = 1.74, P = 0.02), especially in mixed AD and MCI populations (SMD = 3.05, P < 0.00001). Nevertheless, no significant improvements were observed in cognitive function (SMD = 0.16, 95% CI [-0.36 to 0.68], P = 0.55) or activities of daily living (SMD = 0.53, 95% CI [-1.26 to 2.33], P = 0.56), despite the observed structural brain changes. High heterogeneity was observed.

CONCLUSION: GFAVS appears to be well tolerated and may induce structural brain alterations in individuals with Alzheimer's disease or mild cognitive impairment; however, its impact on cognition or daily functioning remains to be established. Large-scale, rigorously designed trials are required to clarify optimal protocols and address the observed heterogeneity.},
}

@article {pmid41381239,
year = {2025},
author = {van den Broek, SL and Bratteby, K and Aguilar, X and Tran, TA and Syvänen, S and Sehlin, D},
title = {Radionuclide Selection Influences Imaging Outcomes in Immuno-PET with a Brain-Penetrating Anti-Amyloid-β Antibody.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.271194},
pmid = {41381239},
issn = {1535-5667},
abstract = {Bispecific antibodies exploiting receptor-mediated transcytosis offer a promising strategy to overcome limited blood-brain barrier permeability in Alzheimer disease immunotherapy and imaging. Lecanemab-Fab8D3 (Lec-Fab8D3), a bispecific amyloid-β (Aβ) antibody with enhanced brain delivery, may complement lecanemab immunotherapy as an immuno-PET imaging agent. Here, we systematically assess how the choice of radionuclide affects PET detection of Lec-Fab8D3 within the brain to evaluate its potential as a companion diagnostic. Methods: Lec-Fab8D3 was conjugated to an octadentate derivative of desferrioxamine (DFO*) or NODAGA for [89]Zr and [64]Cu radiolabeling, respectively, or directly radioiodinated with [124]I. PET imaging was performed in the Tg-ArcSwe Aβ mouse model and wild-type (WT) littermates at multiple time points after radiotracer administration, followed by biodistribution, autoradiography, and Aβ quantification to assess brain uptake, specificity, and distribution. Results: PET imaging demonstrated high cortical brain uptake of all 3 radiotracers in Tg-ArcSwe mice. Labeling with the metals [89]Zr and [64]Cu produced the highest overall brain signal in both Tg-ArcSwe and WT mice. [[89]Zr]Zr-DFO*-Lec-Fab8D3 and [[124]I]I-Lec-Fab8D3 demonstrated the greatest discrimination between Tg-ArcSwe and WT mice, with [[124]I]I-Lec-Fab8D3 exhibiting the most pronounced regional differences. Ex vivo analyses corroborated the PET findings, and immunostaining confirmed radiotracer colocalization with Aβ deposits. Conclusion: Immuno-PET imaging with radiolabeled Lec-Fab8D3 enables specific detection of brain Aβ pathology. Because of its residualizing properties, [89]Zr produced the highest overall signal, whereas [124]I yielded greater regional contrast, despite lower total brain signal. These findings enhance our understanding of the intrabrain distribution of bispecific antibodies and highlight the importance of radionuclide selection and its impact on immuno-PET outcomes.},
}

