@article {pmid41795936,
year = {2026},
author = {Zou, L and Ye, W and Li, C and Yang, S},
title = {Association between stress hyperglycemia ratio and cognitive function in older patients with diabetes or prediabetes: a cross-sectional study from the NHANES.},
journal = {Endocrine journal},
volume = {},
number = {},
pages = {},
doi = {10.1507/endocrj.EJ25-0437},
pmid = {41795936},
issn = {1348-4540},
abstract = {To explore the association between stress hyperglycemia ratio (SHR) levels and cognitive function in older patients with diabetes or prediabetes. Cognitive function was assessed through a composite Z-score, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) subtest, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). SHR was calculated as the fasting blood glucose divided by the estimated average glucose from glycated hemoglobin. In subsequent analyses, SHR was divided into quartiles (quartiles 1 to 4), with the second quartile serving as the reference group. A weighted linear regression model was used to assess the association between SHR and cognitive function. After adjusting the corresponding covariates, the analysis revealed that compared to the second quartile, the first [β: -0.26; 95% confidence interval (CI): -0.39- -0.12], third (β: -0.13, 95% CI: -0.25- -0.02), and fourth (β: -0.21, 95% CI: -0.36- -0.06) quartiles were all associated with a decrease in Z-score. The first quartile was associated with a decline in AFT (β: -1.46, 95% CI: -2.57- -0.36). The first (β: -3.72, 95% CI: -6.06- -1.38) and fourth (β: -2.58, 95% CI: -4.98- -0.17) quartiles were associated with a decline in DSST. No statistically significant associations were observed between any of the quartile groups and CERAD (all p > 0.05). Both higher and lower SHR were associated with poorer overall cognitive function, with higher and lower SHR being related to worse memory dimensions, while lower SHR was associated with impaired executive function.},
}

@article {pmid41795917,
year = {2026},
author = {Sirag, N and Elfadil, H and Ghabban, AJ and Alasiri, AM and Alnasser, IR and Bedaiwi, HS and Alharbi, SF and Almarwani, MJ and Aljohani, OM and Hassan, HM and Al-Gayyar, MMH and Salama, A},
title = {Ligustilide Attenuates Neuroinflammation and Fibrosis in an Aluminum Chloride-induced Rat Model of Alzheimer's Disease via mTOR/STAT3 Signaling Inhibition.},
journal = {The Keio journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.2302/kjm.2025-0017-OA},
pmid = {41795917},
issn = {1880-1293},
abstract = {Alzheimer's disease (AD) affects approximately 50 million individuals worldwide and is projected to triple by 2050. Ligustilide is a naturally occurring compound with varied pharmacological actions. Ligustilide has been reported to ameliorate AD by inhibiting PKA/AKAP1 or inducing α-secretase, but no prior research has examined its ability to activate the inflammasome in AD. We aimed to investigate the potential therapeutic effects of ligustilide in rats with AD by assessing the inflammatory and fibrotic pathways. AD was induced in rats by aluminum chloride. Subsequently, some rats were orally administered 20 mg/kg of ligustilide. For structural assessment, hippocampal brain tissue sections were stained with hematoxylin/eosin and subjected to anti-mTOR and anti-phospho-tau antibody staining. The collected samples were then analyzed for gene expression and protein levels of mTOR, STAT3, TGF-β, β-catenin, NFκB, TNF-α, TLR4, and NLRP3. We found that rats treated with ligustilide displayed marked improvements in their behavior. Furthermore, microscopic analysis of hematoxylin/eosin-stained images revealed that ligustilide reduced inflamed tissues and partially dilated blood vessels, without gliosis or vacuolated neuropil. Additionally, ligustilide decreased the expression of mTOR, STAT3, TGF-β, β-catenin, NFκB, TNF-α, TLR4, and NLRP3. In conclusion, ligustilide improved AD in rats and reduced inflammation and fibrosis. This effect is attributed to ligustilide's ability to reduce mTOR and STAT3 activity, thereby suppressing NFκB, TNF-α, TLR4, and NLRP3, and inhibiting the inflammasome pathway. Consequently, this cascade results in decreased STAT3 and TGF-β levels, thereby reducing fibrosis.},
}

@article {pmid41795685,
year = {2026},
author = {Liu-Ambrose, T and Falck, RS and Dao, E and Crockett, RA and Barha, CK and Silva, NCBS and Alkeridy, WA and Best, JR and Hsiung, GR and Field, TS and Madden, KM and Davis, JC and Ten Brinke, LF and Tam, RC},
title = {Resistance training and subcortical vascular cognitive impairment: A 12-month randomized trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71245},
doi = {10.1002/alz.71245},
pmid = {41795685},
issn = {1552-5279},
support = {//Jack Brown and Family Alzheimer Research Foundation/ ; G-15-0009019//Heart and Stroke Foundation of Canada/ ; },
mesh = {Humans ; Female ; Male ; *Cognitive Dysfunction/therapy/rehabilitation ; Aged ; *Resistance Training/methods ; *Cerebral Small Vessel Diseases/complications ; Neuropsychological Tests ; Treatment Outcome ; Middle Aged ; },
abstract = {INTRODUCTION: It is unknown whether progressive resistance training (PRT) improves cognitive function in adults with cerebral small vessel disease and mild cognitive impairment (i.e., subcortical vascular cognitive impairment [SVCI]).

METHODS: We conducted a 12-month randomized trial comparing PRT versus balance and tone exercises (BAT) on the Alzheimer's Disease Assessment Scale Cognitive Plus (ADAS-Cog-Plus).

RESULTS: Ninety-one participants were randomized (PRT = 45; BAT = 46); 76 completed the trial. Adherence was not different between groups (p = 0.18). At 12 months, PRT significantly improved ADAS-Cog-Plus scores (estimated mean difference: -0.18; 95% confidence interval [CI: -0.35, -0.01]; p = 0.04). Planned contrasts stratified by sex showed a significant PRT effect on ADAS-Cog-Plus scores for females (mean difference: -0.27; 95% CI: [-0.49, -0.05]; p = 0.02), but not for males. PRT also significantly reduced C-reactive protein (estimated mean difference: -2.93; 95% CI: [-5.36, -0.49]; p = 0.02). No significant differences were observed for other secondary outcomes.

DISCUSSION: PRT may have a small beneficial effect on cognitive function in SVCI.

CLINICAL TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT02669394).},
}

Humans
Female
Male
*Cognitive Dysfunction/therapy/rehabilitation
Aged
*Resistance Training/methods
*Cerebral Small Vessel Diseases/complications
Neuropsychological Tests
Treatment Outcome
Middle Aged

@article {pmid41795676,
year = {2026},
author = {Li, J and Xue, H and Leng, Y and Samus, QM and Nowrangi, M and Szanton, SL and Xue, QL and Li, J},
title = {Television and computer use and dementia risk in older adults with limited leisure or social activities: A prospective cohort study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71259},
doi = {10.1002/alz.71259},
pmid = {41795676},
issn = {1552-5279},
support = {//Johns Hopkins University Catalyst Award/ ; },
mesh = {Humans ; *Television/statistics & numerical data ; Male ; Female ; Aged ; *Dementia/epidemiology ; Prospective Studies ; *Leisure Activities ; Risk Factors ; *Computers/statistics & numerical data ; United Kingdom/epidemiology ; Middle Aged ; Sedentary Behavior ; Cohort Studies ; Apolipoproteins E/genetics ; },
abstract = {INTRODUCTION: Associations between television/computer use and dementia in socially inactive older adults remain unclear, and optimal limits are unknown.

METHODS: We followed 89,671 dementia-free, socially inactive adults aged ≥55 from UK Biobank for a mean of 12.2 years. Adjusted Cox models assessed associations with incident all-cause dementia and subtypes.

RESULTS: Computer use ≤2.4 h/day was associated with lower all-cause dementia risk (hazard ratio [HR] 0.88; 95% confidence interval [CI] 0.82-0.94), whereas higher use increased risk (HR 1.19, 95% CI 1.05-1.34); patterns were similar for Alzheimer's and vascular dementia. Television viewing showed no association below 2.06 h/day but higher risk thereafter (HR 1.17; 95% CI 1.03-1.32), with a roughly linear increase for vascular dementia. Heavy computer use in apolipoprotein E (APOE) -ε4 homozygotes and higher television viewing in adults < 65 were more harmful.

DISCUSSION: In socially inactive older adults, moderate computer use may be protective, whereas higher computer use and television viewing are linked to increased dementia risk.},
}

Humans
*Television/statistics & numerical data
Male
Female
Aged
*Dementia/epidemiology
Prospective Studies
*Leisure Activities
Risk Factors
*Computers/statistics & numerical data
United Kingdom/epidemiology
Middle Aged
Sedentary Behavior
Cohort Studies
Apolipoproteins E/genetics

@article {pmid41795672,
year = {2026},
author = {Cicero, EC and Flatt, JD and Kaabi, O and Tangpricha, V and Getahun, D and McCracken, C and Lash, TL and Silverberg, MJ and Vupputuri, S and Perkins, M and Barnes, LL and Goodman, M},
title = {Alzheimer's disease and related dementias among transfeminine adults: A cohort study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71277},
doi = {10.1002/alz.71277},
pmid = {41795672},
issn = {1552-5279},
support = {23AARGD-NTF-1028973/ALZ/Alzheimer's Association/United States ; R01AA030275/AA/NIAAA NIH HHS/United States ; K23AG084851/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology ; Female ; Male ; Aged ; *Transgender Persons/statistics & numerical data ; Cohort Studies ; *Dementia/epidemiology ; Aged, 80 and over ; Prevalence ; Electronic Health Records ; },
abstract = {INTRODUCTION: We investigated whether Alzheimer's disease and related dementias (ADRD) are more common among transfeminine (TF) adults than among demographically similar cisgender people enrolled in the same health system.

METHODS: We analyzed electronic health records of 856 TF adults aged 65+ and matched cisgender men (CM) and cisgender women (CW) and compared ADRD prevalence across groups by calculating enrollment-adjusted odds ratios (aOR) and 95% confidence intervals (CI).

RESULTS: The aOR of ADRD among TF adults were 1.39 (95% CI: 0.99-1.97) relative to CM and 1.29 (95% CI: 0.92-1.82) relative to CW referents. For TF adults with evidence of receiving gender-affirming hormone therapy (GAHT) receipt, the associations were slightly stronger: 1.75 (1.13-2.69) and 1.70 (1.11-2.60). Results restricted to minoritized ethnoracial groups appeared smaller, but imprecise.

DISCUSSION: These findings suggest that ADRD diagnosis and management may represent a priority in the healthcare of older TF people, particularly those with a history of GAHT.},
}

Humans
*Alzheimer Disease/epidemiology
Female
Male
Aged
*Transgender Persons/statistics & numerical data
Cohort Studies
*Dementia/epidemiology
Aged, 80 and over
Prevalence
Electronic Health Records

@article {pmid41795671,
year = {2026},
author = {Lim, S and Lee, J and Min, PH and Moloney, CM and Mester, CT and Ghatamaneni, S and Senjem, ML and Botha, H and Knopman, DS and McCarter, SJ and Ramanan, VK and Savica, R and Fields, JA and Machulda, MM and Dickson, DW and Reichard, RR and Nguyen, AT and Graff-Radford, J and Schwarz, CG and Gunter, JL and Kantarci, K and Boeve, B and Vemuri, P and Jones, DT and Jack, CR and Petersen, RC and Murray, ME and Lowe, VJ},
title = {Tau PET overlap index correlation with neuropathological findings.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71241},
doi = {10.1002/alz.71241},
pmid = {41795671},
issn = {1552-5279},
support = {R01 AG073282/GF/NIH HHS/United States ; RO1 NS124337-02/GF/NIH HHS/United States ; P30 AG62677/GF/NIH HHS/United States ; R01 AG068206/GF/NIH HHS/United States ; U01 AG006786/GF/NIH HHS/United States ; P50 AG016574/GF/NIH HHS/United States ; R01 AG034676/GF/NIH HHS/United States ; R37 AG011378/GF/NIH HHS/United States ; R01 AG041851/GF/NIH HHS/United States ; U19 AG063911/GF/NIH HHS/United States ; R01 NS097495/GF/NIH HHS/United States ; R01 AG056366/GF/NIH HHS/United States ; U01 NS100620/GF/NIH HHS/United States ; RF1 AG069052/GF/NIH HHS/United States ; //GHR Foundation/ ; //Elsie and Marvin Dekelboum Family Foundation/ ; //The Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic/ ; //Liston Award Family Foundation/ ; HY-202400000003953//Hanyang University/ ; //National Research Foundation/ ; RS-2023-00226494//Korean government/ ; //Mayo Foundation for Medical Education and Research/ ; //The Robert H. and Clarice Smith and Abigail van Buren Alzheimer's Disease Research Program, The Schuler Foundation/ ; },
mesh = {Humans ; *Positron-Emission Tomography/methods ; *tau Proteins/metabolism ; Male ; Female ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Aged ; Neurofibrillary Tangles/pathology ; *Tauopathies/pathology/diagnostic imaging/metabolism ; *Brain/pathology/diagnostic imaging/metabolism ; Aged, 80 and over ; Middle Aged ; Entorhinal Cortex/pathology/diagnostic imaging/metabolism ; Carbolines ; },
abstract = {INTRODUCTION: The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal-to-noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology.

METHODS: Fifty-seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses.

RESULTS: Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non-AD tauopathies.

DISCUSSION: These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non-AD tauopathies.},
}

Humans
*Positron-Emission Tomography/methods
*tau Proteins/metabolism
Male
Female
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Aged
Neurofibrillary Tangles/pathology
*Tauopathies/pathology/diagnostic imaging/metabolism
*Brain/pathology/diagnostic imaging/metabolism
Aged, 80 and over
Middle Aged
Entorhinal Cortex/pathology/diagnostic imaging/metabolism
Carbolines

@article {pmid41795668,
year = {2026},
author = {Ling, Y and Sun, P and Wang, C and Peng, G and Wang, Y and Zhou, X and He, Z and Liu, B and Zhang, J and Yu, J and Su, Y and Li, K and Guo, T and Luo, B},
title = {A novel eye-tracking digital marker outperforms plasma biomarkers in detecting cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71253},
doi = {10.1002/alz.71253},
pmid = {41795668},
issn = {1552-5279},
support = {2022C03064//the Key Research and Development Program of Zhejiang/ ; 2025ZFJH01//the Fundamental Research for the Central Universities/ ; 2022KY067//Medical and Health Science and Technology Project of Zhejiang Province/ ; 82422027//the National Natural Science Foundation of China/ ; U24A20340//the National Natural Science Foundation of China/ ; 82171197//the National Natural Science Foundation of China/ ; 82371484//the National Natural Science Foundation of China/ ; 2023B1515020113//Guangdong Basic and Applied Basic Science Foundation for Distinguished Young Scholars/ ; },
mesh = {Humans ; *Biomarkers/blood ; *Cognitive Dysfunction/diagnosis/blood ; Male ; Female ; Amyloid beta-Peptides/blood ; Aged ; tau Proteins/blood ; *Eye-Tracking Technology ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Detecting and monitoring cognitive performance in older adults is critical. In this study, we evaluated the validity of an eye-tracking tool in diagnosing cognitive impairment.

METHODS: We recruited 119 cognitively unimpaired (CU) individuals and 157 cognitively impaired (CI) patients who completed digital eye-tracking tests and cognitive scales. Of them, 154, 120, 53, and 146 underwent plasma biomarker tests, amyloid-β positron emission tomography (Aβ-PET) scans, tau-PET scans, and magnetic resonance imaging (MRI) scans. The diagnostic performance of eye-tracking markers and their relationships to Alzheimer's disease biomarkers and cognition were examined.

RESULTS: The eye-tracking panel exhibited better performance (area under the curve [AUC] = 0.865) in classifying CI from CU compared to plasma Aβ42/40 (AUC = 0.699), p-Tau217 (AUC = 0.769), p-Tau217/Aβ42 (AUC = 0.801), glial fibrillary acidic protein (GFAP; AUC = 0.804), and neurofilament light chain (NfL) (AUC = 0.826).

DISCUSSION: These findings demonstrate the validity of digital eye-tracking markers for screening patients with cognitive impairment, providing a novel digital marker for detecting cognitive decline in older adults.},
}

Humans
*Biomarkers/blood
*Cognitive Dysfunction/diagnosis/blood
Male
Female
Amyloid beta-Peptides/blood
Aged
tau Proteins/blood
*Eye-Tracking Technology
Positron-Emission Tomography
Magnetic Resonance Imaging
Neuropsychological Tests
Aged, 80 and over

@article {pmid41795661,
year = {2026},
author = {Zhang, Y and Qian, XH and Zhuang, H and Zhang, W and Hu, J and Zhao, Y and Li, Y and Jin, W and Xu, C and Meng, Z and Li, W and Chen, S and Jiang, XF and Guo, T and Li, YD and Ye, J and Liang, ZP and Li, B and Zhang, M and Tang, H and Li, Y},
title = {Dual association patterns between microglial activation and neuronal health in Alzheimer's disease: a whole-brain MRSI/PET study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71229},
doi = {10.1002/alz.71229},
pmid = {41795661},
issn = {1552-5279},
support = {82501770//National Natural Science Foundation of China/ ; 82571772//National Natural Science Foundation of China/ ; 82372073//National Natural Science Foundation of China/ ; 21TQ1400203//Shanghai Pilot Program for Basic Research - Shanghai Jiao Tong University/ ; //Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning/ ; YG2025ZD31//Key Program of Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University/ ; YG2025QNA45//Key Program of Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University/ ; YG2023ZD22//Key Program of Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University/ ; YG2023QNA46//Key Program of Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University/ ; 202240031//Shanghai Municipal Health Commission/ ; GCQH2023061//Guangci Clinical Technology and Innovation Program (GCTIP) of Ruijin Hospital/ ; 24dz2260100//Shanghai Key Laboratory of Child Brain and Development/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; *Microglia/metabolism/pathology ; Male ; Female ; Positron-Emission Tomography ; Aged ; *Cognitive Dysfunction/diagnostic imaging/metabolism/pathology ; *Brain/diagnostic imaging/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Magnetic Resonance Spectroscopy ; *Neurons/metabolism/pathology ; Aspartic Acid/analogs & derivatives/metabolism ; Middle Aged ; },
abstract = {INTRODUCTION: Microglial activation can either support neuronal function or exacerbate damage, contributing to Alzheimer's disease (AD) progression. We investigated spatial relationships among microglial activation, neuronal health, and amyloid beta (Aβ) in the AD spectrum.

METHODS: Forty healthy controls, 37 patients with mild cognitive impairment (MCI), and 62 patients with AD underwent whole-brain high-resolution [1]H-magnetic resonance spectroscopic imaging (MRSI), [[1] [8]F]DPA-714, and [[1] [8]F]AV-45 positron emission tomography (PET). Regional and voxel-wise analyses assessed changes and associations of microglial activation with N-acetylaspartate (NAA) and Aβ.

RESULTS: MCI and AD patients showed higher microglial activation and lower NAA, correlating with cognitive decline. In controls and MCI, microglial activation correlated positively with NAA and Aβ in early amyloid-accumulating regions. Conversely, negative correlations with NAA emerged in the hippocampus in MCI and extended to temporal and occipital regions in AD.

DISCUSSION: For the first time, we identified two distinct spatial association patterns between [[1] [8]F]DPA-714 PET and NAA, shedding light on the complex interplay between neuroinflammation and neuronal health in AD.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
*Microglia/metabolism/pathology
Male
Female
Positron-Emission Tomography
Aged
*Cognitive Dysfunction/diagnostic imaging/metabolism/pathology
*Brain/diagnostic imaging/metabolism/pathology
Amyloid beta-Peptides/metabolism
Magnetic Resonance Spectroscopy
*Neurons/metabolism/pathology
Aspartic Acid/analogs & derivatives/metabolism
Middle Aged

@article {pmid41795542,
year = {2026},
author = {Jing, T and Yang, L and Yuan, Z and Ling, G and Zhang, P},
title = {Deciphering the signal of metal ions: the principle, design and multi-field application of DNAzyme fluorescence sensor.},
journal = {Talanta},
volume = {305},
number = {},
pages = {129597},
doi = {10.1016/j.talanta.2026.129597},
pmid = {41795542},
issn = {1873-3573},
abstract = {Metal ion detection is the core link of ecological protection, human health, and food safety. Traditional methods (AAS, ICP-MS, etc.) are expensive and cumbersome, and it is difficult to meet the needs of rapid on-site detection. In this paper, the research progress of DNAzyme fluorescence sensors is systematically reviewed, focusing on the classification characteristics of typical DNAzymes such as 8-17 DNAzyme and GR-5 DNAzyme and their specific response mechanisms to metal ions. The detection principles of quencher mediation (such as gold nanoparticles, MOF, UCNPs, etc.), signal amplification (such as DNA walker, G-quadruplex, etc.), and multi-method combination are deeply analyzed. DNAzyme fluorescence sensors leverage the high specificity and programmability of catalytic DNA. Under optimized conditions, certain architectures achieve pM-level detection sensitivity, whereas others are robustly deployed in the nM to μM range-particularly in complex matrices. It has been widely used in biomedicine (such as tumor ion imaging, Alzheimer's disease AD brain iron ion detection), environment and resources (such as food quality detection, heavy metal pollution prevention and control), and other fields, and the actual sample detection results are in good agreement with the traditional authoritative methods. Finally, this paper reviews the existing challenges and optimization paths in terms of anti-interference in complex matrices and in vivo targeting, and provides a key reference for the innovative breakthroughs of rapid detection technology of metal ions.},
}

@article {pmid41795115,
year = {2026},
author = {Abuawad, M and Rjoub, A and Ghanim, M and ALqub, M and Dwikat, M and Al-Lahham, S and Abuabed, A and Sliman, A and Kanaaneh, A and Hanani, F},
title = {Knowledge and attitudes of clinical physicians towards Alzheimer's disease and related dementias: an observational cross-sectional study from Palestine.},
journal = {BMC medical education},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12909-026-08943-z},
pmid = {41795115},
issn = {1472-6920},
}

@article {pmid41795086,
year = {2026},
author = {Guo, HH and Su, D and Song, B and Geng, Z and Wang, L and Wang, W and Hu, W and Li, X and Li, W and Zhang, G and Fang, M and Dai, Y and Hu, P and Wu, X and Wang, K and Wei, L and , },
title = {CSF microtubule-associated protein 1 light chain 3A and 3B levels are associated with tau pathology and Alzheimer's disease risk through amyloid deposition and microglial signaling.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03758-7},
pmid = {41795086},
issn = {1742-2094},
support = {2025AHGXZK50040//Anhui Provincial Department of Education Scientific Research Project for Doctoral Students/ ; 82101498//Natural Science Foundation of China/ ; 82090034//Natural Science Foundation of China/ ; 82371201//Natural Science Foundation of China/ ; 2021kj19//2021 Youth Foundation training program of the First Affiliated Hospital of Anhui Medical University/ ; 202204295107020006//Anhui Province Clinical Medical Research Transformation Special Project/ ; XZZR202402048//Natural Science Foundation of the Xizang Autonomous Region Group Medical Aid Project to Xizang/ ; 2022zhyx-B11//Research Fund of Anhui Institute of Translational Medicine/ ; },
}

@article {pmid41794902,
year = {2026},
author = {Zhihuan, W and Furusawa-Nishii, E and Miyake, S},
title = {Unique phenotypic and T cell receptor characteristics of CD8[+] T cells accumulated in the brains of Alzheimer's disease mice.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-38351-8},
pmid = {41794902},
issn = {2045-2322},
support = {JPMJMS2024-6//the Visionary Council on the Moonshot Research and Development Program/ ; },
}

@article {pmid41794876,
year = {2026},
author = {Penning, A and Snoeck, S and Ormaechea, OR and Ayyildiz, D and Polzer, O and Buitrago-Arango, M and Capobianco, R and de Winter, F and Balusu, S and Verhaagen, J and Fitzsimons, CP and d'Ydewalle, C and Lucassen, PJ and Moechars, D and Zhou, L and Salta, E},
title = {microRNA-132 attenuates inflammation in induced pluripotent stem cell-derived microglia from Alzheimer's disease patients.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02228-8},
pmid = {41794876},
issn = {2051-5960},
}

@article {pmid41794870,
year = {2026},
author = {Salari, MT and Gholami, K and Khani, L and Ahmadnia, H and Iranshahy, M and Iranshahi, M and Majd, MT and Behnam-Rassouli, M and Yazarlu, O and Hasanpour, M},
title = {Neuroprotective effects of Urolithin A and B in an intracerebroventricular streptozotocin-induced Alzheimer's-like model in rats.},
journal = {BMC pharmacology & toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40360-026-01118-y},
pmid = {41794870},
issn = {2050-6511},
support = {4020387//Mashhad University of Medical Sciences/ ; },
}

@article {pmid41794848,
year = {2026},
author = {Ben-Jaafar, A and Sinha, A and Nkrumah-Boateng, PA and Roy, S and Sanker, V and Mohamed, S and Sarfo-Adu, F and Ali, SH and Wireko, AA},
title = {Artificial intelligence-based biomarkers for the diagnosis and treatment of neurological conditions: a narrative review.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01287-1},
pmid = {41794848},
issn = {1756-6606},
abstract = {Artificial intelligence (AI) is transforming biomarker discovery in neurology by overcoming key limitations of conventional approaches that are often slow, reductionist, and unable to integrate complex multimodal data. In this narrative review, we searched the data bases; PubMed, Scopus, IEEE Xplore, CINAHL, Embase and the Cochrane Library from inception to 2025 to evaluate how AI supports biomarker identification, diagnosis, prognostication, and treatment stratification across neurovascular, neurodegenerative, neuro-oncological and seizure disorders. Evidence demonstrates that AI-driven imaging and multi-omics biomarkers can detect disease earlier, improve prediction accuracy, and support personalised care. For example, AI models improve stroke outcome prediction beyond conventional scores, identify intracranial aneurysms with sensitivities exceeding 90%, predict conversion from mild cognitive impairment to Alzheimer's disease with accuracies approaching 85-90%, and extract radiogenomic biomarkers in gliomas that outperform traditional diagnostic strategies. However, real-world translation remains constrained by dataset bias, limited external validation, interpretability challenges, and gaps in generalisability, particularly in underrepresented populations. Overall, AI-driven biomarker discovery offers a powerful pathway toward precision neurology, with the greatest impact expected when technical innovation is paired with robust clinical validation, regulatory integration, and equitable data representation.},
}

@article {pmid41794826,
year = {2026},
author = {Melgosa-Ecenarro, L and Radulescu, CI and Doostdar, N and Airey, J and Chaloner, FA and Zabouri, N and Pedretti, G and Osso, F and Garrido Perez, L and Pilch, KS and Wang, X and Mallach, A and Sadeh, S and Jackson, J and Matthews, PM and Barnes, SJ},
title = {Selective weakening of population-coupled synaptic activity in vivo in a mouse model of amyloid-beta pathology.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69866-3},
pmid = {41794826},
issn = {2041-1723},
support = {A2022030S//BrightFocus Foundation (BrightFocus)/ ; },
abstract = {Synaptic dysfunction in Alzheimer's disease (AD) may drive synapse loss and cognitive impairment. Whether AD-related synaptic pathophysiology occurs globally, or in specific synapses, is unclear. We investigate in vivo AD-related synaptic dysfunction during early-stage amyloidosis in App[NL-G-F] mice. We find reduced presynaptic GABAergic proteins at c-Fos-positive excitatory neurons and increased calcium-mediated activity at excitatory and inhibitory neuronal assemblies. In vivo synaptic structure/function imaging finds reduced density and calcium-mediated activity of GABAergic axonal boutons. Rather than occurring globally, reduced synaptic activity is focused at GABAergic boutons strongly coupled to population activity in the amyloid microenvironment. The selective weakening of population-coupled synaptic activity also occurs in excitatory dendritic spines. Spatial transcriptomics finds parvalbumin-positive inhibitory neurons show differential gene expression associated with downregulated GABAergic synaptic transmission at early stages. We propose that early-stage AD-related synaptic pathophysiology is focused at population-coupled synapses, with molecular measures implicating abnormal synaptic processing as an early-stage feature in parvalbumin-positive interneurons.},
}

@article {pmid41794745,
year = {2026},
author = {Yang, J and Ding, H and Amini, S and Hao, B and Karjadi, C and Au, R and Paschalidis, IC},
title = {Resource-stratified machine learning framework for cognitive status classification and mild cognitive impairment to dementia progression prediction.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02006-7},
pmid = {41794745},
issn = {1758-9193},
support = {AG062109/AG/NIA NIH HHS/United States ; CCF-2200052//National Science Foundation, United States/ ; DEB-2433726//Office of Inspector General/ ; UL54 TR00413/GF/NIH HHS/United States ; },
}

@article {pmid41794636,
year = {2026},
author = {Li, J and Wang, C and Zhang, JH and Cai, JM and Cao, YP and Sun, XJ},
title = {Retraction notice to "Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress" [Brain Res. 1328 (2010) 152-161].},
journal = {Brain research},
volume = {},
number = {},
pages = {150251},
doi = {10.1016/j.brainres.2026.150251},
pmid = {41794636},
issn = {1872-6240},
}

@article {pmid41794294,
year = {2026},
author = {Jiang, Z and Saleem, K and Fisher, E and Li, L and Yan, Z and Feng, J},
title = {SGK1 inhibition restores excitability of cortical neurons derived from Alzheimer's disease patients.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107345},
doi = {10.1016/j.nbd.2026.107345},
pmid = {41794294},
issn = {1095-953X},
abstract = {The vast majority of Alzheimer's disease (AD) cases are sporadic, without a clear etiology. We have previously found increased expression of Serum and Glucocorticoid-regulated Kinase 1 (SGK1) in mouse models of dementia, postmortem cortical tissues and induced pluripotent stem cells (iPSCs)-derived cortical neurons from patients with sporadic AD (sAD). SGK1 is induced by a variety of cellular stress. The physiological consequences of elevated SGK1 in sAD is unclear. Here, we differentiated iPSCs from four sAD patients and four age- and sex-matched healthy controls into electrophysiologically mature cortical neurons with prolonged culture for more than 100 days. The sAD cortical neurons exhibited significant reductions in voltage-gated Na[+] currents, amplitudes of evoked action potentials, and frequencies of spontaneous excitatory postsynaptic currents and spontaneous action potentials. Application of a selective inhibitor of SGK1 reversed all these phenotypes in sAD neurons without affecting control neurons. The SGK1-dependent hypoexcitability suggests that a convergent and inborn mechanism attenuates neuronal communications despite different genetic background of the sAD patients. Their iPSC-derived cortical neurons have captured the defective neurotransmission, which underlies cognitive and memory symptoms of AD, many decades before clinical manifestations. The study offers a new pathway to restore synaptic transmission in AD.},
}

@article {pmid41794249,
year = {2026},
author = {Li, QM and Zhang-Yang, QQ and Tan, YY and Wu, XL and Zha, XQ and Shang, ZZ and Luo, JP and Zhang, FY},
title = {Dendrobium huoshanense stem polysaccharide protects against Alzheimer's disease by modulating SCFAs/GLP-1 axis-mediated neuroinflammation suppression.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151235},
doi = {10.1016/j.ijbiomac.2026.151235},
pmid = {41794249},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. The stem of Dendrobium huoshanense is a traditional medicinal food. This study aimed to investigate the effect of cultivated D. huoshanense stem polysaccharide (cDHPS) on AD and elucidate its mechanisms using an Aβ1-42-induced AD mouse model. Results showed that cDHPS significantly improved the cognitive dysfunction and ameliorated the hippocampal neuronal injury of AD mice. Meanwhile, cDHPS effectively alleviated the neuroinflammation of AD mice not only by decreasing the expression of caspase-1, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC), as well as their downstream inflammatory cytokines, but also by inhibiting the activation of microglia and astrocytes. Furthermore, the levels of glucagon-like peptide-1 (GLP-1) in the hippocampus, plasma, and intestine of AD mice were markedly elevated by cDHPS, along with an increase in intestinal short-chain fatty acids (SCFAs) levels. However, the treatment of exendin 9-39, a GLP-1 receptor antagonist, weakened the protective effect of cDHPS against AD, and the depletion of SCFAs reversed the beneficial effects of cDHPS on cognitive dysfunction, hippocampal neuronal injury, neuroinflammation, and GLP-1 secretion in AD mice. These results suggest that cDHPS could protect against AD by modulating the SCFAs/GLP-1 axis-mediated neuroinflammation suppression.},
}

@article {pmid41794188,
year = {2026},
author = {Marzetti, E and Di Lorenzo, R and Calvani, R and Coelho-Júnior, HJ and D'Argento, E and Pesce, V and Landi, F and Bucci, C and Guerra, F and Picca, A},
title = {Mitochondrial quality in aging and neurodegeneration: The emerging role of mitochondria-derived vesicles.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {112167},
doi = {10.1016/j.mad.2026.112167},
pmid = {41794188},
issn = {1872-6216},
abstract = {Mitochondria are central to cellular energy metabolism, redox balance, and signaling, and their integrity is maintained by a multilayered mitochondrial quality control (MQC) system. This system includes proteostasis, dynamics, biogenesis, and mitophagy, which together repair or remove damaged organelles. Mitochondria-derived vesicles (MDVs) have emerged as an additional MQC component. MDVs are small vesicles that bud from mitochondria and selectively transport damaged mitochondrial proteins, lipids, and nucleic acids to endolysosomal compartments or other intracellular destinations, enabling rapid and localized responses to mitochondrial stress. Acting upstream of or in parallel with mitophagy, MDVs can delay irreversible mitochondrial damage and help preserve cellular homeostasis. Aging and age-associated disorders are characterized by progressive mitochondrial dysfunction and chronic inflammation. Age-related changes in intracellular trafficking, lysosomal function, and vesicle dynamics may impair MDV formation, cargo selection, and targeting. Under conditions of defective degradation, mitochondrial components may also appear in extracellular vesicles, potentially contributing to altered intercellular signaling and inflammation. In the nervous system, where energetic demands are high and mitochondrial turnover requires tight regulation, such alterations may be especially harmful. This review summarizes MQC mechanisms in neurons, with a focus on MDVs, their dysregulation during aging and neurodegeneration, and implications for biomarkers and therapeutic strategies.},
}

@article {pmid41793956,
year = {2026},
author = {Wu, AH and Wu, J and Tseng, C and Darst, BF and Park, SY and Stram, DO and Larson, T and Fruin, S and Setiawan, VW and Yu, X and Wilkens, LR and Hu, H and Haiman, C and Ritz, B and Crimmins, EM and Lim, U and Cheng, I and Marchand, LL},
title = {Racial and ethnic differences in the impact of air pollution on the risk of Alzheimer's disease and related dementias in the Multiethnic Cohort Study.},
journal = {Environment international},
volume = {209},
number = {},
pages = {110169},
doi = {10.1016/j.envint.2026.110169},
pmid = {41793956},
issn = {1873-6750},
abstract = {BACKGROUND AND OBJECTIVES: Meta-analysis results, based largely among Whites, suggested that fine particulate matter (PM2.5) exposure increases the risk of clinical dementia. This study investigated the association of air pollution and incidence of Alzheimer's disease and related dementias (ADRD) by race and ethnicity.

METHODS: We investigated incidence of AD (n = 4,010) and other dementia (n = 4,971) among 44,954 California Multiethnic Cohort (MEC) participants (28% African American, 14% Japanese American, 44% Latino, 14% White adults) who were enrolled in the fee-for-service component of Medicare (2001-2016). We used Cox proportional hazards regression to examine associations between exposure to PM, airport-related ultrafine particles (aUFP) and gaseous pollutants and incidence of AD, other dementia, and ADRD in a minimally- and fully-adjusted model, considering 12 established ADRD risk factors. We conducted stratified analyses to examine associations by sex, and race/ethnicity.

RESULTS: ADRD incidence was associated with PM2.5 (per 2 µg/m[3]), airport-related UFP (aUFP, per 4400 particles/cm[3]) and nitrogen dioxide (NO2, per 10 µg/m[3]) with hazard ratios (HRs, 95%CI), respectively, of 1.04 (1.02-1.06), 1.03 (1.01-1.05) and 1.09 (1.06-1.12). The AD-associations with PM2.5 and NO2, were stronger than the corresponding associations with other dementia (Pheterogeneity ≤ 0.003). Similar patterns of results were observed by sex and across race and ethnicity. Statistically significant findings for ADRD with PM2.5, aUFP and NO2 were observed among African American (respective HRs 1.03, 1.04, 1.09), and Latino and White participants for NO2 (HR 1.10, 1.08). Results in all and African American participants remained statistically significant in fully-adjusted models. Although the effect of PM2.5 was diluted in a co-pollutant with NO2, both PM2.5 and aUFP were significantly associated with ADRD incidence in a co-pollutant model, and NO2 and aUFP (but not PM2.5) remained associated in a multipollutant model. We did not observe consistent modifying effects for any of the 12 established ADRD risk factors.

CONCLUSIONS: In this multiethnic population, incidence of ADRD increased with exposures to PM2.5, aUFP, and NO2 in all subjects and this pattern was most prominent among African American adults. These results emphasize that ADRD prevention should include not only individual-level factors but also population-wide policies and regulation to curb air pollution.},
}

@article {pmid41793523,
year = {2026},
author = {Xiong, R and Liu, P and Wang, L and Zhang, S and Liu, H and Rong, C and Kehriman, N and Wang, J and Wang, J and Lai, X and Tang, Y},
title = {Elucidating the pharmacological mechanism of Yangming-Kaixin-Yizhi formula in inhibiting neuronal ferroptosis via Nrf2 in Alzheimer's disease: a study combining network pharmacology, transcriptomics, and experimental validation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41793523},
issn = {1573-7365},
support = {82405150//National Natural Science Foundation of China/ ; CSTB2025NSCQ-GPX0082//Natural Science Foundation of Chongqing, China/ ; 2024ZYQN017//Joint Project of Chongqing Health Commission and Science and Technology Bureau/ ; GXHC-MBTCM-01//Open Project of Guangxi Health Commission Guangxi Key Laboratory of Molecular Biology of Preventive Medicine of Traditional Chinese Medicine/ ; ZYJCLLYB-18//Open Fund of High-level Key Discipline of Basic Theory of TCM of the State Administration of Traditional Chinese Medicine, Anhui University of Chinese Medicine/ ; 2025ZNSFSC0740//Sichuan Provincial Science and Technology Support Program/ ; },
mesh = {Animals ; *Ferroptosis/drug effects ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Mice ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *NF-E2-Related Factor 2/metabolism/genetics ; *Neurons/drug effects/metabolism ; Network Pharmacology/methods ; Mice, Transgenic ; Transcriptome/drug effects ; Male ; Hippocampus/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Ferroptosis is considered to be an important pathological driver of Alzheimer's disease (AD), and inhibiting neuronal ferroptosis shows a significant AD improvement effect. Yangming-Kaixin-Yizhi formula (YKY), a traditional Chinese medicine (TCM) formula, has been used for the treatment of forgetfulness for hundreds of years, but its mechanisms remain unclear. This study aimed to delineate the herb-component-target network of YKY in regulating ferroptosis for the treatment of AD, providing modern scientific basis for the traditional use of YKY. After 3×Tg-AD mice were orally treated with YKY for 11 weeks, the learning and memory ability of the mice was evaluated by Morris water maze, and hippocampal neuron loss was observed by hematoxylin-eosin (HE) staining. Transcriptomics and network pharmacology were used to analyze the underlying pharmacological mechanisms. Perls staining and immunofluorescence were used to observe brain iron deposition and hippocampal neuronal ferroptosis, respectively. The effects of YKY on iron deposition, reactive oxygen species (ROS) and lipid peroxidation in HT22 cells were detected by FerroOrange, DCFH-DA and BODIPY [581/591] C11 fluorescent probes, respectively. Western blot was used to detect the expression of Nrf2 and ferroptosis-related proteins to verify the pharmacological mechanism of YKY. YKY significantly improved the learning and memory ability and neuronal loss in 3×Tg-AD mice, and transcriptome and network pharmacology analysis suggested that its pharmacological mechanism may be related to regulation of iron metabolism, ferroptosis and Nrf2 regulated gene transcription. YKY significantly reduced intracellular iron deposition, improved cell viability, reduced ROS and lipid peroxidation levels, promoted the protein expression of Nrf2 and its downstream SLC7A11, GPX4 and FTH1, and inhibited the expression of TFR1 and NCOA4 proteins in 3×Tg-AD mice and RSL3-mediated HT22 cells. YKY may improve AD by targeting Nrf2 to inhibit neuronal ferroptosis, which provides modern scientific evidence for the use of YKY in TCM to treat disorders associated with memory loss.},
}

Animals
*Ferroptosis/drug effects
*Alzheimer Disease/drug therapy/metabolism/genetics
Mice
*Drugs, Chinese Herbal/pharmacology/therapeutic use
*NF-E2-Related Factor 2/metabolism/genetics
*Neurons/drug effects/metabolism
Network Pharmacology/methods
Mice, Transgenic
Transcriptome/drug effects
Male
Hippocampus/drug effects/metabolism
Reactive Oxygen Species/metabolism

@article {pmid41793494,
year = {2026},
author = {Ouyang, Z and Liu, F and Lu, Q and Wang, Y and Shao, N and Liu, H and Cai, B},
title = {Aloe-emodin inhibits p38 MAPK pathway in Alzheimer's disease treatment: a network pharmacology and experimental verification.},
journal = {Journal of molecular histology},
volume = {57},
number = {2},
pages = {},
pmid = {41793494},
issn = {1567-2387},
support = {No.2024AH050951//Scientific Research Foundation of the Education Department of Anhui Province/ ; No.2023xscx096//Postgraduate Quality Engineering Project in Anhui Province/ ; NO. 82374553//National Natural Science Foundation of China/ ; No. 2308085MH295//Natural Science Foundation of Anhui province/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Anthraquinones/pharmacology/chemistry/therapeutic use ; Humans ; Amyloid beta-Peptides/metabolism ; *Network Pharmacology/methods ; Molecular Docking Simulation ; *p38 Mitogen-Activated Protein Kinases/metabolism/antagonists & inhibitors ; Phosphorylation/drug effects ; *MAP Kinase Signaling System/drug effects ; tau Proteins/metabolism ; Peptide Fragments/toxicity ; Cell Survival/drug effects ; Neuroprotective Agents/pharmacology ; Animals ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal amyloid-β protein (Aβ) deposition and tau protein hyperphosphorylation (p-tau), yet effective therapeutics remain scarce. Aloe emodin (AE) is a natural anthraquinone derivative that demonstrates neuroprotective effects. However, its specific therapeutic efficacy and functional mechanism are not fully elucidated. To address this, we investigated AE's mechanism in AD treatment using a network pharmacology approach. This analysis revealed that 83 common targets shared by AE and AD, enriched in processes such as apoptosis and protein phosphorylation. Mitogen-activated protein kinase 14 (MAPK14, also known as p38) was identified as a key target. KEGG pathway analysis further confirmed that the key mechanism of AE in AD treatment was mediated by the MAPK signaling pathway. Subsequent molecular docking and dynamics simulations demonstrated that the AE-p38 complex exhibited strong binding affinity and high stability. Building on these predictions, in vitro studies confirmed that AE enhanced cell viability and modulated the MAPK pathway. Critically, p38-specific inhibition experiments demonstrated that AE alleviated Aβ accumulation and tau hyperphosphorylation through inhibiting p38. In conclusion, this study demonstrates that AE protects against Aβ25-35-induced neurotoxicity in HT22 cells, primarily by inhibiting the p38 MAPK signaling pathway.},
}