@article {pmid41381091,
year = {2025},
author = {Shi, Q and Zhan, D and Wang, W and Wu, X and Sheng, S and Wang, Y},
title = {Causal associations between cognitive impairments and retinal diseases: A two-sample Mendelian randomization study.},
journal = {The Journal of international medical research},
volume = {53},
number = {12},
pages = {3000605251404265},
doi = {10.1177/03000605251404265},
pmid = {41381091},
issn = {1473-2300},
mesh = {Humans ; *Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Retinal Diseases/genetics/complications ; *Alzheimer Disease/genetics ; *Cognitive Dysfunction/genetics ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Macular Degeneration/genetics ; Dementia, Vascular/genetics ; *Lewy Body Disease/genetics ; },
abstract = {ObjectiveThis study employed a bidirectional two-sample Mendelian randomization approach to investigate the causal links between Alzheimer's disease, Lewy body dementia, vascular dementia, and various retinal diseases.MethodsSummary data from large-scale genome-wide association studies of European ancestry were used to select genetic variants as instrumental variables. Causal estimates were derived using the inverse variance-weighted method, complemented by Mendelian randomization-Egger, weighted median, and weighted mode analyses to ensure robustness.ResultsGenetically predicted Alzheimer's disease was associated with a reduced risk of disorders of the choroid and retina (odds ratio = 0.93, 95% confidence interval: 0.88-0.98), retinal detachments and breaks (odds ratio = 0.90, 95% confidence interval: 0.84-0.97), and retinal detachment with retinal break (odds ratio = 0.84, 95% confidence interval: 0.74-0.95). Lewy body dementia was negatively associated with age-related macular degeneration (odds ratio = 0.88, 95% confidence interval: 0.79-0.98), disorders of the choroid and retina (odds ratio = 0.96, 95% confidence interval: 0.93-0.99), and degeneration of the macula (odds ratio = 0.93, 95% confidence interval: 0.88-0.98). Vascular dementia showed negative associations with age-related macular degeneration (odds ratio = 0.93, 95% confidence interval: 0.87-0.99) and degeneration of the macula (odds ratio = 0.96, 95% confidence interval: 0.93-0.99). Conversely, reverse Mendelian randomization indicated that genetic liability to macular degeneration and choroidal/retinal disorders was causally associated with cognitive performance and a reduced risk of Alzheimer's disease.ConclusionsFindings support inverse causal relationships in which specific dementias may reduce retinal disease risk and vice versa, suggesting complex shared biological mechanisms.},
}

Humans
*Mendelian Randomization Analysis
Genome-Wide Association Study
*Retinal Diseases/genetics/complications
*Alzheimer Disease/genetics
*Cognitive Dysfunction/genetics
Polymorphism, Single Nucleotide
Genetic Predisposition to Disease
Macular Degeneration/genetics
Dementia, Vascular/genetics
*Lewy Body Disease/genetics

@article {pmid41380794,
year = {2025},
author = {Robinson-Cooper, L and Davidson, S and Koutoubi, R and Zhang, K and Park, H and Barker-Haliski, M},
title = {Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115586},
doi = {10.1016/j.expneurol.2025.115586},
pmid = {41380794},
issn = {1090-2430},
abstract = {Presenilin 2 (PSEN2) variants increase risk of Alzheimer's disease (AD) and unprovoked seizures. Yet, age-related PSEN2 contributions to seizure susceptibility are understudied. Critically, PSEN proteolytic capacity may regulate hippocampal kainate-type glutamate receptor (KARs) availability. Kainic acid (KA) is a KAR agonist that evokes severe seizures in mice. We hypothesized that PSEN2 knockout (KO) mice would show reduced latency to KA-induced seizures, increased seizure burden, worsened 7-day survival, and altered hippocampal KAR expression compared to wild-type (WT) controls. Using repeated low-dose systemic KA administration to 3-4- and 12-15-month-old PSEN2 KO versus WT mice, we quantified acute seizure latency and neuropathology. GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes 7 days after seizures or sham to assess the impact of PSEN2 loss and seizures on hippocampal KARs. Young PSEN2 KO mice were more seizure-prone than WTs, while genotype did not change latency to first seizure. Aged females seized faster than young females and experienced greater mortality, unlike males. There was no difference in KAR subunit expression between young mouse genotypes and regardless of seizure history. In both genotypes, hippocampal CA3 astrocytes expressed GluK5 after seizures, however, astrocytic GluK2 upregulation only occurred in WTs. GluK5 expression was significantly reduced in aged seizure-naïve PSEN2 KO versus WT mice, while total GluK2 expression did not differ. Seizure-induced astrocytic GluK5 expression only occurred in WT mice in CA3, while astrocytic GluK2 expression occurred in both. Thus, PSEN2 loss may impair age-related hippocampal KAR expression, implicating KARs as understudied contributors to AD-related seizures.},
}