*Alzheimer Disease/drug therapy/metabolism
*Anthraquinones/pharmacology/chemistry/therapeutic use
Humans
Amyloid beta-Peptides/metabolism
*Network Pharmacology/methods
Molecular Docking Simulation
*p38 Mitogen-Activated Protein Kinases/metabolism/antagonists & inhibitors
Phosphorylation/drug effects
*MAP Kinase Signaling System/drug effects
tau Proteins/metabolism
Peptide Fragments/toxicity
Cell Survival/drug effects
Neuroprotective Agents/pharmacology
Animals

@article {pmid41793299,
year = {2026},
author = {Kao, HS and Aguilera, J and Hung, CC and Kiani, S and Nava, A and Montalvo-Liendo, N},
title = {Lessons Learned in a Feasibility Study With U.S. Women Caregivers of Mexican Origin.},
journal = {Health promotion practice},
volume = {},
number = {},
pages = {15248399261426007},
doi = {10.1177/15248399261426007},
pmid = {41793299},
issn = {1552-6372},
abstract = {With the rapidly aging Hispanic/Latino population in the United States and the traditional caregiving roles of women in this culture, it is critical to study caregiving stress in the largest yet understudied subgroup-women caregivers of Mexican origin. This descriptive feasibility study aimed to adapt a research protocol to examine the impact of long-term caregiving stress on coronary heart disease risk among women caregivers of Mexican origin, using the allostatic load model and the Framingham Risk Score. A purposive sample of 20 women providing family care to a dependent older relative for at least 24 hours per week over the past 6 months was recruited through community networks, home health care agencies, promotoras, the local chapter of the Alzheimer's Association, and hospital outpatient services in a U.S.-Mexico border city. Multiple approaches were employed, including structured interviews and the collection of biological samples. Key adjustments included refining terminology to align with participants' preferences, managing complex data collection, and adjusting recruitment criteria to reflect cultural norms. COVID-19-related delays necessitated further adaptations, including proactive licensing management and alternative recruitment strategies. Inclusion and exclusion criteria were revised multiple times to better reflect family caregiving dynamics, ensuring continuity despite staff turnover and rising costs due to the study's extended duration and inflation. By addressing these challenges, we laid the groundwork for research on long-term caregiving among women of Mexican origin. Future research will focus on developing preventive interventions to reduce caregiving stress and coronary heart disease risk, ultimately supporting aging-in-place for dependent older adults in their care.},
}

@article {pmid41793281,
year = {2026},
author = {Nafikov, RA and Sohi, HK and Nato, AQ and Horimoto, AR and Day, TRC and Bird, TD and DeStefano, AL and Blue, EE and Wijsman, EM},
title = {Variant Prioritization by Pedigree-Based Haplotyping.},
journal = {Genetic epidemiology},
volume = {50},
number = {3},
pages = {e70039},
doi = {10.1002/gepi.70039},
pmid = {41793281},
issn = {1098-2272},
support = {U01 AG058589/AG/NIA NIH HHS/United States ; U01 AG049507/AG/NIA NIH HHS/United States ; T32 AG052354/AG/NIA NIH HHS/United States ; T32 GM007454/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *Haplotypes ; *Pedigree ; Genetic Predisposition to Disease ; Alzheimer Disease/genetics ; Gene Frequency ; Polymorphism, Single Nucleotide ; Whole Genome Sequencing ; Male ; Computer Simulation ; Genetic Variation ; Models, Genetic ; Alleles ; Female ; },
abstract = {Whole genome sequence (WGS) data provides opportunities for comprehensive evaluation of variants that may influence complex traits. However, prioritizing the large number of variants, particularly those in non-coding regions, is a challenge. Here we present an approach that uses pedigree-based haplotyping to identify the risk haplotype and resulting set of prioritized variants in a region of interest (ROI) defined by identity-by-descent (IBD) sharing among familial cases. The approach is applicable for use in both a full range of pedigree sizes and for the full allele frequency spectrum of variants without the need for a large reference sample. By determining haplotype sharing among individuals with WGS data, we demonstrate the ability to accurately identify a risk haplotype and a strongly reduced list of potential risk alleles for a trait of interest along with the cases who carry the risk haplotype. This is important in the context of complex traits where the disease may be etiologically heterogeneous even within a single pedigree. Application to both simulated and real Alzheimer's disease family data shows that the approach leads to accurate risk-haplotype identification with marked reduction in the number of potential trait-associated variants. Simulation also shows that the approach provides accurate risk haplotypes in ROIs.},
}

Humans
*Haplotypes
*Pedigree
Genetic Predisposition to Disease
Alzheimer Disease/genetics
Gene Frequency
Polymorphism, Single Nucleotide
Whole Genome Sequencing
Male
Computer Simulation
Genetic Variation
Models, Genetic
Alleles
Female

@article {pmid41793191,
year = {2026},
author = {Barry-Simonnet, C and Crouzier, L and Moujellil-Legagneur, T and Chaieb-Errass, H and Idres, YA and Ferrare, K and Rolland, M and Cazals, G and Poucheret, P and Maurice, T and Tousch, D},
title = {Xanthatin-13-(Pyrrolidine-2-Carboxylic Acid), a Sesquiterpene Lactone Isolated From Burdock Leaf, Attenuated Aβ25-35 Toxicity and Memory Deficits in a Pharmacological Mouse Model of Alzheimer's Disease.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70294},
pmid = {41793191},
issn = {1099-1573},
support = {Soutien à la Recherche 2023 Accélérateur d'Innovation//Université de Montpellier/ ; },
abstract = {Alzheimer's disease (AD) is a severe form of dementia, which occurrence increases with age and lifestyle conditions. It is characterized by amyloid protein accumulation forming senile plaques, hyperphosphorylated tau protein forming neurofibrillary tangles, neuroinflammation, and oxidative stress, leading to synapse loss and cell death. Pharmacological alternatives to conventional treatments include alkaloids with anti-inflammatory and antioxidant properties. Sesquiterpene lactones, such as Xanthatin-13-(pyrrolidine-2-carboxylic acid) (XPc) from burdock leaf, show promise due to their antioxidant activity targeting glucose-6-phosphate dehydrogenase. This study evaluated XPc's protective effects in vivo using Aβ25-35-treated mice, a pharmacological AD model, and explores its synergistic potential with neuroprotective agents like TSPO activators or sigma-1 receptor agonists. Mice were administered Aβ25-35 peptide (9 nmol ICV) and XPc (0.3-3 mg/kg) daily for 4 days. Behavioral tests assessed memory deficits and anxiety. Post-sacrifice, brains were analyzed for neuroinflammation and oxidative stress markers. Combination studies involved XPc with the TSPO activator PK11195 or the sigma-1 receptor agonist PRE-084, with memory evaluated in two behavioral tests. Combination indices were calculated to assess synergy. XPc (1-3 mg/kg) prevented Aβ25-35-induced memory impairments and anxiety. It reduced astroglial reaction, blocked microglial activation, and confirmed antioxidant activity by lowering lipid peroxidation and protein nitrosylation. Combinations with PK11195 or PRE-084 showed synergistic protection in memory tests. XPc is a potent neuroprotective agent against AD-like toxicity in this murine model, effective alone or in synergistic combinations with other drugs.},
}

@article {pmid41793080,
year = {2026},
author = {Inagawa, S and Inagawa, Y and Tsugawa, A and Takenoshita, N and Saito, K and Ishii, K and Kasuga, K and Ikeuchi, T and Shimizu, S},
title = {Eligibility for Anti-Amyloid-β Monoclonal Antibodies in Patients With Primary Progressive Aphasia due to Alzheimer's Disease in Japan.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {2},
pages = {e70152},
doi = {10.1111/psyg.70152},
pmid = {41793080},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; Male ; Female ; *Aphasia, Primary Progressive/drug therapy/etiology/diagnosis ; Aged ; Japan ; *Amyloid beta-Peptides/immunology ; Tomography, Emission-Computed, Single-Photon ; *Antibodies, Monoclonal/therapeutic use ; Biomarkers/cerebrospinal fluid ; Neuropsychological Tests ; Positron-Emission Tomography ; Middle Aged ; Magnetic Resonance Imaging ; Aged, 80 and over ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: Primary progressive aphasia (PPA) is a clinical syndrome characterized by progressive language impairment. The logopenic variant (lvPPA) is frequently associated with Alzheimer's disease (AD) pathology. With the approval of anti-amyloid-β monoclonal antibodies, such as lecanemab and donanemab, for the treatment of AD, accurately differentiating lvPPA due to AD (lvAD) from the other PPA variants has become highly important.

METHODS: Thirteen patients with PPA who underwent cognitive testing, including the Standard Language Test of Aphasia (SLTA), brain magnetic resonance imaging, single-photon emission computed tomography (SPECT), cerebrospinal fluid (CSF) biomarker analysis, and amyloid positron emission tomography (PET) imaging were enrolled in this study. Patients were classified into the lvPPA, semantic variant PPA (svPPA), and nonfluent/agrammatic variant PPA (nfaPPA) groups based on the results of clinical and neuropsychological assessments. We determined the proportion of PPA patients in each group who met the optimal use guidelines for anti-amyloid monoclonal antibody therapy.

RESULTS: Six (86%) of the 7 lvPPA patients were amyloid positive (A+), and 5 (71%) were eligible for lecanemab or donanemab. In most lvPPA patients, SPECT displayed an AD-typical pattern of hypoperfusion in the bilateral temporoparietal regions, posterior cingulate gyrus, and precuneus. One lvPPA patient was negative for AD biomarkers and demonstrated an atypical perfusion pattern for AD, and was subsequently rediagnosed as having frontotemporal lobar degeneration.

CONCLUSIONS: These results suggest that SPECT may play a supportive role in differentiating lvAD from PPA. In the current clinical era of anti-amyloid-β monoclonal antibody therapy, accurate identification of lvAD among patients with language-predominant symptoms is increasingly important. Larger studies should be performed in the near future to validate these findings.},
}

Humans
*Alzheimer Disease/complications/drug therapy
Male
Female
*Aphasia, Primary Progressive/drug therapy/etiology/diagnosis
Aged
Japan
*Amyloid beta-Peptides/immunology
Tomography, Emission-Computed, Single-Photon
*Antibodies, Monoclonal/therapeutic use
Biomarkers/cerebrospinal fluid
Neuropsychological Tests
Positron-Emission Tomography
Middle Aged
Magnetic Resonance Imaging
Aged, 80 and over
Brain/diagnostic imaging

@article {pmid41792880,
year = {2026},
author = {Zahran, A and Abu-Khazneh, O and Bdair, M and Hajjeh, O and AbuBaha, M and Shehadeh, W and Awashra, A and Alazizi, I and Fuqha, R and Saife, S and Fuqha, H and Milhem, F and Hamshary, H and Abuzahra, D and Shuaib, U},
title = {Glymphatic System Dysfunction in Central Nervous System Diseases.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {3},
pages = {e70810},
doi = {10.1002/cns.70810},
pmid = {41792880},
issn = {1755-5949},
abstract = {BACKGROUND: The glymphatic system is a perivascular cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange pathway that supports brain homeostasis by clearing metabolic waste and neurotoxic proteins. Across central nervous system diseases, converging evidence indicates that glymphatic dysfunction represents a shared pathophysiological axis linking vascular, astroglial, inflammatory, and sleep-related disturbances to impaired solute clearance.

RESULTS AND CONCLUSION: In this review, we synthesize mechanistic and clinical evidence for glymphatic impairment in acute brain injury (ischemic and hemorrhagic stroke, traumatic brain injury) and chronic neurological disorders (Alzheimer's disease, Parkinson's disease, cerebral small vessel disease, multiple sclerosis, idiopathic normal pressure hydrocephalus, idiopathic intracranial hypertension, epilepsy, and headache disorders). Major mechanisms include (i) aquaporin-4 (AQP4) depolarization/mislocalization at astrocytic endfeet, reducing perivascular water transport; (ii) perivascular space compression or obstruction from cytotoxic/vasogenic edema, blood-derived products, protein aggregates, or altered extracellular matrix; (iii) loss of arterial pulsatility and vascular stiffening, weakening the driving forces for convective exchange; (iv) blood-brain barrier disruption and neuroinflammation, which remodel perivascular architecture and amplify clearance failure; and (v) sleep and autonomic dysregulation, including altered noradrenergic tone, which suppresses glymphatic activity during periods when clearance is normally maximal. Clinically, glymphatic dysfunction can be probed using diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS), contrast-enhanced MRI approaches, and structural surrogates such as enlarged perivascular spaces, with emerging associations to cognition, mood, and disease severity. Finally, we discuss translational strategies aimed at restoring clearance, including sleep/circadian optimization, vascular risk control, anti-inflammatory approaches, AQP4- and TRPV4-oriented targets, and neuromodulation. Mechanism-guided, standardized imaging and longitudinal interventional studies are needed to establish glymphatic biomarkers as actionable therapeutic and prognostic tools.},
}

@article {pmid41792827,
year = {2026},
author = {Mastrangelo, A and Caldera, S and Baiardi, S and Magliocchetti, F and Mammana, A and Testa, M and Ranieri, A and Ruggeri, E and Bentivenga, GM and Mastrangelo, V and Mometto, N and Ferri, C and Marti, A and Santangelo, M and Longoni, M and Mazzoli, S and Chiari, A and Biscetti, L and Capellari, S and Parchi, P},
title = {Prevalence and clinical effects of Lewy Body pathology in non-prion rapidly progressive dementias: a retrospective cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02004-9},
pmid = {41792827},
issn = {1758-9193},
support = {MNESYS (PE0000006)//Ministero dell'Università e della Ricerca/ ; RF-2021-12374386//Ministero della Salute/ ; },
}

@article {pmid41792667,
year = {2026},
author = {Kiene, F and Notbohm, A and Roheger, M and Duning, T and Hildebrandt, H},
title = {Cognitive tests distinguish biomarker-verified early Alzheimer's disease from other patients.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04742-7},
pmid = {41792667},
issn = {1471-2377},
}

@article {pmid41792456,
year = {2026},
author = {Abdulkhaliq, AA and Alasiri, G and Kim, B and Khan, J and Ajoolabady, A and Yousof, SM and Ren, J and Tuomilehto, J and Borai, A and Alrfaei, BM and Pratico, D},
title = {TREM2 in neurodegeneration and diseases.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41792456},
issn = {1476-5578},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface transmembrane receptor from the TREM receptor family, predominantly expressed on the microglia in the central nervous system (CNS). TREM2-initiated signaling plays a crucial role in regulating neuroinflammation and neurodegeneration, particularly in the context of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), through the activation of downstream signaling pathways and transcriptional regulation of relevant genes. In this review, we aim to provide a concise review of the role and mechanistic implications of TREM2 in neurodegeneration and neuroinflammation, with a specific focus on AD and PD. We will discuss the most recent preclinical studies to highlight current advancements in the field. This review is intended to support both basic researchers and clinicians by enhancing their understanding of microglial function in the pathophysiology of AD and PD, as well as its role in neuroinflammation and neurodegeneration. Ultimately, we hope this contribution will pave the way for new discoveries and the development of potential therapeutic interventions.},
}

@article {pmid41792386,
year = {2026},
author = {Kaczmarek, B and Ilkowska-Adamczewska, Z and Remlinger-Molenda, A and Kaluzniak-Szymanowska, A and Stachnik, K and Wieczorowska-Tobis, K and Tobis, S},
title = {The use of screening tests in panel studies to monitor cognitive functioning in senior participation programme groups using ACE-III and M-ACE.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-42595-9},
pmid = {41792386},
issn = {2045-2322},
}

@article {pmid41792369,
year = {2026},
author = {Huang, S and Zhang, T and Wang, Y and Du, H and He, J and Zeng, H and Ma, L and Deng, D and Zhou, Y and Liu, S and Zhao, W and Yang, X and Han, L and Zhao, S and Shu, S and Yao, S and Zhong, Q and Chen, X and Wang, J},
title = {Interaction between transient receptor potential vanilloid 4 and glutamate NMDA receptor subunit 1 mediates endoplasmic reticulum stress and neuroinflammation in postoperative delirium.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {41792369},
issn = {2662-8651},
support = {82471504//National Natural Science Foundation of China/ ; 32271148//National Natural Science Foundation of China/ ; 82471251//National Natural Science Foundation of China/ ; 82201350//National Natural Science Foundation of China/ ; 82401847//National Natural Science Foundation of China/ ; 23SWAQ24//Biosecurity Research Project/ ; 2024MZFS002//Research Grant of Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education/ ; },
abstract = {Postoperative delirium (POD) is a serious and prevalent neurocognitive complication that poses a major clinical challenge because its mechanism is unclear. This study identifies a pathogenic pathway centred on the direct interaction between transient receptor potential vanilloid 4 (TRPV4) and the essential N-methyl-D-aspartate receptor (NMDAR) subunit GluN1. Using a murine POD model, the neuron-centric glutamatergic dysfunction in the hippocampus was initially confirmed through ex vivo metabolic kinetic analysis. Transcriptomic analysis revealed upregulation of Trpv4, predominantly in neurons. Co-immunoprecipitation coupled with mass spectrometry revealed that TRPV4 directly interacts with GluN1. This enhanced TRPV4-GluN1 coupling promoted GluN1 phosphorylation at serine 896 and hyperactivated NMDAR signalling. We subsequently observed the concurrent induction of endoplasmic reticulum (ER) stress, as evidenced by a dilated ER ultrastructure and the upregulation of the expression of UPR markers (ATF6, p-PERK, p-IRE1α, and CHOP), as well as neuroinflammation, characterized by microglial activation and elevated expression of proinflammatory mediators (IL-6, IL-1β, and ICAM-1). These molecular pathologies were associated with decreased neuronal activity and the characteristic cognitive-affective deficits associated with POD. Critically, both pharmacological inhibition of TRPV4 (HC067047) and hippocampal CA3-specific Trpv4 knockdown reversed these pathologies and rescued the behaviour. Inhibiting NMDAR with MK801 recapitulated these therapeutic benefits. Furthermore, TRPV4 was significantly upregulated in early-onset Alzheimer's disease patients. Our study defines a novel TRPV4-GluN1 axis that drives POD pathogenesis, suggesting that it is a promising therapeutic target.},
}

@article {pmid41792330,
year = {2026},
author = {Song, Z and Hu, H and Zhang, W and Zheng, X and Liang, L and Zhao, B and Song, G and Li, J and Li, S and Wen, Y and Zhang, B and Wang, W and Deng, G and Zhang, C and Jiang, H and Hu, S and Tu, H and Wu, M and Li, H},
title = {The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41792330},
issn = {2662-8465},
support = {32341003//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.},
}

@article {pmid41792234,
year = {2026},
author = {Yu, H and Wang, F and Yuan, JQ and Chen, J and Zhang, KY and Jia, D and Gong, J and Mao, Y and Bi, S and Zhang, YQ and Lan, ZC and Yu, HY and Chai, GS},
title = {HMGCS2-dependent β-OHB/H3K9bhb ameliorates synaptic plasticity and cognition in Alzheimer's disease.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41792234},
issn = {2092-6413},
support = {82401671//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82505712//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81601121//National Natural Science Foundation of China (National Science Foundation of China)/ ; BK20211238//Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation)/ ; },
abstract = {Ketogenic diet (KD) can significantly ameliorate cognition in Alzheimer's disease (AD), but the specific mechanism is not clear. Histone3-lysine9-β-hydroxybutyrylation (H3k9bhb), a novel histone modification mark induced by ketogenesis-generated β-hydroxybutyrate (β-OHB), may be involved in the prevention and treatment of AD. Here we report that β-OHB and H3K9bhb were reduced in the hippocampus of triple transgenic AD male mice (3xTg-AD) mice. Reduced H3K9bhb levels were also observed in patients with AD. The 3xTg-AD mice exhibited a low enrichment of H3K9bhb on the promoters of NMDA receptor subunits and Syn1 and axon-related genes together with impaired synaptic plasticity, all of which were rescued by 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2, a rate-limiting enzyme of β-OHB synthesis) upregulation. Moreover, β-OHB replenishment enhanced H3K9bhb in 3xTg-AD mice, leading to an increase of NMDA receptor subunits and Syn1 and cognitive function in an HMGCS2-dependent manner. Thus, HMGCS2 is a key molecular switch of cognitive impairment, and targeting HMGCS2 or β-OHB replenishment appropriately may serve as a novel therapeutic strategy for AD treatment.},
}

@article {pmid41792133,
year = {2026},
author = {Xu, Q and Li, G and Zhang, H and Jiang, Z and Gao, X and Li, Z and Langhi Prata, LGP and Kirkland, JL and Zhang, G and Sun, Y},
title = {The natural flavonoid dihydromyricetin targets senescent cells via PRDX2 and alleviates age-related diseases.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-70302-9},
pmid = {41792133},
issn = {2041-1723},
support = {82130045, 82350710221 and 82571777//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Aging is a primary risk factor for chronic diseases, with cellular senescence as an effective target to delay, prevent or alleviate age-related disorders. Here we report in vitro screening outputs from a natural medicinal agent library, wherein dihydromyricetin, a natural flavonoid, showed senotherapeutic potential. Dihydromyricetin protects senescent fibroblasts against further DNA damage and attenuates the senescence-associated secretory phenotype, acting as a senomorphic agent. Proteomics suggests that dihydromyricetin promotes nuclear translocation of peroxiredoxin 2 (PRDX2) to facilitate DNA repair in senescent cells. In prematurely aged mice, dihydromyricetin administration mitigates tissue aging and age-related physiological decline. In anticancer regimens, dihydromyricetin improves outcomes of chemotherapy. However, dihydromyricetin demonstrates senolytic activity against senescent microglial cells, whose basal PRDX2 expression remains low, by impairing mitochondrial function to promote apoptosis. In mice developing Alzheimer's disease, dihydromyricetin eliminates senescent microglial cells from amyloid β-protein plaques and alleviates neurodegenerative symptoms. Together, our study proposes dihydromyricetin as a natural senotherapeutic agent for mitigating age-related morbidities, including but not limited to cancers and Alzheimer's disease.},
}

@article {pmid41792131,
year = {2026},
author = {Cao, Y and Willis, BA and Horie, K and Wildsmith, KR and Koyama, A and Sachdev, P and Penner, N and Charil, A and Irizarry, M and Reyderman, L},
title = {Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model describing Alzheimer's disease pathophysiology and treatment effects.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00677-4},
pmid = {41792131},
issn = {2056-7189},
abstract = {Lecanemab, an anti-amyloid antibody, has demonstrated a significant clinical benefit in slowing cognitive decline in early Alzheimer's disease (AD). A mechanistic Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model was developed to capture the temporal and biological complexity of AD progression. This QSP model incorporates three interlinked modules reflecting core aspects of AD pathology: Aβ accumulation, tau pathology, and cognitive decline, where Aβ accumulation promotes tau pathology, which leads to neuronal damage and cognitive impairment. A large multivariate dataset was assembled from 4056 subjects participating in lecanemab studies and the Alzheimer's Disease Neuroimaging Initiative (ADNI) to inform and validate the model. Virtual populations-based model simulations successfully reproduced the hallmark cascade of AD pathology, consistent with the well-known Jack curve, from amyloid buildup to tau spread and cognitive decline over decades. Simulations accurately predicted all endpoints evaluated from the lecanemab trials and were further validated against data from other anti-Aβ therapies. Importantly, the model revealed that Aβ protofibrils are more potent drivers of tau pathology than plaques. In summary, the Neuro-Dynamic QSP model is the first of its kind to mechanistically link amyloid accumulation, tau pathology, and cognitive decline in AD, providing a powerful framework for simulating clinical scenarios and understanding disease mechanisms.},
}

@article {pmid41791567,
year = {2026},
author = {Guo, P and Zhao, J and Wang, C and Bai, Y and Zhang, B and Liu, A},
title = {Effect of DL0410 and tetrahydrocurcumin (LG0367) alone and in combination on learning and memory in vascular dementia.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178730},
doi = {10.1016/j.ejphar.2026.178730},
pmid = {41791567},
issn = {1879-0712},
abstract = {Vascular dementia (VaD) is one of the most common neurodegenerative diseases, and there is no effective therapy to prevent or cure VaD to date. 1,1'-(1,1'-Biphenyl-4,4'-diyl)bis(3-piperidino-1-propanone) dihydrochloride (DL0410) is a novel multi-target small-molecule drug against Alzheimer's disease (AD), with particularly outstanding acetylcholinesterase (AChE) inhibitory activity and Histamine H3 receptor (H3R) inhibitory activity. Natural derivative 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (LG0367) is a metabolite of curcumin. Previous studies have demonstrated that LG0367 exhibited better pharmacokinetic properties and therefore displayed better pharmacological activity than curcumin. Here, using bilateral common carotid artery occlusion (2VO) rat model, we found that the combined treatment of DL0410 and LG0367 had a much better effect on improving cognitive function in rats than single-drug treatment or donepezil, suggesting a synergistic effect between the small-molecule drug DL0410 and the natural derivertive LG0367. In addition, we found that the combined DL0410 and LG0367 treatment had significant synergic effects on inhibiting AChE production in cortex of 2VO rats. Furthermore, compound-target network and enrichment analyses revealed that DL0410 and LG0367 exhibit synergistic potential against VaD based on multiple mechanisms. In addition, the study also showed that the combination treatment had remarkable synergic effects on decreasing inflammatory responses and oxidative stress, protecting mitochondrial structure, reducing the release of astrocytes, and decreasing neuronal damage and activating the expression of SHH protein in the cortex and hippocampus of 2VO rats. Our findings not only demonstrated a potent synergistic effect between the synthetic small-molecule DL0410 and the natural derivative LG0367, but also illuminate a promising "symptom-to-root" therapeutic strategy for VaD, providing a systematic and evidence-based model for modernizing phytotherapy. Ultimately, this study will provide important information for future clinical trials aimed at translating this synergistic combination into a tangible "multi-target, multi-mechanism" treatment option for VaD patients.},
}

@article {pmid41791565,
year = {2026},
author = {Cui, J and Huang, R and Dong, X},
title = {Efficacy and mechanisms of Icariin in the treatment of Alzheimer's disease: a systematic review and Meta-analysis of a preclinical study.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178706},
doi = {10.1016/j.ejphar.2026.178706},
pmid = {41791565},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition that predominantly affects elderly individuals, characterised by progressive cognitive dysfunction, memory impairment and behavioural changes. Icariin (ICA), the primary active ingredient of the traditional Chinese medicine Epimedium spp., has demonstrated significant potential in the treatment of neurological disorders. Nevertheless, the precise mechanisms through which it exerts its anti-AD effects remain to be elucidated. And this meta-analysis aimed to discuss the mechanisms by which ICA exerts its anti-AD effects and the differences in the efficacy of different doses of ICA by evaluating behavioral indicators and biochemical characteristics. A total of 31 pre-clinical studies were included, and the results showed that ICA treatment significantly improved cognitive dysfunction in animal models of AD in terms of resistance to neurotoxic substances, inhibition of oxidative stress, anti-inflammation, inhibition of apoptosis, modulation of neuronal autophagy, and protection of nerves to promote regeneration. Furthermore, 68 mg/kg of ICA was identified as the most effective doses in terms of improving cognition. However, further research is required, incorporating studies of higher quality and larger sample sizes, in addition to clinical trials, in order to verify the efficacy and safety of this approach in neurological disorders.},
}

@article {pmid41791447,
year = {2026},
author = {Pettis, JA and Orshoski, M and Pal, S and Allen, AM and Ortega Zepeda, M and Wysocki, VH and Kuret, J},
title = {Efficient tag-less purification of recombinant human tau proteins.},
journal = {Analytical biochemistry},
volume = {},
number = {},
pages = {116095},
doi = {10.1016/j.ab.2026.116095},
pmid = {41791447},
issn = {1096-0309},
abstract = {Tau proteins normally function as part of the neuronal cytoskeleton but aggregate to form filamentous inclusions in tauopathies such as Alzheimer's disease. The diverse functions of tau protein are frequently interrogated using biochemical assays that require highly purified tau as substrate. Conventional recombinant tau purification leverages polyhistidine (His6) tags to enable rapid and efficient isolation through immobilized metal affinity chromatography (IMAC). Preparation of native tau by this approach requires removal of His6 tags through additional processing steps. Here we report a protocol for purifying native recombinant full-length tau protein that retains the speed, convenience, broad availability and scalability of IMAC while eliminating the need for post-purification proteolytic cleavage. The method has been validated across a wide array of tau constructs, including full-length isoforms, missense mutants, and a truncation construct containing an aggregation-prone region of the microtubule-binding domain. Owing to its scalability and reproducibility, the method is well suited for structure-activity relationship investigations involving curated tau variant libraries.},
}

@article {pmid41791248,
year = {2026},
author = {Yuki, A and Nishita, Y and Nakamura, A and Kato, T and Tange, C and Zhang, S and Ando, F and Shimokata, H and Otsuka, R},
title = {Ten-year longitudinal effects of physical activity and apolipoprotein E ..4 genotype on precuneus atrophy in Japanese older adults.},
journal = {Archives of gerontology and geriatrics},
volume = {145},
number = {},
pages = {106194},
doi = {10.1016/j.archger.2026.106194},
pmid = {41791248},
issn = {1872-6976},
abstract = {BACKGROUND: The apolipoprotein E ε4 (APOE ε4) allele, a major genetic risk factor for Alzheimer's disease, is associated with early atrophy in the precuneus and posterior cingulate cortex. Whether physical activity can mitigate this atrophy in high-risk APOE ε4 carriers remains unclear. This study aimed to determine whether physical activity can reduce such neurodegenerative changes in older adults carrying this allele.

METHODS: This 10-year longitudinal study included 295 community-dwelling older adults (154 men and 141 women; age ≥65 years). Baseline physical activity was measured using accelerometers and analyzed according to activity intensity. Participants were categorized as APOE ε4 carriers or non-carriers. Volumes of the precuneus and posterior cingulate cortex were assessed using longitudinal magnetic resonance imaging. Sex-stratified linear mixed models examined the interaction between physical activity and APOE ε4 status on brain volume changes, adjusting for relevant covariates.

RESULTS: The moderate-to-vigorous physical activity (MVPA) × APOE ε4 × year effect in women's left precuneus was significant unadjusted but not after false discovery rate (FDR; 16 models) and exploratory. Left precuneus volume declined significantly over 10 years regardless of MVPA level or APOE ε4 genotype (each p < 0.0001). However, among APOE ε4 carriers, greater time spent in MVPA slowed the rate of volume decline. No similar effect was observed in men.

CONCLUSIONS: Higher habitual MVPA may be associated with slower left precuneus decline in APOE ε4-positive women. As this exploratory three‑way effect was FDR‑nonsignificant, targeted replication is needed to clarify the role of everyday activity in genetically vulnerable groups.},
}

@article {pmid41791120,
year = {2026},
author = {Peng, Y and Yao, SY and Wu, SL and Yang, H and Zhang, X and Kazuo, S and Liu, J and Du, MQ and Lin, LX and Kang, XH and Jiang, DY},
title = {New Perspective: Bench to Bedside Evidence of the Role of CD8+ T Cells in Alzheimer's Disease.},
journal = {Immunity, inflammation and disease},
volume = {14},
number = {3},
pages = {e70380},
doi = {10.1002/iid3.70380},
pmid = {41791120},
issn = {2050-4527},
support = {C202303076574//Scientific Research Project of the Hunan Provincial Health Commission, People's Republic of China/ ; 2023039//Key Plans of Hunan Administration Traditional Chinese Medicine, PR China/ ; 2022XYLH19//University-Hospital Joint Fund of Hunan University of Chinese Medicine, PR China/ ; 2021B-003//Fund for Creative Research Groups at the Affiliated First Hospital of Hunan Traditional Chinese Medical College, PR China/ ; 2021-009//Technology Plan Project of Zhuzhou City, Hunan Province, PR China/ ; //Fund for Research Chief of Clinical Department of Affiliated First Hospital of Hunan Traditional Chinese Medical College, PR China/ ; },
abstract = {INTRODUCTION: Amyloid beta plaques and tau tangles are the primary hallmarks of Alzheimer's disease (AD). Recently, passive anti-Aβ immunotherapy for AD has markedly advanced, as supported by evidence from AD animal models and clinical trials. Whereas innate immunity significantly contributes to AD pathology, it does not fully represent the immune mechanisms linked to this condition. Therefore, focus should be directed toward adaptive immunity, encompassing both humoral and cellular immunity.

METHODS: Relevant publications and clinical trial data up to February 2026 were systematically reviewed to summarize the mechanisms, therapeutic targets, safety profiles, and translational applications of CD8+ T cells in AD.

RESULTS: Clinical and animal studies have particularly suggested a potential involvement of T cells in AD pathogenesis. T cells that infiltrate the central nervous system (CNS) exert both protective and detrimental effects on neural tissue in AD. Because autoreactive CD8+ T cells are generally expected to have cytotoxic effects on CNS cells, they have received less attention. Nevertheless, accumulating evidence suggests that CD8+ Treg cells are involved in various diseases.

CONCLUSION: However, the function of anti-Aβ-specific CD8+ T cells in Alzheimer's disease (AD) remains ambiguous. Many subsets of CD8+ T cells have been well-studied in autoimmunity. We suggest that CD8+ T cell subsets identified in AD studies may constitute a promising area for future AD research.},
}

@article {pmid41791118,
year = {2026},
author = {Al-Hindawi, F and Wu, T and Wen, Y and Serhan, P and Forzani, E and Tsow, F and Geda, YE},
title = {Leveraging Naturalistic Driving Digital Biomarkers for Early Mild Cognitive Impairment Detection: Deep Learning Strategies.},
journal = {JMIR medical informatics},
volume = {14},
number = {},
pages = {e83622},
doi = {10.2196/83622},
pmid = {41791118},
issn = {2291-9694},
abstract = {BACKGROUND: Alzheimer disease and related dementias are increasing worldwide, with early detection during the mild cognitive impairment (MCI) stage critical for timely intervention. Driving behavior, which reflects everyday cognitive functioning, has emerged as a promising, noninvasive, and inexpensive digital biomarker when paired with machine learning. However, prior research has often relied on controlled settings, high-level features, or assumptions that fail to capture the sporadic nature of MCI, leaving a gap in modeling naturalistic driving data for robust early detection.

OBJECTIVE: This study aims to address the limitations of prior work by developing deep learning strategies that leverage driving data collected in a naturalistic setting as digital biomarkers for early detection of MCI.

METHODS: Clinically classified participants (8 with MCI and 14 cognitively normal; N=22) drove their personal vehicles under naturalistic conditions for several consecutive days. A total of 3 participants (2 cognitively normal and 1 MCI) withdrew before completing the experiments. In-vehicle sensors recorded GPS, accelerometer, and gyroscope signals, which were segmented into full trips and turning maneuvers. Three modeling strategies were compared: (1) single-view, (2) feature-level fusion, and (3) model-level late fusion. Classification models were trained and evaluated to assess their accuracy, discriminative ability, and participant-level performance.

RESULTS: Models using full-trip data consistently outperformed turn-only inputs, with the best-performing model achieving 78% accuracy and an area under the receiver operating characteristic curve of 77%. Turn-based inputs alone demonstrated limited discriminative power; however, combining them with trip data through late fusion improved performance, though not beyond the full-trip baseline. Participant-level analysis indicated that classification accuracy improved with increased data volume, and trip-wise modeling more effectively captured the episodic nature of MCI than majority-vote aggregation. A frequency-based risk score was proposed as an interpretable and flexible output, enabling practical application in clinical and community settings.

CONCLUSIONS: Naturalistic driving behavior offers a scalable and noninvasive approach for early cognitive screening. Deep learning models using full-trip naturalistic driving data show promise for detecting MCI, with fusion strategies providing supplementary insights. This framework supports proactive, real-world monitoring of cognitive decline, laying the foundation for digital health interventions in dementia prevention.},
}

@article {pmid41791097,
year = {2026},
author = {Salma, SU and Renduchintala, CR and Siddique, I and Sterling, E and Sneha, S and Sakib, N},
title = {AI-Driven Mental Health Support for Caregivers of Individuals With Alzheimer Disease: Systematic Literature Review and Development of a Conceptual Framework.},
journal = {JMIR mental health},
volume = {13},
number = {},
pages = {e79973},
doi = {10.2196/79973},
pmid = {41791097},
issn = {2368-7959},
abstract = {BACKGROUND: Caregivers supporting individuals with Alzheimer disease and related dementias (AD/ADRD) frequently encounter prolonged emotional strain, psychological distress, and social isolation, yet their needs are largely overlooked in current technological and clinical interventions. The special routines and obligations of caregivers of individuals with AD/ADRD are frequently not well-suited to the many artificial intelligence-driven (AI-driven) mental health solutions that are currently available. This reveals a critical need for sophisticated, customized solutions created especially to help the mental health of caregivers for patients with AD/ADRD.

OBJECTIVE: To address the existing limitations of personalized mental health interventions, we aimed to identify existing literature on personalized mental health interventions using AI for specific purposes and to develop a new framework for the caregivers of individuals with AD/ADRD.

METHODS: We followed an iterative approach to design the new framework. First, we did a systematic literature review of current literature to identify data analysis, AI methods, and personalized interventions. Second, we focused on the underlying gaps of this research, and by synthesizing our findings from the review, we proposed a conceptual framework.

RESULTS: The systematic literature review identified 73 unique results, and from external sources, we found 3 unique potential papers. Of these, 28 papers were eligible for inclusion, on which we performed our analysis. Based on the findings, we developed a new conceptual framework with 3 special features that are specifically for caregivers of patients with AD/ADRD. The 3 unique features are a personalized daily routine scheduler, which will take both patients with AD/ADRD and caregiver's information to make it personalized, a daily reward system to keep patients motivated, and an educational repository to get the bite-sized knowledge for the lesson of handling patients in an efficient manner and taking care of one's own mental health.

CONCLUSIONS: The proposed framework provides a chance for caregivers to receive mental health care, which will be personalized. The framework is developed with more updated methods than existing approaches, with a lack of personalization in this sector. This framework can be implemented with a goal of personalization and explainable approaches and can undergo further iterations to ensure it is appropriate for specific purposes.},
}

@article {pmid41790889,
year = {2026},
author = {Smits, JFM and Ligthart, TW and Jorge-Oliva, M and Middelhoff, S and Schipper, F and Pita-Illobre, D and Li, KW and Scheper, W},
title = {Neurons with granulovacuolar degeneration bodies are resilient to tau-induced protein synthesis impairment.},
journal = {Science advances},
volume = {12},
number = {10},
pages = {eaea8940},
doi = {10.1126/sciadv.aea8940},
pmid = {41790889},
issn = {2375-2548},
abstract = {In Alzheimer's disease, many surviving neurons with tau pathology contain granulovacuolar degeneration bodies (GVBs), neuron-specific lysosomal structures induced by pathological tau assemblies. This could indicate a neuroprotective role for GVBs; however, the mechanism of GVB formation and its functional implications are elusive. Here, we demonstrate that casein kinase 1δ (CK1δ) activity is required for GVB formation. CK1δ is sequestered in the GVB during this process in an autophagy-dependent manner. We show that neurons with GVBs (GVB[+]) are resilient to tau-induced impairment of global protein synthesis and are protected against tau-mediated neurodegeneration. GVB[+] neurons do not exhibit differential activation of transient translational stress responses but have increased ribosomal content. Unlike neurons without GVBs, GVB[+] neurons fully retain the capacity to induce long-term potentiation-induced protein synthesis in the presence of tau pathology. Our results have identified CK1δ as a key regulator of GVB formation that confers a protective neuron-specific stress response to tau pathology. These findings provide opportunities for targeting neuronal resilience in tauopathies.},
}

@article {pmid41790841,
year = {2026},
author = {Mao, Z and Peng, Y and Lin, R and Guo, X and Cui, X and Yu, Y and Zheng, X},
title = {Association of intraindividual differences in estimated glomerular filtration rates based on cystatin C and creatinine with dementia: A cohort study of the UK Biobank.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0344566},
doi = {10.1371/journal.pone.0344566},
pmid = {41790841},
issn = {1932-6203},
abstract = {BACKGROUND: Dementia is a leading cause of cognitive decline, with Alzheimer's disease (AD) and vascular dementia (VaD) being the most common subtypes. The intraindividual difference between the estimated glomerular filtration rate based on cystatin C and creatinine (eGFRdiff) may serve as an indicator of the overall health status of an individual. However, the relationships between the eGFRdiff and dementia risk, dementia subtypes, dementia-related neuroimaging changes, and cognitive functions remain unclear.

METHODS: This study analysed data from over 450,000 participants in the UK Biobank who were followed for up to 15 years. The estimated glomerular filtration rate based on cystatin C (eGFRcys) and creatinine (eGFRcr) was calculated using the CKD-EPI equation, and eGFRdiff was defined as the difference between these values (eGFRdiff = eGFRcys - eGFRcr). Multivariate Cox regression models were used to evaluate the associations between the eGFRdiff and all-cause dementia (ACD), AD, and VaD, whereas cross-sectional analysis were used to examine the relationship among the eGFRdiff, dementia-related neuroimaging changes, and cognitive functions.

RESULTS: Over a median follow-up of 13.5 years, 8,710 participants developed dementia, including 3,910 with AD and 1,893 with VaD. Each one standard deviation increase in eGFRdiff was associated with a reduced risk of dementia, with hazard ratios (95% confidence intervals) of 0.92 (0.90-0.94) for ACD, 0.94 (0.91-0.98) for AD, and 0.90 (0.85-0.94) for VaD. A negative eGFRdiff was associated with adverse neuroimaging changes, including lower total brain and gray matter volumes and higher white matter hyperintensities. Additionally, a negative eGFRdiff was associated with poorer performance across multiple cognitive domains.