@article {pmid41380753,
year = {2025},
author = {Ding, H and Wu, S and Huang, D and Shan, L},
title = {Astrocyte regulates neuroinflammation and myelination in BCCAO-Related cognitive impairment via the PIAS1-STAT1 pathway.},
journal = {Brain research},
volume = {},
number = {},
pages = {150107},
doi = {10.1016/j.brainres.2025.150107},
pmid = {41380753},
issn = {1872-6240},
abstract = {Vascular dementia (VaD) ranks as the second most common form of cognitive impairment worldwide, surpassed only by Alzheimer's disease (AD), yet its pathophysiological mechanisms are still not fully understood. This study sought to explore the mechanisms underlying secondary cognitive decline after transient cerebral ischemia, employing a temporary bilateral common carotid artery occlusion (BCCAO) model to mimic clinical cerebral ischemia-reperfusion (I/R) conditions. Dynamic detection of model mice revealed no significant loss of hippocampal neurons after surgery. Nevertheless, at 12 weeks post-surgery, the mice exhibited obvious myelin loss accompanied by cognitive decline. Further intervention studies showed that the microglial depleter PLX5622 failed to effectively rescue myelin damage and cognitive impairment, while astrocytes remained persistently activated. Analysis of the differential expression profile of astrocytes from a VaD patient brain tissue database identified Protein Inhibitor of Activated STAT1 (PIAS1) as a key regulator, which was significantly downregulated in the astrocytes of VaD patients-this finding was validated in model mice. Behavioral assessments revealed that targeted overexpression of PIAS1 in astrocytes, achieved through adeno-associated viral (AAV) delivery, markedly ameliorated cognitive deficits, attenuated myelin injury, and suppressed astrocytic inflammatory responses. In parallel, in vitro studies using primary astrocyte cultures demonstrated that PIAS1 exerts its anti-inflammatory effects by modulating the signal transducer and activator of transcription 1 (STAT1) signaling pathway. In summary, the findings of this study demonstrate that reduced expression of PIAS1 in astrocytes following mild cerebral ischemia plays a crucial role in triggering secondary cognitive deficits and myelin degeneration. Furthermore, PIAS1 regulates astrocyte-mediated inflammatory responses via a STAT1-dependent pathway, offering new perspectives on the underlying mechanisms of VaD and potential therapeutic interventions.},
}

@article {pmid41380294,
year = {2025},
author = {Cacciamani, F and Houot, M and Tezenas du Montcel, S and Thibeau-Sutre, E and Vannini, P and Migliaccio, RL},
title = {Multimodal neural correlates of cognitive awareness in aging and Alzheimer's disease.},
journal = {NeuroImage. Clinical},
volume = {49},
number = {},
pages = {103922},
doi = {10.1016/j.nicl.2025.103922},
pmid = {41380294},
issn = {2213-1582},
abstract = {Impaired cognitive awareness-anosognosia-is a core symptom of Alzheimer's disease (AD), yet its neural correlates remain poorly defined. This study examined how cognitive awareness, measured both cross-sectionally and longitudinally via subject-informant discrepancy on the Everyday Cognition (ECog) questionnaire, relates to three AD biomarkers: amyloid burden, glucose hypometabolism, and cortical atrophy. We included 785 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), spanning cognitively normal (CN), mild cognitive impairment (MCI), and AD dementia. All biomarkers were assessed at baseline across the same 86 cortical regions, enabling anatomically harmonized, cross-modality comparisons. Linear mixed models incorporating all three biomarkers revealed no significant associations in CN. In MCI, declining awareness was associated with widespread cortical amyloid deposition (significant in 80/86 regions), sparing some limbic areas. Atrophy in 11 regions-including limbic, lateral temporal, and occipital cortices-also predicted awareness decline (all p < 0.044). In AD, no significant associations were found between amyloid and awareness, suggesting a plateau effect at advanced stages. In both MCI and AD, lower baseline glucose metabolism in the left posterior cingulate cortex (PCC) was associated with poorer awareness (MCI: β ± SE = - 0.14 ± 0.04, p = 0.006; AD: β ± SE = - 0.24 ± 0.07, p = 0.042). No significant biomarker-time interactions were found in AD, suggesting relatively stable awareness levels at advanced disease stages. These findings indicate that anosognosia in AD is linked to distinct biomarker and regional profiles that vary by disease phase. Multimodal analysis across harmonized regions reveals the left PCC as a robust metabolic correlate of awareness, underscoring its potential as a key target in understanding and monitoring self-awareness impairment in neurodegenerative disease.},
}