CONCLUSION: A negative eGFRdiff was associated with an increased risk of dementia, adverse neuroimaging outcomes, and cognitive decline. These findings suggest that the eGFRdiff might be considered a potential associative indicator for dementia and cognitive impairment, suggesting potential clinical value in risk assessment and early intervention strategies.},
}

@article {pmid41790768,
year = {2026},
author = {Brady, JJR and Bartlett, L and Roccati, E and Norris, K and Vickers, JC and Sinclair, D},
title = {Psychosocial hierarchies of modifiable risk for Alzheimer's disease: A networks analysis.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0333148},
doi = {10.1371/journal.pone.0333148},
pmid = {41790768},
issn = {1932-6203},
abstract = {Thirty per-cent of multidomain risk reduction trials for Alzheimer's disease and related dementias (ADRD) report limited efficacy. Identifying potential cascading influences between psychosocial ADRD risk factors is a promising strategy for increasing this efficacy rate. We aimed to identify relational hierarchies among modifiable ADRD risk factors to inform temporally optimized prevention strategies. We applied a dual network approach-regularized partial correlation network (RPCN) and a Bayesian directed acyclic graph (DAG) generated via a novel ensemble method-to cross-sectional data from 898 community-dwelling older adults enrolled in an ADRD prevention initiative. The RPCN revealed clustering among mental health domains. The DAG suggested directional associations from stress, anxiety, and coping to downstream factors including depression, social support, cognitive activity, and cardiometabolic domains (physical activity, BMI, blood pressure, and MIND diet adherence). This dual-network framework highlights upstream psychosocial factors statistically associated with multiple ADRD-related risks. Models suggest targeting stress and coping may offer broad, cascading, benefits for ADRD risk reduction. Further exploration of strategically staggered and/or needs-based individualization of future modifiable ADRD prevention initiatives is warranted.},
}

@article {pmid41790706,
year = {2026},
author = {Wang, X and Liu, Y and Yin, Y and Huang, H and Chen, J and Chen, Z and Liu, S and Xiao, L and Chen, S and Peng, C},
title = {The effects of structured aerobic exercise and mind-body exercise on cognitive function in older adults with MCI: Systematic review and meta-analysis.},
journal = {Medicine},
volume = {105},
number = {10},
pages = {e47633},
doi = {10.1097/MD.0000000000047633},
pmid = {41790706},
issn = {1536-5964},
abstract = {BACKGROUND: Global aging has increased the prevalence of dementia, with mild cognitive impairment (MCI) representing a critical window for intervention. While exercise is recognized for mitigating cognitive decline, the comparative effectiveness of mind-body versus structured aerobic exercise remains unclear.

METHODS: Search sources included PubMed, Web of Science, and the Cochrane Library. Randomized controlled trials (RCTs) assessing mind-body exercise (tai chi, yoga, and dance) or structured aerobic exercise (walking and cycling) in patients with MCI aged over 50 years were included. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were used as outcome measures. Random- or fixed-effects meta-analyses were conducted using RevMan 5.4.1. Heterogeneity was assessed using the I2 statistic. Subgroup analyses examined intervention parameters.

RESULTS: Twenty-six randomized controlled trials (n = 2,555) were included. Mind-body exercise significantly improved MMSE (mean difference [MD] = 1.27, 95% confidence interval [CI]: 0.99-1.55, P < .01), MoCA (MD = 1.89, 95% CI: 0.78-3.00, P = .0008), and ADAS-Cog (MD = -2.09, 95% CI: -2.94 to -1.25, P < .00001) versus controls. Structured aerobic exercise showed non-significant effects on MMSE (MD = 0.37, P = .21) and MoCA (MD = -0.49, P = .26), with modest improvement on ADAS-Cog (MD = -1.41, P = .002). Optimal mind-body parameters include ≥20 weeks' duration, ≥60 minutes per session, and ≥3 times per week.

CONCLUSIONS: Mind-body exercise demonstrates superior cognitive benefits compared with structured aerobic exercise in older adults with MCI. It is advised to prioritize mind-body exercise interventions at least 3 times per week, for 60 minutes per session, for at least 20 weeks. Limitations include heterogeneity and geographic bias; these findings warrant confirmation through multicenter trials.},
}

@article {pmid41790675,
year = {2026},
author = {Alnazari, M and Bakhsh, A and Abdullah, S and Al Qahtani, S and Borhan, W and Rajih, E and Alshehri, AM},
title = {Biological implications and therapeutic potential of phosphodiesterase inhibitors: A review.},
journal = {Medicine},
volume = {105},
number = {10},
pages = {e47683},
doi = {10.1097/MD.0000000000047683},
pmid = {41790675},
issn = {1536-5964},
support = {IF2/PSAU/2022/03/22660//The Deputyship for Research &Innovation, Ministry of Education in Saudi Arabia/ ; },
abstract = {Phosphodiesterase (PDE) inhibitors regulate cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways, which influence neurodevelopment, cardiovascular function, and immune responses. Multiple PDE families exist, classified as dual-substrate (PDE1, PDE2, PDE3, PDE10, PDE11) or non-dual-substrate (PDE4, PDE5, PDE6, PDE7, PDE8, PDE9), each with distinct biological roles. This review summarizes the therapeutic applications of PDE inhibitors, evaluates evidence across different disease domains, and highlights challenges and future research priorities. A narrative review of published studies and clinical trial data was conducted, focusing on pharmacological properties, therapeutic relevance, and safety profiles of PDE inhibitors. Sources included PubMed, ClinicalTrials.gov, and regulatory reports. Dual-substrate PDEs demonstrate therapeutic potential in Alzheimer disease (PDE1), anxiety and memory enhancement (PDE2), and heart failure (PDE3), although chronic PDE3 inhibition may increase risks. Non-dual-substrate PDEs, such as PDE4 and PDE5, are clinically established for asthma, chronic obstructive pulmonary disease, psoriasis, erectile dysfunction, and pulmonary hypertension. Advances in structure-activity relationship studies have produced more selective and potent inhibitors. However, adverse effects, such as nausea (PDE4 inhibitors) and cardiovascular risks (long-term PDE3 inhibitors), remain limiting factors. PDE inhibitors represent a rapidly evolving therapeutic class with broad clinical applications. Their further development requires strategies to minimize adverse effects, improve selectivity, and better define disease-specific roles. Future research should focus on precision medicine approaches to fully harness their therapeutic potential.},
}

@article {pmid41790569,
year = {2026},
author = {Bubu, OM and Mullins, AE and Shah, S and Gills, JL and Kam, K and Parekh, A and Umasabor-Bubu, OQ and Turner, AD and Bernard, M and Briggs, A and Ramos-Cejudo, J and Valkanova, E and Mbah, AK and Pahari, P and Debure, L and Ghuman, M and Boutajangout, A and Williams, NJ and Hwang, J and Williams, MK and Rapoport, DM and Ayappa, I and de Léon, M and Jean-Louis, G and Varga, AW and Osorio, RS},
title = {Obstructive sleep apnea severity, Alzheimer's disease plasma markers, and CSF brain amyloidosis and tau pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71270},
doi = {10.1002/alz.71270},
pmid = {41790569},
issn = {1552-5279},
support = {L30-AG064670/NH/NIH HHS/United States ; P30AG059303/NH/NIH HHS/United States ; T32HL129953/NH/NIH HHS/United States ; K23AG068534/NH/NIH HHS/United States ; R01AG082278/NH/NIH HHS/United States ; RF1AG083975/NH/NIH HHS/United States ; R01HL118624/NH/NIH HHS/United States ; R21AG049348/NH/NIH HHS/United States ; R21AG055002/NH/NIH HHS/United States ; R01AG056031/NH/NIH HHS/United States ; R01AG022374/NH/NIH HHS/United States ; R01AG066970/NH/NIH HHS/United States ; R01AG080609/NH/NIH HHS/United States ; R01AG056531/NH/NIH HHS/United States ; K07AG05268503/NH/NIH HHS/United States ; K23HL125939/NH/NIH HHS/United States ; AARG-21-848397/ALZ/Alzheimer's Association/United States ; A2022033S//BrightFocus Foundation/ ; SCN-25-1474727//Alzheimer's Association/Michael J. Fox Foundation/CurePSP/ ; },
abstract = {INTRODUCTION: We examined obstructive sleep apnea (OSA) severity's association with Alzheimer's disease (AD) plasma biomarkers, independent or synergistic with cerebrospinal fluid (CSF) amyloid, and as a proof of concept, whether plasma amyloid beta (Aβ)42/Aβ40 with OSA severity improves detection of amyloidosis and tau pathology.

METHODS: In 120 cognitively normal older adults (70 with CSF data) from New York University sleep and aging studies (2013-2021), OSA severity was measured using apnea/hypopnea index with 4% desaturation; plasma Aβ40, Aβ42, tau, and neurofilament light chain (NfL) via single molecule array; CSF amyloid and tau via enzyme-linked immunosorbent assay. Associations evaluated adjusted correlations and generalized models; receiver operating characteristic analyses evaluated diagnostic accuracy.

RESULTS: OSA severity correlated with plasma Aβ40 (r = 0.21), Aβ42 (r = 0.26), and Aβ42/Aβ40 (r = 0.20). Plasma tau and NfL associations depended on CSF-Aβ42. OSA severity with Aβ42/Aβ40 improved CSF amyloidosis (area under the curve [AUC] = 0.78) and tau pathology (AUC = 0.71) detection.

DISCUSSION: OSA severity relates to elevated plasma Aβ and, with CSF amyloid, to tau/NfL. Combined plasma and OSA measures aid non-invasive AD associations' detection.},
}

@article {pmid41790564,
year = {2026},
author = {Horton, M and Whiley, DJ and Mayhew, M and McLean, S},
title = {Association between spirochaetal infection and neurodegenerative diseases: a systematic review and quantitative synthesis of observational studies.},
journal = {Journal of medical microbiology},
volume = {75},
number = {3},
pages = {},
doi = {10.1099/jmm.0.002136},
pmid = {41790564},
issn = {1473-5644},
abstract = {Introduction. Neurodegenerative diseases, including Alzheimer's and Parkinson's, are a growing global health concern. While age remains the primary risk factor, infectious agents have been proposed as potential contributors to disease onset or progression.Gap statement. Spirochaetal bacteria, such as Treponema pallidum, Borrelia burgdorferi and Leptospira spp., can invade the central nervous system, yet the extent to which these infections influence neurodegenerative outcomes remains unclear.Aim. This systematic review aimed to evaluate observational evidence on the association between spirochaetal infections and neurodegenerative diseases and to identify gaps in the literature to inform future research.Methodology. A systematic search of SCOPUS, EMBASE, PubMed/MEDLINE, Web of Science and CINAHL was conducted for studies published between January 2000 and May 2025. Eligible studies were observational, involved adult human populations and reported both spirochaetal infection and cognitive or neurodegenerative outcomes using standardized methods. Data were extracted using a standardized form. Owing to heterogeneity in study design, diagnostic approaches, outcome measures and reporting formats, an overall pooled meta-analysis was not feasible; however, a quantitative synthesis using meta-analytic methods was conducted for studies reporting mini-mental state examination data. Risk of bias was assessed using the Newcastle-Ottawa Scale.Results. Twenty-seven studies met the inclusion criteria: 13 on T. pallidum, 13 on B. burgdorferi and one on Leptospira spp. No eligible studies were found for Brachyspira spp., and studies involving Treponema denticola were excluded due to confounding by periodontitis. Studies investigating syphilis and leptospirosis consistently reported cognitive impairment and increased dementia risk. In contrast, findings for Lyme disease were heterogeneous, with some studies reporting persistent symptoms or increased Alzheimer's risk, while others found no long-term cognitive effects.Conclusion. This review highlights a potential link between spirochaetal infections and neurodegenerative outcomes, particularly for syphilis and leptospirosis. Evidence for Lyme disease remains inconclusive. Future research should prioritize longitudinal studies with standardized diagnostic criteria, integration of neuroimaging and biomarker data and improved diagnostic accuracy for spirochaetal infections.},
}

@article {pmid41790563,
year = {2026},
author = {Tee, BL and Spat-Lemus, J and Zhang, SX and Upendra, S and Zhao, X and Chen, G and Chen, Y and Wen, X and Yao, A and Leng, F and Li, C},
title = {Advancing global precision in dementia research: Examining Normative Heterogeneity of Aging and Neurodegeneration in Chinese Elders (ENHANCE).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71166},
doi = {10.1002/alz.71166},
pmid = {41790563},
issn = {1552-5279},
support = {R61AG083582 to C.L/NH/NIH HHS/United States ; R01AG083840 to C.L/NH/NIH HHS/United States ; R01AG080469 to C.L/NH/NIH HHS/United States ; R21AG077649 to C.L/NH/NIH HHS/United States ; UH3AG083258 to C.L/NH/NIH HHS/United States ; R01AG095513 to C.L/NH/NIH HHS/United States ; R01AG080469 to B.L.T./NH/NIH HHS/United States ; R01AG083840 to B.L.T./NH/NIH HHS/United States ; U19AG079774 to B.L.T./NH/NIH HHS/United States ; P01AG019724 to B.L.T./NH/NIH HHS/United States ; U01NS128913 to B.L.T./NH/NIH HHS/United States ; AACSFD-22-972143 to B.L.T./ALZ/Alzheimer's Association/United States ; K24DC015544 to B.L.T./DC/NIDCD NIH HHS/United States ; RF1NS050915 to B.L.T./DC/NIDCD NIH HHS/United States ; R01 NS100440-01 to B.L.T./DC/NIDCD NIH HHS/United States ; R01AG058233 to B.L.T./DC/NIDCD NIH HHS/United States ; P30 AG062422 to B.L.T.//Alzheimer's Disease Research Center of California/ ; },
abstract = {The Examining Normative Heterogeneity of Aging and Neurodegeneration in Chinese Elders (ENHANCE) project addresses gaps in Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD) research by prioritizing Chinese-speaking communities-an underrepresented but rapidly growing population in the United States (US) and globally. ENHANCE uses a transadaptation approach to develop cognitive assessments that reflect the language and culture of Cantonese and Mandarin speakers, making tools more relevant and appropriate. The project brings together data from older Chinese American participants at University of California San Francisco (UCSF) and Icahn School of Medicine at Mount Sinai (ISMMS), guided by community input and pilot testing results of research instruments. By combining data from ISMMS, UCSF, and the National Alzheimer's Coordinating Center (NACC), ENHANCE explores meaningful cross-cultural differences in AD/ADRD risk and progression. The goal is to improve diagnostic accuracy and representation in AD/ADRD research. ENHANCE helps make AD/ADRD research more responsive to language and cultural backgrounds in the older Chinese American community, supporting the goal of precision medicine in diverse population.},
}

@article {pmid41790486,
year = {2026},
author = {Ruuth, J and Tamminen, T and Toropainen, E and Tanila, H and Hyttinen, JMT and Malm, T and Kaarniranta, K and Koskela, A},
title = {Overproduction of 42 Amino Acids Long Amyloid Beta Leads to Activation of Secretory Autophagy and Development of Drusen-Like Structures Originating From Retinal Pigment Epithelium.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {5},
pages = {e71608},
doi = {10.1096/fj.202502464RRR},
pmid = {41790486},
issn = {1530-6860},
support = {333302//Academy of Finland/ ; //GeneCellNano/ ; //Paivikki ja Sakari Sohlberg Foundation/ ; 5503770//Kuopio University Hospital district/ ; //Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse)/ ; //Silmäsäätiö (Finnish Eye Foundation)/ ; //De Blindas Vänner (DBV)/ ; //Finnish eye and Tissue Bank Foundation/ ; //Mary and Georg C. Ehrnrooths Foundation/ ; //Finnish Cultural Foundation-North-Savo/ ; },
abstract = {Age-related macular degeneration (AMD) is a global vision threatening disease affecting the macular region of the retina. AMD is classified into two forms: dry and wet AMD. There are no effective treatment options available for dry AMD (80% of cases). The cellular pathology includes oxidative stress and dysfunctional autophagy challenging the homeostasis of the retinal pigment epithelial (RPE) cells. Clinical findings include the formation of drusen deposits beneath the RPE cells consisting of 42 amino acids long amyloid beta (Aβ) among other components. However, the origin of drusen remains elusive. The 5xFAD (familiar Alzheimer's disease) mouse model of Alzheimer's disease produces abundant levels of Aβ making it an interesting model to study the possible relationship of Aβ to the formation of extracellular deposits and AMD-like pathology. An immunohistology analysis of the 5xFAD mouse model showed accumulation of autophagic markers SQSTM1 (sequestosome 1) and ubiquitin in the RPE. Concurrently, the markers of secretory autophagy enabling the delivery of the intracellular material to the extracellular lumen were upregulated. Aβ, SQSTM1, ubiquitin, catalase, and TRIM16 (tripartite motif containing 16) shifted age-dependently from intracellular origin to drusen-like deposits beneath the RPE cells. Additionally, classical proteins secreted via secretory autophagy, IL-1β (interleukin 1β), HMGB1 (high mobility group box-1), and ferritin showed similar accumulation which became visible in fundus age-dependently. These findings suggest a role for Aβ in the cellular pathogenesis of AMD. Furthermore, this model showed activated secretory autophagy pathway suggesting a role for Aβ in drusen-like deposition formation.},
}

@article {pmid41790466,
year = {2026},
author = {Chung, YE and Chung, RH and Hsu, CC and Liu, YL and Lai, RH and Hung, WJ and Wu, RC and Jiang, YJ and Chuang, SY and Tsai, SF and Kuo, CC and Hsiung, CA and Chen, WJ},
title = {APOE ε4 and Accelerated Cognitive Decline Among Cognitively Healthy Middle-Aged and Older Adults.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e260853},
doi = {10.1001/jamanetworkopen.2026.0853},
pmid = {41790466},
issn = {2574-3805},
abstract = {IMPORTANCE: Alzheimer disease (AD) pathology may begin decades before symptoms. Genetic factors, such as APOE ε4 carrier status and polygenic risk scores (PRS), influence AD risk, but their roles in cognitive decline among Asian populations remain unclear.

OBJECTIVE: To evaluate whether APOE ε4 carrier status and a non-APOE polygenic risk score (PRS_ADnapoe) are associated with age-related cognitive decline in community-dwelling older adults in Taiwan.

This prospective cohort study used data from 2 assessment waves of the Healthy Aging Longitudinal Study in Taiwan, spanning 2009 to 2019. Participants were aged 55 years and older and had both genetic data and Mini-Mental State Examination (MMSE) scores. Data analyses were conducted from August to December 2025.

EXPOSURES: APOE ε4 carrier status (noncarrier, heterozygote, homozygote) and PRS_ADnapoe score, derived from genome-wide association summary statistics excluding APOE variants.

MAIN OUTCOMES AND MEASURES: The primary outcome was change in MMSE scores, which were assessed cross-sectionally and longitudinally, modeled with mixed-effects regression accounting for age-related effects and covariates including sex, education, smoking, and population structure.

RESULTS: Among 4392 participants (mean [SD] age, 68.2 [7.8] years; 2359 [53.7%] women), 723 (16.5%) were APOE ε4 heterozygotes and 33 (0.8%) were APOE ε4 homozygotes. Over a mean (SD) follow-up of 6.3 (0.9) years, the mean (SD) annual MMSE decline was -0.2 (0.5). APOE ε4 carriage was associated with a significantly steeper quadratic age-associated decline in MMSE scores compared with noncarriers (estimate, -0.005; SE, 0.001; P = .001). This association was strongest among homozygotes (estimate, -0.017; SE, 0.008; P = .03), with MMSE trajectories diverging after approximately age 70 years. In contrast, PRS_ADnapoe scores were not associated with MMSE decline. Sensitivity analyses restricted to participants with 2-wave data and adjusted with inverse probability of censoring weighting confirmed these findings.