@article {pmid41380234,
year = {2025},
author = {Zhu, X and Wang, Z and Tang, Q and Shi, L and Li, B and Jin, Y},
title = {Self-assembled DNA micelle-GNP for simultaneous detecting miRNAs of Alzheimer's disease via lateral flow assays.},
journal = {Biosensors & bioelectronics},
volume = {295},
number = {},
pages = {118300},
doi = {10.1016/j.bios.2025.118300},
pmid = {41380234},
issn = {1873-4235},
abstract = {Alzheimer's disease (AD), a leading age-related neurodegenerative disorder, causes severe memory loss and cognitive impairment. Although no definitive cure currently exists, early diagnosis and continuous monitoring can help slow disease progression. Herein, we developed a lateral flow assay (LFA) for portable and sensitive detection of AD-related miRNA. DNA micelles (DM) were first designed to carry more gold nanoparticle (GNP) for improving the sensitivity of visual assay. Three types of DM-GNP probes were constructed for simultaneous detection of miR-34a, miR-125b, and miR-15a. These target miRNAs were visually identified within 20 min, with detection limits of 25 pM, 50 pM, and 10 pM, respectively. Importantly, the LFA enabled multiplexed miRNA detection without cross-interference. Importantly, the LFA platform enabled multiplexed miRNA detection without cross-interference. Therefore, the DM-GNP probe provides a sensitive and practical tool for LFA-based biosensing, offering a cost-effective, specific, and portable strategy for detecting AD-related miRNAs and other biomarkers.},
}

@article {pmid41379977,
year = {2025},
author = {},
title = {Erratum for the Report "Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice" by A. Ittner et al.},
journal = {Science (New York, N.Y.)},
volume = {390},
number = {6778},
pages = {eaee4634},
doi = {10.1126/science.aee4634},
pmid = {41379977},
issn = {1095-9203},
}

@article {pmid41379906,
year = {2025},
author = {Zhang, L and Li, L and Cao, P and Yang, J and Zaiane, OR and Wang, F},
title = {An Efficient Transfer Learning With Prompt Learning for Brain Disorders Diagnosis.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3625375},
pmid = {41379906},
issn = {2168-2208},
abstract = {The limited availability of training data significantly restricts the performance of deep supervised models for brain disease diagnosis. It is crucial to develop a learning framework through cross-disease transfer learning that can extract more information from the limited data. To address this challenge, we concentrate on prompt learning and endeavor to extend its application to the brain networks. Specifically, we propose a novel prompt learning framework called BPformer, which integrates knowledge transferred across diseases via specific prompts while keeping the original architecture of BPformer unchanged. The specific prompts incorporate 1) a mask prompt to determine whether the edges are noisy or discriminating, 2) disorder prompts for modeling consistent and disorder-specific knowledge, and 3) adaptive instance-level prompts to account for inter-individual variations. We evaluate BPformer on the private center Nanjing Medical University dataset, the public Autism Brain Imaging Data Exchange dataset, and the public Alzheimer's Disease Neuroimaging Initiative dataset. We demonstrate the effectiveness of the proposed model across various disease classification tasks, including major depressive disorder, bipolar disorder, alzheimer's disease, and autism spectrum disorder diagnoses. In addition, the proposed method enables disease interpretability and subtype analysis, empowering physicians to provide patients with more accurate and fine-grained treatment plans.},
}

@article {pmid41379854,
year = {2025},
author = {Shehadeh, A and Malak, MZ and Harazni, L and Mousa, FA},
title = {Spiritual Coping Among Palestinian Muslim Family Caregivers of People With Dementia: A Qualitative Study.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012251408700},
doi = {10.1177/14713012251408700},
pmid = {41379854},
issn = {1741-2684},
abstract = {Caring for a family member with dementia is highly challenging. Many family caregivers rely on spirituality and religion to cope, particularly in Palestine, where health and social support services are severely limited. This study aimed to explore how spirituality is used by Muslim family caregivers of people with dementia in Palestine. A qualitative exploratory design was employed. Semi-structured in-depth interviews were conducted with a convenience sample of 21 participants from January to March 2025. Data were analyzed using content analysis. Participants had a mean age of 47.4 (±5.8) years, were all adult children of their care recipients, and were predominantly female (90.5%). The analysis revealed several interconnected spiritual coping strategies, categorized into four major themes: "blessing in disguise", focusing on the afterlife, stoicism, and intermissions. Spirituality is vital for supporting Muslim family caregivers of people with dementia. The findings can inform the development of high-quality, tailored, and culturally sensitive spiritual care interventions.},
}

@article {pmid41379750,
year = {2025},
author = {Soncini, C and Chiari, A and Rothman, KJ and Martini, N and Cherubini, A and Despini, F and Costanzini, S and De Girolamo, G and Tondelli, M and Vinceti, G and Zamboni, G and Teggi, S and Maffeis, G and Vinceti, M and Filippini, T},
title = {Environmental factors and risk of early-onset dementia: a population-based case-control study.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-22},
doi = {10.1159/000549445},
pmid = {41379750},
issn = {1423-0208},
abstract = {INTRODUCTION: Dementia with symptom onset before the age of 65 is referred to as early-onset dementia (EOD). Many gaps exist regarding EOD etiology, including the role of environmental factors.

METHODS: We conducted a population-based case-control study in Modena province, Northern Italy, enrolling and geocoding 326 EOD cases and 1941 sex- and age-matched controls, to investigate the association of traffic-related benzene, green spaces around the place of residence, and exposure to artificial outdoor light at night. We used non-linear modeling to assess the relation between environmental variables and disease risk, overall and separately for Alzheimer's dementia (AD) and non-AD.

RESULTS: Green spaces generally showed an inverse association with EOD risk that was almost linear for AD and inverted U-shaped for non-AD. We observed a weak positive association between traffic-related benzene exposure and EOD risk that seemed limited to AD, with little change in risk for non-AD. Exposure to light at night showed an inverse linear association with small differences across the two disease subgroups. Analyses stratified by sex and age showed generally stronger (but statistically imprecise) associations in females and older individuals.

CONCLUSION: Overall, these results are consistent with some environmental influences on EOD risk, particularly with a beneficial effect of green spaces and light at night, as well as a possible adverse role of air pollution, particularly for AD.},
}

@article {pmid41379747,
year = {2025},
author = {Hoang, MT and Le, NT and Thi Hoai Nguyen, T and Nguyen, TD and Nguyen, TX and Ngoc Nguyen, A and Kim Dang, T and Thanh Nguyen, B and Thi Thanh Nguyen, H and Pham, T and Nguyen, AT and Nguyen, TA and Vu, HTT},
title = {Polypharmacy following dementia diagnoses in Vietnam: results from real-world data in outpatient settings.},
journal = {Gerontology},
volume = {},
number = {},
pages = {1-20},
doi = {10.1159/000550017},
pmid = {41379747},
issn = {1423-0003},
abstract = {INTRODUCTION: Polypharmacy might be clinically appropriate if it improves health outcomes of people with dementia. However, polypharmacy was associated with higher risks of impairment in cognitive, physical, and emotional abilities. Several studies on polypharmacy among people with dementia were performed globally, but not in Vietnam. This study aimed to investigate the epidemiology of polypharmacy among people with dementia in Vietnam.

METHODS: This retrospective cohort study included outpatient individuals who were diagnosed with dementia between 01 January 2023 and 15 April 2024 in the Vietnam National Geriatric Hospital. Data was extracted from medical records, including dementia diagnosis, drug utilization, medical history before dementia diagnosis, comorbidities, and sociodemographic. The monthly quantity of drugs used was categorized as 'no polypharmacy' 0-4 drugs, 'polypharmacy' ≥5 drugs, and 'hyperpolypharmacy' ≥10 drugs. The primary outcome was the incidence of polypharmacy following dementia diagnosis. The prescription of potentially inappropriate medications in people with dementia, identified by using the American Geriatrics Society Beers criteria, was also evaluated. Multivariable logistic regression was employed to find associated risk factors of polypharmacy.