CONCLUSIONS AND RELEVANCE: In this cohort study of middle-aged and older adults in Taiwan, APOE ε4 carriage, particularly homozygosity, was associated with accelerated age-related cognitive decline detectable after age 70 years, whereas non-APOE polygenic risk was not associated with cognitive decline over the current follow-up. These results highlight the potential utility of early genetic risk awareness and support consideration of targeted preventive strategies for APOE ε4 carriers.},
}

@article {pmid41790409,
year = {2026},
author = {Zhang, X and Wu, L and Hua, D and Zhang, B and Wang, X and Li, L and Wang, Y and Zhu, J},
title = {Bisphenol S and Neurological Health: An Integrated Overview of Neurotoxicity and Underlying Mechanisms.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41790409},
issn = {1559-1182},
support = {82504453//the National Natural Science Foundation of China/ ; 24YF2757800//the Yangfan Program of the Shanghai Science and Technology Commission/ ; 20244Y0040//the Youth Clinical Research Program of the Shanghai Municipal Health Commission/ ; },
abstract = {Bisphenol S (BPS), a pervasive contaminant used in consumer and industrial products, has been widely detected in human serum, urine, hair, placenta, and breast milk. Although initially studied mainly as an endocrine disruptor, accumulating evidence indicates that BPS also exerts neurotoxicity by perturbing neuroinflammatory responses, neuroendocrine regulation, and neuronal development. However, its neurotoxic profile and mechanistic basis remain incompletely defined. This review systematically retrieved and synthesized epidemiological, animal, and cellular studies published between 2000 and February 2026 across multiple databases to delineate the neurotoxic features and mechanisms of BPS. Evidence from 14 epidemiological and 76 experimental studies consistently indicates neurotoxic risk. Epidemiological data associate BPS exposure with increased risks of neuropsychiatric outcomes, including attention-deficit/hyperactivity disorder (ADHD), Alzheimer's disease (AD), and depression, often with sex-specific patterns. Animal studies show that exposure across life stages induces behavioral impairments, encompassing social deficits, cognitive and emotional disturbances, motor dysfunction, and memory decline. In vitro studies further elucidate molecular underpinnings. Mechanistically, BPS neurotoxicity involves endocrine-axis disruption, neurotransmitter imbalance, oxidative stress, and transcriptional dysregulation and extends to gut-brain axis perturbation, brain region-specific vulnerability, and neural circuit dysfunction. These pathways interact and are modified by toxicokinetics, exposure dose and timing, sex, and species. Future work should integrate longitudinal human cohorts with mechanistic studies to clarify BPS's contribution to neurological disease development and inform regulation. We propose an integrative framework summarizing BPS neurotoxicity and its key modifying factors.},
}

@article {pmid41790404,
year = {2026},
author = {Emam, M and Albadri, S and Ahmed, AM and Mirza, IM and Hafiz, HA and Elnaeem, M and Alzamil, Y and Alazzam, MB and , },
title = {Higher Total Omega-3 PUFA Levels and a Lower Omega-6:Omega-3 Ratio Are Associated with Lower Temporal Lobe Volume in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41790404},
issn = {1559-1182},
abstract = {Research suggests varying effects of fatty acids on cognitive function and brain structure in neurocognitive disorders, but inconsistent findings call for further investigation and advanced neuroimaging techniques. This study investigated the relationship between serum fatty acid levels (omega-3 PUFAs, omega-6 PUFAs, omega-6:omega-3 ratio, MUFAs, and SFAs) and temporal lobe volume in cognitively normal (CN) individuals, those with mild cognitive impairment (MCI), and those with Alzheimer's disease (AD). The results indicated that, as expected, there was a significant difference in temporal lobe volumes (p < 0.001), with the AD group showing more pronounced reductions in volume compared to both the CN and MCI groups. Unexpectedly, higher plasma omega-3 PUFA levels were associated with reduced temporal lobe volume (β = - 0.31, p = 0.021), and a lower omega-6:omega-3 ratio was also associated with diminished temporal lobe volume (β = 0.26, p = 0.039), both observed only in the AD group, after adjustment for age, gender, education, and APOE ε4 allele status as potential confounders. No significant associations were observed for any lipids with temporal lobe volumes in the CN or MCI groups. Interestingly, the only significant association observed between fatty acids and cognitive function was in the CN group, where higher MUFAs and SFAs were both associated with worse cognitive scores. In short, higher omega-3 PUFA levels and a lower omega-6:omega-3 ratio were associated with reduced temporal lobe volume in Alzheimer's patients not using fatty acid supplements. Notably, this observational cross-sectional study cannot establish causality and should be interpreted cautiously, as the findings may be influenced by residual confounding, non-fasting sampling, potential reverse causality, lack of detailed dietary and longitudinal data, and methodological constraints including limited lipid characterization and region-specific morphometric analysis. Further research is needed to confirm these findings and investigate potential mechanisms.},
}

@article {pmid41790170,
year = {2026},
author = {Bousiges, O and Cretin, B and Battista, L and Schaeffer-Agalède, C and Philippi, N and Hamied, L and Ravier, A and Demuynck, C and Muller, C and Blanc, F},
title = {CSF elevated Tau and P-Tau and normal Aβ42 mainly corresponds to Alzheimer's disease with dementia with Lewy bodies.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41790170},
issn = {2509-2723},
abstract = {Some cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker profiles are difficult to interpret. We investigated one such case: normal Aβ42 and pathologically increased levels of Tau and P-Tau (Tau&PTau profile). We first extracted details of 184 patients with a Tau&PTau profile who had been followed up in Strasbourg, France (cohort 1) and whose diagnosis has been reviewed. Secondly, we recovered and analyzed the AD biomarker results and clinical diagnoses of a cohort of 1199 patients also followed up in Strasbourg (cohort 2). In cohort 1, 57% of patients were patients with comorbidity: they had both Alzheimer's disease and dementia with Lewy bodies (DLB) (AD+DLB). In cohort 2, among patients with a Tau&PTau profile: between 39.6 and 53.1% had comorbidity with AD, with more than half of the comorbidities being DLB. In cohort 2, among patients with AD+DLB, the majority (64.4%) had a Tau&PTau profile. These results show that patients with AD+DLB comorbidity mainly have a Tau&PTau profile. These results are relatively counterintuitive, given that AD and DLB are two diseases in which it is common, even systematic, to find a CSF Aβ42 decrease. However, the combination of the two diseases, or more broadly, AD comorbidity, indicates higher levels of Aβ42 than in pure AD.},
}

@article {pmid41790026,
year = {2026},
author = {Napolitano, E and Marino, C and Grimaldi, M and Buonocore, M and Santoro, A and D'Ursi, AM},
title = {Analyzing Nicotine Action Against Amyloid Toxicity by NMR-Pharmacometabolomics: An Exploratory Study.},
journal = {NMR in biomedicine},
volume = {39},
number = {4},
pages = {e70255},
doi = {10.1002/nbm.70255},
pmid = {41790026},
issn = {1099-1492},
abstract = {Alzheimer's disease (AD) is the primary neurodegenerative disease spread worldwide. One of the main histopathological hallmarks of AD is the deposition of amyloid plaques in the brain. Despite some epidemiological studies demonstrating that cigarette smoke is a factor in predisposing people to AD, nicotine, the principal alkaloid of Nicotiana Tobacco, has been widely studied for its ability to improve cognitive performance, both in animal models and in human studies. Several hypotheses have been proposed to explain the mechanism of action underlying the beneficial effect of nicotine in AD; however, this is still questioned. To gain new insights into the molecular mechanism underlying nicotine's neuroprotective action in AD, we performed NMR metabolomics on SH-SY5Y neuroblastoma cells treated with Aβ(1-42) in the presence of nicotine. Our data show that the neuroprotective action of nicotine resides in its ability to restore the systemic unbalanced metabolism associated with AD. In particular, nicotine reverses most Aβ(1-42)-induced metabolic impairments, including those related to amino acid metabolism, especially neurotransmission, as well as alterations in energy and membrane phospholipid metabolism.},
}

@article {pmid41789871,
year = {2026},
author = {Lv, M and Wang, Q and Yu, G and Chen, J and Zhou, X and Chen, Z and Li, R and Huang, S and Liang, Y and Que, Y and He, W and Xia, J and , },
title = {Choroid plexus-glymphatic axis disruption in Alzheimer's disease: Cerebrospinal fluid expansion as a mediator of metabolic dysfunction and cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261426578},
doi = {10.1177/13872877261426578},
pmid = {41789871},
issn = {1875-8908},
abstract = {BackgroundThe choroid plexus (ChP) and glymphatic system are crucial for cerebrospinal fluid (CSF) homeostasis and brain waste clearance. While their individual roles in Alzheimer's disease (AD) are recognized, the mechanisms linking ChP structural changes, glymphatic dysfunction, and CSF dynamics to metabolic and cognitive decline remain unclear.ObjectiveWe aimed to investigate the interrelationships among ChP volume, glymphatic function, CSF volumetric changes, cerebral glucose metabolism, and cognitive status across the AD spectrum.MethodsThis cross-sectional study included 142 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, categorized as cognitively normal (NC, n = 38), early mild cognitive impairment (EMCI, n = 31), late mild cognitive impairment (LMCI, n = 31), and AD (n = 42). We analyzed multimodal neuroimaging data, including normalized ChP volume (nChP), CSF sub-volumes, the diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and [18F]-FDG-PET standardized uptake value ratios. Partial correlation and mediation analyses were performed, adjusting for covariates.ResultsIncreased nChP correlated with larger CSF (nTotal-CSF: r = 0.324, FDR-p = 0.004), lower DTI-ALPS, and reduced FDG. nChP drove cognitive decline via two paths: "nChP→nTotal-CSF→ Mini-Mental State Examination (MMSE)" (44.1% total effect) and "nChP→DTI-ALPS→FDG→MMSE" (9.9%, p < 0.001). CSF showed spatial mediation: nCSF-LV (66.20% on metabolism) outperformed external CSF (38.90%); DTI-ALPS negatively correlated with nCSF-LV (r = -0.406, FDR-p < 0.01).ConclusionsOur findings demonstrate that ChP enlargement is linked to cognitive impairment through pathways involving CSF dynamics and glymphatic function, with cerebral hypometabolism as a key downstream effector. This study posits a "CSF dynamics imbalance" cascade in AD, highlighting the potential of targeting Choroid Plexus-CSF-glymphatic axis for early diagnosis and intervention.},
}

@article {pmid41789867,
year = {2026},
author = {Balsliemke, AL and Ahlemeyer, B and Schmidl, E and Acker, T and Schänzer, A and Baumgart-Vogt, E},
title = {Region-specific ups and downs in mitochondrial numerical densities during Alzheimer's disease progression: A pilot study in human brains.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261418994},
doi = {10.1177/13872877261418994},
pmid = {41789867},
issn = {1875-8908},
abstract = {BackgroundMitochondrial dysfunction is an important pathogenic factor in Alzheimer´s disease (AD) progression. Most studies analysed disturbances in the mitochondrial metabolism and oxidative stress or focussed on mitochondrial dynamics such as mitochondrial trafficking, fusion-fission and mitophagy.ObjectiveVery limited data exist regarding changes in the mitochondrial numerical density at different levels of AD neuropathologic changes (ADNC) in human brains.MethodsMitochondrial numerical densities were analysed by morphometry using the marker protein ATP5B in sections of 13 brain areas of 8 patients with either low, mid or high ADNC, 6 patients with tauopathy and 10 control patients. Patient samples were classified according to the ABC score.ResultsIn comparison to control patients, we detected increases in mitochondrial densities at low (not in all cases), mid and high ADNC in neurons of the frontal (25%) and temporal (11%) neocortices, pontine nuclei (30%) and Purkinje neurons of the cerebellum (30%). Contrarily, mitochondrial densities decreased by 20% in hippocampal neurons of the entorhinal cortex and CA3 region at mid and high ADNC. Only minor changes occurred in other brain regions investigated (e.g., parietal and occipital neocortices, inferior olive, substantia nigra, striatum). In tauopathy patients, changes in mitochondrial densities were comparable to those in AD patients, except for a stronger decrease in the entorhinal cortex (40%) and a greater increase in the temporal neocortex (30%).ConclusionsIn the neocortex, primarily affected by extracellular amyloid-β (Aβ) deposits, mitochondrial densities in neurons increased, whereas they decreased in the hippocampus, at first enriched in intracellular neurofibrillary tangles.},
}

@article {pmid41789865,
year = {2026},
author = {Li, Z and Wang, D and Xia, F and Liu, Y and Liu, Y},
title = {Identification of causally linked blood biomarkers for Alzheimer's disease via reverse transcriptome-wide Mendelian randomization.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261422501},
doi = {10.1177/13872877261422501},
pmid = {41789865},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder with poorly understood molecular mechanisms and limited early detection biomarkers.ObjectiveTo identify genes causally associated with AD risk using reverse transcriptome-wide Mendelian randomization (revTWMR) and bulk RNA-sequencing (RNA-seq).MethodsWe analyzed publicly available RNA-seq data from peripheral blood samples of patients with clinically diagnosed AD and cognitively normal controls, obtained from the GEO database. Differential expression analysis was performed to identify differentially expressed genes (DEGs). We used revTWMR by integrating genome-wide association study (GWAS) summary statistics with expression quantitative trait loci (eQTL) data to infer causal relationships between gene expression and AD risk.ResultsUsing RNA-seq data from peripheral blood samples of AD patients and cognitively normal controls, we identified 126 DEGs. Through revTWMR analysis, we narrowed down to 91 genes with significant causal associations with AD, and further prioritized 5 genes with strong causal effects (|α| ≥ 0.8). Among these, PSMA6, CD19, and CMTM6 have potential roles in AD pathogenesis and may serve as promising blood-based biomarkers for early detection and therapeutic targeting.ConclusionsOur findings highlight the utility of revTWMR in identifying causally relevant genes in AD and suggest several blood-based candidate biomarkers for early detection and therapeutic development. This integrative approach provides novel insights into the molecular underpinnings of AD.},
}

@article {pmid41789863,
year = {2026},
author = {Gibbs, D and Black, B and Petersen, M and Johnson, L and Hall, J and O'Bryant, SE and Zhang, F and , },
title = {Exploring feature importance in machine learning for neuroimaging traits in Alzheimer's disease across a multiethnic cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261426563},
doi = {10.1177/13872877261426563},
pmid = {41789863},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) affects 55 million people worldwide, projected to reach 139 million by 2050; yet, most machine learning (ML)-based AD classifiers have been developed in Non-Hispanic White (NHW) cohorts, limiting generalizability.ObjectiveAssess ethnic differences in AD prediction using classification performance and feature importance derived from multimodal neuroimaging biomarkers across African American (AA), Hispanic, and NHW participants.MethodsSupport vector machine classifiers were applied to multimodal neuroimaging data from a multi-ethnic cohort, incorporating structural magnetic resonance imaging measures, diffusion tensor imaging metrics, and positron emission tomography-based amyloid and tau measures. Models classified cognitively unimpaired (CU) versus cognitively impaired (CI) individuals and mild cognitive impairment (MCI) versus AD dementia, with and without adjustment for age, sex, and education.ResultsClassification performance varied by ethnicity and disease stage. NHW participants showed the strongest overall performance, particularly for CU versus CI, while Hispanic participants demonstrated high sensitivity and balanced performance for MCI versus AD. AA participants exhibited lower AUC and accuracy across tasks but maintained high negative predictive value. Demographic adjustment improved performance primarily for AA and NHW participants. Feature importance analyses revealed shared and population-specific patterns: tau positron emission tomography (PET) measures, especially posterior cingulate and lateral parietal standardized uptake value ratios, consistently ranked highest for CU versus CI across groups, whereas MCI versus AD classification diverged, with amyloid PET predominating in AA participants, tau PET in NHW participants, and mixed medial temporal atrophy and white matter signatures in Hispanics.ConclusionsShared early AD neuroimaging signatures exist across ethnic groups, but biomarker importance diverges at later disease stages, underscoring the need for ethnicity-aware ML models to improve prediction and equitable clinical translation.},
}

@article {pmid41789852,
year = {2026},
author = {Driscoll, I and Wilson, RE and Johnson, SC and Asthana, S and Gallagher, CL and Hermann, BP and Sager, MA and Carlsson, CM and Blennow, K and Zetterberg, H and Dubal, DB and Okonkwo, OC},
title = {Age-related alterations in plasma biomarkers of relevance to Alzheimer's disease are attenuated in KLOTHO KL-VS heterozygotes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261422411},
doi = {10.1177/13872877261422411},
pmid = {41789852},
issn = {1875-8908},
abstract = {BackgroundThe literature supports an attenuation of unfavorable age-related changes, in both cognitive performance and CSF biomarkers of significance to Alzheimer's disease (AD), in association with a functionally advantageous KLOTHO KL-VS genotype (KL-VSHET).ObjectiveTo examine whether KL-VSHET attenuation of unfavorable age-related biomolecular changes is detectable in AD-relevant plasma biomarkers.MethodsSample consisted of 298 cognitively unimpaired adults (MeanAGE = 65 ± 6.8, 67% female) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies with available data of interest. Covariate (sex, education, APOE4+/- status, parental history of AD)-adjusted multivariate regression examined relationships between age group (Younger (N = 140), Older (N = 158); mean split at age 65) and AD-relevant plasma biomarkers [amyloid-β (Aβ) 42/40, phosphorylated tau (pTau)181, pTau217, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)] and whether these relationships differ for KL-VSHET [N = 86; Younger = 51 (59%), Older = 35 (41%)] compared to non-carriers [KL-VSNC: N = 212; Younger = 89 (42%), Older = 123 (58%)].ResultsIn the pooled sample, older age was associated with less favorable plasma biomarker profiles (all ps ≤ 0.001), except Aβ42 (p = 0.39). When the analyses were stratified by genotype, KL-VSNC continued to exhibit the same age-related pattern of changes in plasma biomarkers (all ps ≤ 0.009; except Aβ42, p = 0.63), which was attenuated in KL-VSHET for Aβ40, Aβ40/42, pTau181, pTau217, and pTau231 (all ps ≥ 0.1).ConclusionsUnfavorable age-associated changes in core AD plasma biomarkers were attenuated in KLOTHO KL-VSHET. KL-VSHET seems to be protective against age-related biomolecular alterations known to confer risk for developing AD.},
}

@article {pmid41789850,
year = {2026},
author = {Yang, Y and Yang, F and Yao, M and Li, L and Li, H},
title = {Decoding the key mechanisms of ferroptosis and inflammation: Emerging therapeutic targets for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427028},
doi = {10.1177/13872877261427028},
pmid = {41789850},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a common progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) deposition leading to the formation of senile plaques and hyperphosphorylation of tau protein resulting in NFTs. Ferroptosis, a newly identified form of programmed cell death, promotes neuroinflammation through mechanisms such as iron metabolism dysregulation, lipid peroxidation, and redox imbalance. Neuroinflammation, in turn, accelerates ferroptotic processes, creating a vicious cycle that drives the progression of neurodegenerative diseases. Recent studies have revealed a close association between ferroptosis and neuroinflammation in AD, and several ferroptosis-targeted agents have shown promising therapeutic effects in AD cell and animal models. This review explores the pathogenesis of ferroptosis in AD and elucidates the mechanistic role of the regulatory interplay between ferroptosis and neuroinflammation in AD, recent advances in ferroptosis-targeted therapeutic strategies are also discussed. Together, these insights may offer new perspectives for treating this devastating disorder.},
}

@article {pmid41789727,
year = {2026},
author = {Lee, J and Cho, Y and Choi, BY and Kim, HK and Lee, Y and Kim, E and Han, J and Sul, JH and Kim, JS and Baek, SH and Cho, Y and Park, J and Bahn, G and Bae, HG and Jun, JH and Lai, MKP and Arumugam, TV and Jo, DG},
title = {HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag089},
pmid = {41789727},
issn = {1460-2156},
abstract = {Alzheimer's disease (AD) is marked by amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation. The β-site APP cleaving enzyme 1 (BACE1) is a key driver of Aβ production, while the NLRP3 inflammasome mediates microglial inflammatory responses. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase, is upregulated in AD, yet its role in disease mechanisms remains unclear. Here, we show that HDAC6 promotes BACE1 protein stability through direct deacetylation of its C-terminal lysine (K501), thereby increasing Aβ production. HDAC6 also facilitated NLRP3 inflammasome activation in microglia, increasing IL-1β production in a catalytic domain-dependent manner. HDAC6 deficiency in 5xFAD mice reduced BACE1 accumulation, Aβ deposition, ASC speck formation, and IL-1β levels, accompanied by improved cognitive performance. Transcriptomic profiling further revealed downregulation of disease-associated microglial and neurotoxic astrocyte signatures alongside enrichment of synaptic pathways. These findings establish HDAC6 as a dual regulator of Aβ production and neuroinflammation, highlighting it as a promising therapeutic target in AD.},
}

@article {pmid41789717,
year = {2026},
author = {Yuste, R},
title = {Neuronal ensembles in cortical function and disease.},
journal = {Physiological reviews},
volume = {},
number = {},
pages = {},
doi = {10.1152/physrev.00003.2025},
pmid = {41789717},
issn = {1522-1210},
support = {RM1NS132981//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01EY035248//HHS | NIH | National Eye Institute (NEI)/ ; R01MH115900//HHS | NIH | National Institute of Mental Health (NIMH)/ ; 2203119//National Science Foundation (NSF)/ ; N000142012828//DOD | USN | Office of Naval Research (ONR)/ ; },
abstract = {Neuronal ensembles, defined as groups of coactive neurons, are physiological modules of the cerebral cortex. Calcium imaging and optogenetics have enabled mapping and manipulating ensembles with single cell resolution in mouse visual cortex, providing evidence of their importance. Ensembles dominate cortical activity, are generated endogenously or by sensory stimulation. Ensembles are imprinted by activating neurons synchronously and can be reactivated by "pattern completion" trigger cells. Intrinsic excitability mediates ensemble coactivation and reactivation, while UP states shield ongoing ensembles from external inputs. Neurons can belong to different ensembles, forming a combinatorial system that encodes visual stimuli accurately and stably. Ensembles contain pyramidal neurons and interneurons and inhibited "offsemble" cells. Cross-inhibition makes ensembles orthogonal from one another, while astrocytic activation increases ensemble occurrence. Ensembles can last for weeks, providing a substrate for long-term information storage, and they capture the recent history of stimulus presentation, implementing short-term memory. Optogenetic manipulation of ensembles demonstrates that they are necessary and sufficient for visual discrimination and perceptual states. Ensembles are altered in mouse models of epilepsy, schizophrenia, Alzheimer's disease, autism spectrum disorders and medically-induced loss of consciousness. An ensemble model of the cortex is proposed in which ensembles are functional units that activate each other via trigger cells and silence non-desired ensembles by cross-inhibition. This generates a map of orthogonal attractor states, forming a computationally powerful memory and processing system. Ensembles are likely involved in many brain diseases, so manipulating them could offer avenues for new therapeutics.},
}

@article {pmid41789706,
year = {2026},
author = {Levin, S and Engel, B and Carlson, C and Hinson, J and Holland, M and Figdore, D and Lim, HK and Tiers, L and Bhatt, K and Schlichtmann, B and Hoffmann, K and Bae, YE and Szabo, M and Lehmann, S and Um, YH and Algeciras-Schimnich, A},
title = {An automated plasma-based proteotyping immunoassay for APOE ε4 zygosity classification in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71143},
doi = {10.1002/alz.71143},
pmid = {41789706},
issn = {1552-5279},
support = {//Beckman Coulter/ ; },
abstract = {INTRODUCTION: Determining apolipoprotein E (APOE) ε4 allele status, a key genetic risk factor for Alzheimer's disease (AD), requires molecular genotyping infrastructure not widely accessible beyond specialized centers.