RESULTS: During the follow-up from dementia diagnosis to 30 June 2024, there were 64 people having polypharmacy (median age at dementia diagnosis 73.5, 68.8% females) and 342 people without polypharmacy (median age at dementia diagnosis 74.0, 64.0% females). Age at dementia diagnosis, sex, regions of residence and education were not associated with having polypharmacy in people with dementia. Compared to people with Alzheimer's disease, significantly higher probabilities of having polypharmacy were seen in people with vascular dementia (odds ratio (OR) 4.63, 95% confidence interval (CI) 2.16 - 9.92), and other dementias (OR 4.61, 95% CI 2.31 - 9.18). People with dementia at severe stage were at lower chance of having polypharmacy (OR 0.19, 95% CI 0.05 - 0.63). Potentially inappropriate medications were more frequent in the polypharmacy group (n = 27, 42.2%), compared to the non-polypharmacy group (n = 59, 17.3%). Prescribing antipsychotics in the polypharmacy group doubled that in the non-polypharmacy group (34.4% versus. 16.1%).

DISCUSSION/CONCLUSION: Lower incidence of polypharmacy among people with dementia compared to previous studies might either imply the improvement in managing the prescription of potentially inappropriate medications or be underestimated by not including inpatient individuals. Future studies are necessary to clarify the impact of polypharmacy on health outcomes of people with dementia.},
}

@article {pmid41379647,
year = {2025},
author = {Xu, J and Bai, L and Wang, T and Yi, Z and Han, H and Dong, P},
title = {Combining Retip Retention Time Prediction with High-Resolution Mass Spectrometry: A Systematic Analysis of Schisandra chinensis-Evodia Conducted for the First Time.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c05620},
pmid = {41379647},
issn = {1520-6882},
abstract = {Schisandra chinensis-Evodia Herbal Pair (SEHP) is one of the classic Chinese herbal formulas for treating Alzheimer's disease (AD), but its complex chemical composition renders traditional analytical methods inefficient. Retention time (RT) provides complementary information to mass spectrometry, supporting qualitative identification. To enhance identification accuracy and efficiency, this study pioneered the integration of Retip retention time prediction with five machine learning models (Random Forest, BRNN, XGBoost, LightGBM, and Keras) for the systematic identification of SEHP chemical constituents. Using UPLC-Q-Exactive Orbitrap MS technology combined with MS-DIAL and Compound Discoverer software, 165 compounds were identified, including alkaloids, organic acids, and lignans. The LightGBM model achieved high-precision RT prediction within a ±1 min tolerance, significantly reducing false positive identification rates. Through in vivo experiments, 56 parent compounds and 281 metabolites were identified in plasma, urine, feces, liver, and brain tissues of 3xTg-AD mice, revealing their Phase I and II metabolic characteristics. Network pharmacology and molecular docking analysis suggested that SEHP may exert anti-AD effects by regulating key targets such as TNF, AKT1, STAT3, and inflammation-related pathways, including PI3K and MAPK. This study established an efficient and reliable strategy for identifying Chinese herbal medicine components and analyzing their in vivo metabolism, providing scientific evidence for the pharmacodynamic basis and mechanism of action of SEHP.},
}

@article {pmid41379535,
year = {2025},
author = {Jayakody, O and Ceïde, M and Verghese, J and Carrera, R and Doriwala, H and Agrawal, S and Pa, J and Blumen, H},
title = {Feasibility of a Virtual Reality Intervention Protocol to Improve Cognitive and Behavioral Skills in Older Adults at Increased Risk of Developing Dementia.},
journal = {JMIR formative research},
volume = {9},
number = {},
pages = {e77111},
doi = {10.2196/77111},
pmid = {41379535},
issn = {2561-326X},
mesh = {Humans ; *Dementia/prevention & control ; Feasibility Studies ; Aged ; Pilot Projects ; *Virtual Reality ; Female ; Male ; *Cognition ; Aged, 80 and over ; },
abstract = {This pilot study offers preliminary evidence that a virtual meal-preparation task is feasible for older adults and highlights that the community engagement studios are an effective approach to generate community-informed strategies to enhance intervention designs and reach.},
}

Humans
*Dementia/prevention & control
Feasibility Studies
Aged
Pilot Projects
*Virtual Reality
Female
Male
*Cognition
Aged, 80 and over