METHODS: A fully automated high-throughput apoE E4 proteotyping immunoassay was evaluated for clinical performance (460 participants across three cohorts) and analytical validity. Concordance with polymerase chain reaction (PCR)-based genotyping and measures of analytical validity were reported.

RESULTS: The apoE E4 immunoassay demonstrated 99.6% (95% confidence interval [CI]: 98.4% to 99.9%) concordance with PCR-based APOE ε4 genotype results across the pooled clinical cohort; 100.0% (95% CI: 97.1% to 100.0%) in those with AD (N = 127) and 99.4% (95% CI: 97.8% to 99.8%) in those without AD (333). The assay met analytical validity criteria for E4 isoform specificity, interference, precision, and stability.

DISCUSSION: The apoE E4 immunoassay demonstrated high concordance with PCR-based genotyping and robust analytical validity, offering an accessible alternative for APOE ε4 zygosity assessment.

HIGHLIGHTS: A novel high-throughput plasma-based proteotyping immunoassay for APOE ε4 zygosity classification was developed and evaluated for clinical performance and analytical validity. The apoE E4 immunoassay demonstrated high concordance (99.6%) with PCR-based APOE ε4 genotyping across a diverse international cohort, and a robust analytical profile. An apoE E4 immunoassay may offer a more cost-effective and accessible alternative to DNA genotyping approaches currently used for AD risk evaluation and anti-amyloid treatment decisions.},
}

@article {pmid41789587,
year = {2026},
author = {Talmasov, D and Santillo, AF and Hof, PR},
title = {Von Economo Neuron Loss in Frontotemporal Dementia: A Meta-Analysis of Neuropathological Studies.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70362},
pmid = {41789587},
issn = {2328-9503},
support = {25AACSF-1411581/ALZ/Alzheimer's Association/United States ; P30AG066514/AG/NIA NIH HHS/United States ; 5T32MH020004/MH/NIMH NIH HHS/United States ; },
abstract = {Von Economo neurons (VENs) have been reported to be vulnerable to neurodegeneration in frontotemporal dementia (FTD), particularly the behavioral variant (bvFTD), but these findings have not been systematically assessed across independent brain banks. We conducted a meta-analysis of neuropathological studies measuring VEN density in the anterior cingulate cortex or frontoinsular cortex in FTD using random-effects models with cluster-robust variance estimation. Seven studies (135 FTD, 68 controls) from four international brain banks showed significantly reduced VEN density in FTD with a large effect size (g = -1.45, 95% CI [-1.69, -1.21], p < 0.001) and remarkable consistency (I[2] = 0%). VEN loss was greater in FTD than Alzheimer's disease and occurred across TDP-43 and tau pathological subtypes.},
}

@article {pmid41789476,
year = {2026},
author = {Rajicic, A and Mol, MO and Melhem, S and Kisic, H and van Swieten, JC and Seelaar, H and van Rooij, JGJ},
title = {Transcriptomic signature of frontotemporal lobar degeneration with TDP-43 type C pathology.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag085},
pmid = {41789476},
issn = {1460-2156},
abstract = {Semantic variant of primary progressive aphasia is a clinical subtype of frontotemporal lobar degeneration and is marked by TDP-43 subtype C pathology (FTLD-TDP C). It is a sporadic disease, yet has a strikingly homogeneous clinicopathological presentation, suggesting a common pathophysiology. The aim of this study was to discover dysregulated pathways in FTLD-TDP C through transcriptomics of the temporal cortex, its most affected region. Bulk RNA sequencing was conducted on temporal cortices of a post-mortem cohort of 18 FTLD-TDP C patients and 23 sex- and age-matched controls. Differential expression and functional analyses were run to detect differentially expressed genes with FDR<0.05 (DEG) and functionally annotate them. We assessed enrichment of TARDBP's protein interactors and RNA targets in DEG. Our findings were compared to other published RNA sequencing data of tauopathies (Alzheimer's dementia, progressive supranuclear palsy and FTLD with MAPT), FTLD-TDP (subtypes A&B) and available proteomics of this cohort. Furthermore, we performed weighted gene co-expression network analysis (WGCNA). We adjusted for differences in cell type composition between cases and controls using cell deconvolution, and removed genes dysregulated in temporal cortices of other datasets. In DEG of FTLD-TDP we focused on enrichment of synaptic processes using SynGO. We found upregulation of damage response, cell structure, RNA splicing processes and downregulation of synaptic processes in 6322 DEG and five disease-related WGCNA modules. TARDBP-related genes were enriched in DEG. Additionally, transmembrane transport across the neurovascular unit was dysregulated. After cell deconvolution and removal of common tau-genes, postsynaptic processes remained dysregulated, specifically gene ontology terms 'modulation of chemical synaptic transmission' and 'neurotransmitter receptor localisation to postsynaptic specialisation membrane'. We found eleven synaptic FTLD-TDP C-specific genes affected on both RNA- and protein-level in the temporal cortex, which were involved in synaptic adhesion (CADM1, NCAN), signal transmission (COMT, RGS144, SLC1A2, TUBB2B) and synaptic plasticity (BEGAIN, ITPKA, LRFN1, RAB3B, SYNPO). In conclusion, a wide range of processes were dysregulated on RNA-level in the temporal cortex of FTLD-TDP C, including commonly affected processes in neurodegeneration, such as structural cell alterations. Dysregulation of TARDBP-related genes and RNA splicing has also been observed in other TDP-43 proteinopathies. Importantly, we found that postsynaptic processes were downregulated in FTLD-TDP C, after removing tauopathy-related genes and after cell deconvolution. In particular, assembly of receptors at the postsynaptic membrane and synaptic signal transmission were affected, both on RNA and protein level. Future research on these pathways could elucidate distinct pathophysiological mechanisms and guide targeted clinical approaches.},
}

@article {pmid41789119,
year = {2026},
author = {Höglinger, G and Vandenberghe, W and Woitalla, D and Corvol, JC and Van Tricht, H and Ewen, C and Van Den Steen, B and Rebollo Mesa, I and Germani, M and Garric, E and Arnould, T and Jose, J and Strong, N and De Bruyn, S and Buchanan, TJ},
title = {Safety, tolerability and biomarker results of bepranemab in participants with progressive supranuclear palsy: a randomised, multicentre, double-blind, placebo-controlled, phase 1b trial.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001396},
pmid = {41789119},
issn = {2632-6140},
abstract = {BACKGROUND: Preclinical evidence suggests targeting the mid-region of tau as a viable therapeutic strategy in diseases such as progressive supranuclear palsy (PSP): a rare, fatal, neurodegenerative tauopathy with no currently approved treatments. Bepranemab is a recombinant, humanised, full-length immunoglobulin G4 monoclonal antibody binding to a mid-region tau epitope. We assessed safety, tolerability and pharmacokinetics of bepranemab in participants with PSP.

METHODS: PSP003 (NCT04185415), a multicentre, double-blind, placebo-controlled, phase 1b study, recruited participants in hospital settings across 13 centres. Participants (aged ≥40 years) met Movement Disorder Society-PSP criteria for possible/probable PSP, could walk ≥5 steps with minimal/no assistance and were stable on treatment for ≥2 weeks prior to baseline. Participants were randomised 3:1 to receive intravenous bepranemab (90 mg/kg) or placebo every 4 weeks for 52 weeks. Primary endpoint: incidence of treatment-emergent adverse events (TEAEs) from baseline to last visit.

RESULTS: Twenty-five participants were enrolled (male: 44%; bepranemab n=18, placebo n=7). Seventeen (94.4%) in the bepranemab group reported ≥1 TEAE (five participants; ten investigational medicinal product (IMP)-related TEAEs), versus placebo (n=7; 100%). In the bepranemab and placebo groups, respectively, three participants (16.7%) and one participant (14.3%) discontinued due to TEAEs. Incidence of IMP-related TEAEs and severe TEAEs was similar between groups; no deaths were reported. Reduction (80.41%) in mean free tau cerebrospinal fluid levels was observed in the bepranemab group.

CONCLUSIONS: Multiple doses of bepranemab 90 mg/kg were well tolerated with an acceptable safety profile in participants with PSP. High target occupancy was observed.},
}

@article {pmid41789102,
year = {2026},
author = {Wang, T and Liu, X and Wang, X and Hua, F and Yan, L},
title = {TREM2 and microglial immunity in Alzheimer's disease: mechanisms, genetics, and therapeutic opportunities.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1739875},
pmid = {41789102},
issn = {1664-3224},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder of innate immune dysregulation within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2), a microglial immunoreceptor, has emerged as a pivotal genetic risk factor for late-onset AD, underscoring the critical role of neuroimmune interactions in disease pathogenesis. This review synthesizes recent advances concerning TREM2's modulation of core microglial functions, including phagocytosis, inflammatory signaling, cellular metabolism, and survival, processes that are essential for responding to amyloid-β plaques and neuronal damage. We highlight the TREM2-APOE pathway as a central mechanism driving the disease-associated microglia (DAM) phenotype and examine how loss-of-function mutations such as R47H disrupt immune surveillance, aggravate amyloid pathology, and promote neuroinflammation. Additionally, we explore the diagnostic and therapeutic potential of soluble TREM2 (sTREM2) and TREM2-targeted immunotherapies, which enhance plaque encapsulation and cognitive outcomes in preclinical models. By integrating genetic, molecular, and clinical evidence, this review establishes TREM2 as a keystone regulator linking amyloidosis, tauopathy, and neuroinflammation, highlighting its promise as a target for disease-modifying therapies.},
}

@article {pmid41788972,
year = {2026},
author = {Distefano, A and Calcagno, D and Grasso, G and Monasson, O and Peroni, E and Oliveri, V},
title = {Tolcapone Interferes With Key Pathological Features in Alzheimer's Disease.},
journal = {Bioinorganic chemistry and applications},
volume = {2026},
number = {},
pages = {1036276},
pmid = {41788972},
issn = {1565-3633},
abstract = {Tolcapone, a clinically approved drug for the treatment of Parkinson's disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid-β aggregation and toxicity, which are hallmark features of Alzheimer's disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age-related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid-β and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal-amyloid-β species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper-free amyloid-β and copper-associated amyloid-β complexes, using a combination of techniques including UV-vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid-β monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid-β for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal-free and metal aggregation pathways by preventing metal coordination to amyloid-β or disrupting preformed amyloid-β-metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.},
}

@article {pmid41788921,
year = {2026},
author = {Raj, AP and Simon, M and Bhat, RM and Vaishnav, R and Al Siyabi, MY and Al Maamari, YI and Amr, M},
title = {Knowledge, awareness, and practice of undergraduate medical students on Alzheimer's disease and dementia in Oman.},
journal = {Journal of education and health promotion},
volume = {15},
number = {},
pages = {16},
pmid = {41788921},
issn = {2277-9531},
abstract = {BACKGROUND: Dementia is an acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. Alzheimer's disease is the most common type of dementia, which accounts for 60% to 70% of cases. There are no accurate statistics yet on the percentage of Alzheimer's patients in Oman, and it is expected that the number of patients with this disease will increase. Medical students are exposed to different aspects of Alzheimer's disease very late in their medical curriculum. Early exposure to the disease will increase the level of awareness and interest in the disease. The study might also help in the curricular changes in terms of integration of Dementia-related topics in neurobiology and other relevant preclinical courses. To assess first-year medical students' knowledge and attitude toward Alzheimer's disease and related dementias.

MATERIALS AND METHOD: A cross-sectional survey was carried out among first-year students at the College of Medicine and Health Sciences, National University, Oman, after getting their consent. The sociodemographic data will be collected from the students initially. We also adapted components from the published and previously tested Alzheimer's Disease Knowledge Scale, the Alzheimer's Disease Awareness Scale, and the Dementia Attitudes Scale, in addition to incorporating questions to specifically assess the local practices related to management of the disease.

RESULTS: 127 students participated in the study. 82.7% were females (n = 105), and 17.3% (n = 22) were males. The average age of participants was 19.30 years (SD = 0.769). In our sample, 54.4% of the respondents had correctly identified that loss of memory and forgetting names, appointments, and task repetition in the elderly need medical attention. Approximately half of the students, 47.6%, disagreed that Alzheimer's disease could be caused by black magic or evil eye. As a whole, 53.1% of participants were against hiding diagnoses and advocated for transparency. On the other hand, 73.4% of participants expressed strong disapproval of socially isolating Alzheimer's disease patients to prevent them from experiencing personal embarrassment. 56.7% of the students acknowledged the possibility that certain foods, such as fish, leafy greens, and berries, could reduce the chance of developing Alzheimer's disease. There is a moderate tendency toward belief in the existence of traditional remedies in Oman (45.3%), according to the data, which indicate that there is a mixed assessment of the availability of traditional remedies in Oman.

CONCLUSION: The study indicates a well-informed understanding of Alzheimer's disease and dementia within the studied community, especially concerning dietary influences and the possibilities of medicinal interventions. The divergent opinions on standard and alternative medicines suggest that additional education and study could be advantageous. As Alzheimer's disease research progresses, continuous public education initiatives will be essential to align attitudes with the most recent scientific findings and accessible treatment alternatives.},
}

@article {pmid41788860,
year = {2026},
author = {Mehmood, A and Farman, M and Afzal, F and Nisar, KS and Ahmed, MA and Hafez, M},
title = {A Physics Informed Neural Network (PINN) framework for fractional order modeling of Alzheimer's disease.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1748481},
pmid = {41788860},
issn = {1662-5196},
abstract = {This study presents a novel fractional order model of Alzheimer's disease (mental disorder) using the Caputo derivative to accurately capture long term memory and hereditary effects in neurodegeneration. The mathematical model incorporates key pathological constituents including neurons, amyloid beta (A β), tau proteins and microglial responses, allowing detailed simulation of their dynamic interactions. Fundamental properties of the model, including positivity, boundedness, invariant regions and equilibrium points, are rigorously analyzed to ensure biological feasibility. Sensitivity analysis identifies amyloid toxicity as the most influential driver of neuronal loss underscoring its central role in AD progression. Furthermore, a Physics Informed Neural Network (PINN) is developed to approximate system dynamics from noisy observations while ensuring compliance with biological and physical constraints. Compared to standard neural networks the PINN exhibits superior accuracy and robustness especially under data scarcity. By integrating fractional calculus, optimal control and machine learning, this work advances computational modeling of Alzheimer's disease and offers insights into therapeutic optimization.},
}

@article {pmid41788548,
year = {2026},
author = {Zheng, Y and Zhou, W and Chang, H and Zheng, K},
title = {Brain organoids as precision models for neurodegenerative diseases: from disease modeling to drug discovery.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1764964},
pmid = {41788548},
issn = {1662-4548},
abstract = {Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have become major global causes of disability and mortality. Their complex pathogenic mechanisms remain incompletely understood, and effective disease-modifying therapies are still lacking. Traditional animal models and two-dimensional (2D) cell culture systems exhibit notable limitations in structural complexity, human relevance, and translational validity, making it difficult to faithfully recapitulate human-specific neuropathology. In recent years, brain organoid technology derived from induced pluripotent stem cells (iPSCs) has advanced rapidly, enabling the self-organization of diverse neuronal and glial cell types within a three-dimensional (3D) architecture that partially mimics human brain development and disease-related pathological events. When integrated with CRISPR-Cas9-based genome editing and multi-omics profiling, organoids support causal mechanism studies, target validation, and individualized drug-response prediction, highlighting their growing value in early-stage drug discovery. Despite current challenges-including insufficient maturation, lack of vascularization and immune components, and batch variability-the continuous progress in bioengineering, microfluidic systems, and artificial intelligence (AI)-driven multimodal data analysis is steadily expanding the translational potential of organoids as human-relevant preclinical models. Overall, brain organoids provide an essential foundation for constructing physiologically relevant and predictive research platforms for neurodegenerative diseases, offering new opportunities for therapeutic development and precision medicine.},
}

@article {pmid41788409,
year = {2026},
author = {Chen, R and Fan, S and Di, C and Wu, H and Shi, Z and Liu, F and Lv, Z and Liu, S and Ji, Y},
title = {Insulin resistance (TyG index) and body mass index as metabolic biomarker combined with ApoE genotype to diagnose Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1731547},
pmid = {41788409},
issn = {1663-4365},
abstract = {BACKGROUND: Growing evidence suggests that both ApoE genotype and metabolic disturbances including insulin resistance (IR) and obesity constitute risk factors for Alzheimer's disease (AD). However, large-scale studies investigating whether ApoE genotype interacts with metabolic abnormalities to indirectly impair cognitive function in AD remain scarce.

OBJECTIVE: This cross-sectional study aimed to explore the associations between ApoE genotype, metabolic disturbances [IR assessed by triglyceride-glucose (TyG) index and body mass index (BMI)], and cognitive function in AD patients.

METHODS: We analyzed 1,162 clinically diagnosed probable AD patients from the Cognitive Impairment Clinic at Tianjin Huanhu Hospital. Participants were categorized by ApoE ε4 carrier status. Metabolic parameters were evaluated using the TyG index and BMI. Mediation effect models were employed to assess the relationships between ApoE genotype, metabolic indices, and cognitive function.

RESULTS: ApoE ε4 carriers exhibited significantly lower BMI (P < 0.001) and higher TyG index (P < 0.001) compared to non-ApoE ε4 carriers. Significant TyG index elevation in ApoE ε4 carriers was observed in AD patients with Mini-Mental State Examination (MMSE) > 20 (P = 0.0036) and MMSE 10-20 (P = 0.009). Mediation analysis revealed that ApoE ε4 exerted 73.4% of its negative effect on cognition through direct pathways, while 9.7 and 16.9% were mediated through BMI reduction and TyG elevation, respectively.

CONCLUSION: ApoE ε4 carriers demonstrate a distinct metabolic profile characterized by lower BMI and elevated TyG index, associated with poorer cognitive performance. Our findings suggest that ApoE ε4 may indirectly influence AD cognition through metabolic pathways, highlighting early interventions targeting ApoE-related metabolic dysregulation as potential strategies to delay AD progression.},
}

@article {pmid41788296,
year = {2026},
author = {Guo, ZL and Cui, MW and Dong, YL and Wang, S},
title = {The oral microbiome as a regulatory hub for systemic health: a systematic review of mechanistic links and clinical implications.},
journal = {Journal of oral microbiology},
volume = {18},
number = {1},
pages = {2635233},
pmid = {41788296},
issn = {2000-2297},
abstract = {BACKGROUND: The human oral microbiome is a highly diverse ecosystem with important roles in oral and systemic health. Beyond dental caries and periodontitis, oral dysbiosis has been increasingly implicated in the development of multiple non-communicable diseases.

OBJECTIVE: To systematically synthesize evidence on the mechanisms linking oral dysbiosis to systemic diseases and to summarize its diagnostic and therapeutic implications.

DESIGN: A systematic review was performed using major electronic databases. We screened 1,128 records and included 104 studies that met predefined eligibility criteria.

RESULTS: Evidence indicates that oral dysbiosis may influence systemic health through several mechanisms, including hematogenous dissemination of oral pathogens and virulence factors (e.g. lipopolysaccharide), chronic systemic inflammation, molecular mimicry in autoimmune disorders, and microbial metabolic byproducts. The reviewed studies support associations between oral microbiome alterations and atherosclerotic cardiovascular disease, type 2 diabetes, Alzheimer's disease, rheumatoid arthritis, and gastrointestinal cancers. The literature also highlights the promise of non-invasive oral microbiome-based biomarkers for early detection and disease monitoring. Emerging microbiome-modulating interventions, including probiotics, prebiotics, and bacteriophage therapy, show potential for restoring oral eubiosis and improving systemic outcomes.

CONCLUSIONS: Oral dysbiosis is an important regulator of systemic disease processes and a promising target for diagnosis, prevention, and therapy. Integrating oral health and oral microbiome assessment into broader disease management may improve outcomes, although methodological standardization and stronger causal evidence are still needed.},
}

@article {pmid41788194,
year = {2026},
author = {Municio, C and Sapidou, K and Apsley, EJ and Fernandez-Otero, M and Arber, CE and Wray, S and Carro, E and Pellegrini, L},
title = {Choroid plexus organoids mimic amyloid uptake at the blood-cerebrospinal fluid-barrier.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1769911},
pmid = {41788194},
issn = {1662-5102},
abstract = {The choroid plexus (ChP) is a specialised tissue of the central nervous system that produces cerebrospinal fluid (CSF), maintains cerebral homeostasis and forms the blood-CSF barrier (B-CSF-B), a key interface that regulates the exchange of substances between the blood and the brain. Despite its physiological importance, the involvement of the ChP in neurodegenerative diseases such as Alzheimer's disease (AD), remains poorly understood. This is largely due to the reliance on murine models and the limited availability of human brain tissue. Recent advances in human stem-cell derived ChP organoids now offer a more physiologically relevant model to interrogate ChP role in human health and disease. Given that in AD pathology beta-amyloid (Aβ) accumulation has been linked to early disruption of brain barriers, studying the B-CSF-B is particularly relevant. Transthyretin (TTR), the predominant protein secreted by the ChP, is thought to play a role in the transport and clearance of Aβ, although its exact mechanisms are not yet fully elucidated. Here, we propose the use of ChP organoids to investigate the role of the B-CSF-B in amyloid uptake which may contribute to barrier dysfunction and disease progression in AD.},
}

@article {pmid41788190,
year = {2026},
author = {Matsuura, S and Tagai, K and Tatebe, H and Goto, R and Matsumoto, H and Oyama, A and Momota, Y and Ichihashi, M and Kataoka, Y and Matsuoka, K and Kokubo, N and Kamada, T and Osawa, K and Chishiki, Y and Moriguchi, S and Komatsu, Y and Seki, C and Takahata, K and Endo, H and Kudo, T and Higuchi, M and Tokuda, T},
title = {Comparison of three plasma p-tau217 assays to detect PET-confirmed Alzheimer's pathologies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70294},
pmid = {41788190},
issn = {2352-8729},
abstract = {INTRODUCTION: Plasma phosphorylated tau 217 (p-tau217) has emerged as a promising blood-based biomarker for Alzheimer's disease (AD) diagnosis, but cross-platform comparability remains unclear. We evaluated three platforms-single-molecule array (Simoa), Ella, and Lumipulse.

METHODS: We measured plasma p-tau217 from 113 participants underwent amyloid and tau positron emission tomography (PET; 55 AD, 36 controls, 22 non-AD; classified by amyloid PET status). Diagnostic performance and PET correlations were assessed across all three platforms.

RESULTS: All assays distinguished amyloid-positive from -negative individuals with high accuracy (89%-95%). Simoa showed superior sensitivity, Ella the smallest gray zone in a two-cutoff framework, and Lumipulse strongest tau correlation (r = 0.770). Multiple regression revealed higher amyloid β-values for Simoa/Ella (0.420-0.518) and higher tau β-values for Lumipulse (0.630). All platforms detected elevated p-tau217 in amyloid-positive individuals with substantial tau pathology despite relatively low Centiloid.

DISCUSSION: All platforms accurately detect AD with platform-specific differences, which inform platform selection for clinical and research applications.

TRIAL REGISTRATION: Clinical Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR), Trial ID: UMIN000057548, Registration Date: April 8, 2025.},
}

@article {pmid41788162,
year = {2026},
author = {Tomlin, M and Podpolny, M and Salinas, PC},
title = {Progressive changes in synapses and glial cells in App[NL-G-F] mice, a model of Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {1},
pages = {fcaf484},
pmid = {41788162},
issn = {2632-1297},
abstract = {It is well documented that synapse loss correlates with cognitive decline in Alzheimer's disease. However, the mechanisms that contribute to synapse loss remain poorly understood. Studies have shown that amyloid-β directly signals to neurons to trigger changes in synaptic function leading to the subsequent loss of synapses. Other studies have demonstrated that glial cells directly target synapses in Alzheimer's disease. In this study, we determine the temporal relationship between changes in synapses and glial cells (microglia and astrocytes) in the NL-G-F knock-in mouse model of Alzheimer's disease. We evaluated synapse number and histological changes in glial cells in the hippocampus of NL-G-F mice using confocal microscopy across three timepoints, 2, 5, and 9 months, compared to their wild-type littermates. Using real-time quantitative PCR, we also evaluated molecular changes in glial cells. At 2 months of age, when very few amyloid-β plaques are present, inhibitory synapse number was transiently increased by more than 50% in NL-G-F mice, accompanied by a small increase in the microglial marker, Cx3cr1, and considerable changes in astrocyte markers, including a decreased level of Thbs1/2. At 5 months, when amyloid-β plaque load is notable, excitatory synapse number was decreased immediately proximal to plaques, whereas inhibitory synapse number was no different between NL-G-F and wild-type mice. At the cellular level, changes in microglia and astrocytes were also observed in NL-G-F mice in regions closely surrounding plaques. From 5 months, PCR analyses indicated marked and progressive changes in microglia and astrocyte markers, including increased Trem2 and Gfap expression. By 9 months, changes in excitatory synapse number and microglia at the cellular level were exacerbated, with evident synapse loss extending up to 30 µm away from plaques. Together, our data show that inhibitory synapses are the earliest change in NL-G-F mice occurring concomitantly with molecular changes in glial cells and preceding substantial plaque deposition, excitatory synapse loss, and glial cellular alterations.},
}

@article {pmid41788154,
year = {2026},
author = {Wu, Y and Mai, N},
title = {Structural Alterations and Cognitive Impairment in Late-Onset Depression: A Reverse Correlation Analysis.},
journal = {Alpha psychiatry},
volume = {27},
number = {1},
pages = {44585},
pmid = {41788154},
issn = {2757-8038},
abstract = {BACKGROUND: Late-onset depression (LOD), particularly when accompanied by cognitive impairment, represents a significant risk factor for dementia. Prevailing perspectives emphasize that cognitive impairment arises from interactions among multiple brain regions. However, current approaches to identifying brain network patterns associated with cognitive impairment largely rely on group-level analyses with multiple-comparison corrections, which may obscure complex and interconnected relationships between brain regions. Our previous research demonstrated that alterations in brain network properties in patients with LOD are closely associated with cognitive function. We therefore hypothesised that aberrant interactions among multiple brain regions in LOD lead to changes in network properties and subsequent cognitive dysfunction.

METHODS: This study aimed to investigate the interregional brain interactions underlying cognitive impairment in LOD by leveraging the robust interpretability of neural network models. Specifically, we sought to: (1) develop a neural network model of LOD-related cognitive impairment based on brain network properties; and (2) apply a reverse correlation approach to identify connectivity features associated with cognitive impairment in LOD.

RESULTS: No statistically significant differences were observed in tthe structural network properties when comparing the LOD and control participant groups across various thresholds. Using a neural network-based reverse correlation method, the most prominent differences were identified in the inferior, middle, and anterior regions of the left temporal pole when comparing patients with LOD with and without mild cognitive impairment (MCI).

CONCLUSION: Alterations in the internal structure of the temporal lobe may represent potential anatomical biomarkers for the early prediction of Alzheimer's disease, providing novel insights into the pathophysiological mechanisms underlying LOD-related MCI. The research framework proposed in this study effectively addresses the challenge of detecting subtle intergroup anatomical differences in studies with limited sample sizes. Moreover, the reverse correlation approach is not restricted to multilayer neural networks; as machine learning models become increasingly powerful and accessible, this method offers a practical and interpretable alternative for exploratory neuroimaging research.},
}

@article {pmid41788046,
year = {2026},
author = {Ledingham, D and Sathyanarayana, S and Stewart, CB and Iredale, R and Foster, V and Galley, D and Lad, M and Baker, MR and Pavese, N},
title = {Alzheimer's Biomarkers and Visuospatial Cognition in Parkinson's Disease: Modification by α-Synuclein and Mediation of Age Effects.},
journal = {Movement disorders clinical practice},
volume = {},
number = {},
pages = {},
doi = {10.1002/mdc3.70576},
pmid = {41788046},
issn = {2330-1619},
abstract = {BACKGROUND: Visuospatial deficits in Parkinson's disease (PD) often precede dementia and complicate daily functioning. Alzheimer's disease (AD) pathology and α-synuclein aggregation frequently co-occur in PD, but their combined impact on cognition is unclear.

OBJECTIVES: To examine whether AD biomarker burden relates to visuospatial performance in PD, whether this effect differs by α-synuclein status, and whether AD biomarkers mediate age-related decline.

METHODS: We analyzed 416 participants from the Parkinson's Progression Markers Initiative. AD biomarker burden was indexed by the cerebrospinal fluid pTau181/Aβ42 ratio; α-synuclein aggregation was assessed using seed amplification assay. Models adjusted for age, sex, education, and motor severity. Sensitivity analyses included genetic stratification and subgroup exclusion.

RESULTS: Higher AD biomarker burden was associated with poorer visuospatial performance and delayed recall. In participants with concurrent biomarker data (n = 246), AD burden interacted with α-synuclein status to predict worse visuospatial outcomes, with the greatest impairment observed in individual's positive for both biomarkers. Mediation analysis indicated that AD biomarker burden accounts for approximately 10-14% of the age effect on visuospatial performance.

CONCLUSIONS: AD and α-synuclein biomarkers show associations consistent with synergistic effects on visuospatial cognition in PD. These findings are exploratory and require replication in pre-specified independent cohorts. However, if validated, testing both biomarkers could help identify individuals at higher risk of early visuospatial decline and inform hypothesis-driven stratification in future clinical trials.},
}

@article {pmid41787981,
year = {2026},
author = {Huang, T and Zhang, M and Zhang, Y and Su, C and He, E and Wang, J and Yang, J and Liu, Y and Zeng, Y and Chen, X},
title = {Hippocampal Hap1 downregulation exacerbates Alzheimer's disease-related neuropathology through impairment of glucocorticoid receptor nuclear translocation in APP/PS1 mice.},
journal = {Zoological research},
volume = {},
number = {},
pages = {},
doi = {10.24272/j.issn.2095-8137.2025.436},
pmid = {41787981},
issn = {2095-8137},
abstract = {Although impaired nuclear translocation of glucocorticoid receptor (GR) contributes to hippocampal vulnerability in Alzheimer's disease (AD), its regulatory mechanisms remain poorly understood.Here, we identify Huntingtin-associated protein 1 (Hap1) as a critical regulator of GR nuclear translocation in the hippocampus. Specifically, Hap1 expression progressively declines in the APP/PS1 mouse hippocampus with aging and pathological progression. Hippocampal Hap1 knockdown induces cognitive deficits and synaptic loss, manifested as reduced dendritic complexity and spine density alongside impaired long-term potentiation (LTP), while exacerbating Aβ deposition in APP/PS1 mice. Crucially, Hap1 deficiency promotes GR ubiquitination and proteasomal degradation and, more critically, disrupts ligand-dependent GR nuclear translocation, thereby impairing GR-dependent BDNF transcription. Additionally, Hap1 knockdown elevates corticosterone levels and induces depressive-like behaviors, confirming hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Our results establish disruption of Hap1-mediated GR nuclear translocation as a key pathomechanism linking intracellular transport defects to synaptic failure in AD, suggesting Hap1 modulation as a potential therapeutic avenue.},
}

@article {pmid41787940,
year = {2026},
author = {Conti, M and Teghil, A and Schettino, M and D'Antonio, F and Sepe Monti, M and Talarico, G and Bruno, G and Di Vita, A and Alessandri, G and Guariglia, C and Boccia, M},
title = {Subtle alterations of autobiographical memory and spatiotemporal processing in subjective cognitive decline.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/13803395.2026.2637509},
pmid = {41787940},
issn = {1744-411X},
abstract = {INTRODUCTION: The deterioration of autobiographical memory (AM) and autonoetic consciousness is central in Alzheimer's Disease (AD). Here, we investigated the presence of AM alterations in a potential preclinical stage of AD known as Subjective Cognitive Decline (SCD), characterized by a self-reported worsening in cognitive functioning without an objective cognitive impairment. Considering the key role of spatial and temporal components in episodic features of AM, we further hypothesized that alterations in such components may be highlighted in SCD, and investigated possible modifications in these functions with tasks tapping environmental navigation and duration processing. Finally, the level of cognitive complaints was also considered a factor that may modulate performance.

METHOD: Performance of 31 individuals with SCD was compared with that of 31 healthy control participants matched for age, gender, and education. AM was assessed using the Autobiographical Interview and the Autobiographical Fluency Task (AFT). Environmental navigation was investigated using a battery assessing route, landmark, and survey knowledge, and landmark ordering. Temporal processing was assessed with computerized tasks investigating retrospective and prospective duration processing.

RESULTS: SCD produced more items in the personal semantics condition of the AFT compared with healthy controls, while showing reduced performance in landmark recognition and survey knowledge. When considering cognitive complaints, which are known to play a role in modulating performances in SCD, results showed a positive association between scores on the Cognitive Failure Questionnaire and scores on the semantic condition of the AFT, and a significant negative correlation between scores on the Cognitive Failure Questionnaire and performance in retrospective duration processing.

CONCLUSIONS: Findings suggest that subtle alteration of AM and spatiotemporal processing can be identified in SCD, and that the level of cognitive complaints may be a relevant factor in modulating spatiotemporal processing and autobiographical memory in this population.},
}

@article {pmid41787649,
year = {2026},
author = {Seok, J and Lee, H and Seo, J},
title = {Investigating the Causal Links between the Aging Process and Alzheimer's Disease Pathogenesis.},
journal = {International journal of stem cells},
volume = {},
number = {},
pages = {},
doi = {10.15283/ijsc25100},
pmid = {41787649},
issn = {2005-3606},
abstract = {As global societies age, the prevalence of neurodegenerative disorders, such as Alzheimer's disease, is rapidly increasing, intensifying the need to understand the mechanisms of aging and their contribution to these conditions. Consequently, the focus of aging research has shifted from the traditional concept of chronological age to a more nuanced understanding of biological age. This has spurred active investigation into robust biomarkers, including cellular senescence. However, the application of classical senescence markers to the brain presents a substantial challenge, as their validity in post-mitotic cells, such as neurons, remains unclear. In this review, we highlight the limitations of the current metrics for cellular senescence as indicators of biological aging, and propose a path forward focused on identifying and modeling cell-type-specific aging markers within the brain.},
}

@article {pmid41787549,
year = {2026},
author = {Tan, YJ and Mohammadi, R and Saffari, SE and Tan, NI and Lim, LS and Low, SH and Tan, LC and Chiew, HJ and Ng, KP and Hameed, S and Ting, SK and Ng, AS},
title = {Evaluating the real-world performance of plasma pTau217 and pTau181 in a Southeast Asian tertiary memory clinic.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02008-5},
pmid = {41787549},
issn = {1758-9193},
support = {MOH-CNIG22jul-0006//National Medical Research Council/ ; MOH-OFLCG18May-0002//National Medical Research Council/ ; MOH-CSAINV21-0005, NMRC/CG2/005a/2022-NNI//National Medical Research Council/ ; SHF(U)/22/GC-5C/007(EC), SHF(U)/23/GC-2C/002(EC)//SingHealth Fund- NNI Fund/ ; },
}

@article {pmid41787516,
year = {2026},
author = {Horikoshi, K and Nakajima, M and Miyajima, M and Miyahara, R and Sakamoto, K and Kawamura, K and Akiba, C and Kamohara, C and Ogino, I and Tsunemi, T and Karagiozov, K and Kondo, A},
title = {Plasma p-Tau217 and amyloid-β oligomers as complementary biomarkers for differential diagnosis, comorbidity detection and disease monitoring in idiopathic normal pressure hydrocephalus.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00784-8},
pmid = {41787516},
issn = {2045-8118},
support = {22GB1002//Juntendo Research Branding Project, Health, Labor and Welfare Sciences Research Grants/ ; 20K09355, 20K09398, and 24K10497//Japan Society for the Promotion of Science under Grants-in-Aid for Scientific Research/ ; },
}

@article {pmid41787435,
year = {2026},
author = {Bermudez, C and Hofrenning, E and Fought, AJ and Gunter, JL and Cogswell, PM and Jones, DT and Schwarz, CG and Lowe, V and Elder, BD and Petersen, RC and Vemuri, P and Algeciras-Schimnich, A and Mielke, MM and Knopman, DS and Graff-Radford, NR and Jack, CR and Graff-Radford, J},
title = {Plasma biomarkers of Alzheimer's disease and their association with disproportionately enlarged subarachnoid space hydrocephalus.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00789-3},
pmid = {41787435},
issn = {2045-8118},
support = {P30 AG062677/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; RF1 AG069052/AG/NIA NIH HHS/United States ; },
}

@article {pmid41787238,
year = {2026},
author = {Mayeri, Z and Woods, G and Rane, A and Kifle, A and Chamoli, M and Shukla, S and Walton, CC and Andersen, JK},
title = {A compound enhancing lysosomal function reduces tau pathology, microglial reactivity and rescues working memory in 3xTg AD mice.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41787238},
issn = {2509-2723},
support = {R01AG067325/AG/NIA NIH HHS/United States ; },
abstract = {Recent advancements in Alzheimer's disease (AD) therapeutics have validated the use of amyloid beta (Aβ)-clearing antibodies, which reduce Aβ pathology but leave other disease hallmarks largely unaddressed. Since AD involves multiple pathological processes, additional strategies are needed to target complementary mechanisms. One such target is autophagy, a lysosomal mediated degradation pathway essential for cellular homeostasis that removes toxic protein aggregates and damaged organelles. This process is implicated in AD, as impaired lysosomal function promotes Aβ and tau accumulation. Our laboratory recently identified a novel natural mitophagy inducing compound (MIC) that may serve as a therapeutic intervention for AD. We evaluated the effects of MIC in aged 3xTgAD mice, a transgenic model displaying both Aβ and tau pathology. Mice received either standard diet or diet containing MIC beginning at age 4 months until 20 months on alternating weeks. Age-matched non-transgenic (NonTg) controls were included under standard and MIC-supplemented diets to assess compound effects during normal aging. Neuropathological changes were assessed using immunohistochemistry (IHC) for Aβ, phosphorylated tau (pTau), and microglial reactivity. Cognitive performance was evaluated using the Morris Water Maze (MWM) to assess spatial learning and memory and the Y-maze to measure working memory. At 20 months of age, our neuropathological assessment showed that 3xTgAD mice fed an MIC-supplemented diet had a significant reduction in pTau accumulation and microglial reactivity, although Aβ burden remained unchanged. At 15 months, MIC diet also improved spatial learning and memory in aged NonTg controls but not in 3xTgAD mice. However, in younger 8 month-old 3xTgAD mice, MIC restored working memory performance to NonTg levels, indicating an age-dependent therapeutic response. MIC emerges as a potential modulator of tau pathology and neuroinflammation. As a naturally derived compound, MIC offers potential for combination therapy with FDA-approved Aβ-clearing antibodies, enabling a multimodal approach to AD treatment that addresses amyloid, tau, and microglia-related pathology.},
}

@article {pmid41787187,
year = {2026},
author = {Zhu, Z and Ni, M and Lv, X and Peng, J and Gao, F and Pan, B and Shen, Y and Wang, S and Shi, J},
title = {Regional cerebral hypometabolism and pathological heterogeneity in sporadic early onset alzheimer's disease: China Aging and Neurodegenerative Initiative (CANDI) study.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {41787187},
issn = {1619-7089},
support = {XDB39000000//the Strategic Priority Research Program of the Chinese Academy of Sciences/ ; YD9100002033//the Joint Fund for New Medicine of USTC/ ; 2308085QH265//the Natural Science Foundation of Anhui Province/ ; 202304295107020056//the Anhui Provincial Key R&D Programmes/ ; 20230429510702 0053//the Anhui Provincial Key R&D Programmes/ ; MAI2023Q024//the Joint Fund for Medical Artificial Intelligence/ ; },
}

@article {pmid41787137,
year = {2026},
author = {Marano, G and Da Cas, R and Ippoliti, I and Caffarra, P and Locuratolo, N and Vanacore, N and Ancidoni, A},
title = {Regulatory, clinical, and post-marketing challenges of lecanemab for Alzheimer's disease: insights from real-world data.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {4},
pages = {},
pmid = {41787137},
issn = {1590-3478},
}

@article {pmid41787135,
year = {2026},
author = {Rekha, D and Kamala Kumari, PV and Thummala, UK and Dastagiri Reddy, Y and Prasanth, D and Praveen Kumar, P},
title = {Machine Learning-Integrated Pharmacophore, DFT Analysis, and molecular dynamics of Diosmetin as a potent ache inhibitor with neuroprotective activity in a Scopolamine-Induced alzheimer's zebrafish model.},
journal = {Journal of computer-aided molecular design},
volume = {40},
number = {1},
pages = {},
pmid = {41787135},
issn = {1573-4951},
abstract = {Alzheimer's Disease (AD) is a degenerative disorder of the brain that causes a gradual loss of cognitive function. The cholinergic hypothesis suggests that acetylcholine deficiency is the main cause of AD, which explains why blocking acetylcholinesterase (AChE) is the most effective way to treat AD. Nevertheless, there are some drawbacks to the currently available AChE inhibitors; thus, new molecules with better therapeutic effects and fewer side effects are needed. In this study, the anti-Alzheimer activity of diosmetin, a natural flavonoid, was investigated via an integrated computational and experimental approach. Pharmacophore mapping revealed that the essential chemical features of diosmetin are responsible for AChE inhibition, and density functional theory calculations were employed to investigate its electronic properties and chemical behavior. Molecular docking experiments indicated that diosmetin could bind firmly to AChE with a binding energy of -9.49 kcal/mol. Molecular dynamics simulations strengthened this hypothesis by showing that the diosmetin-AChE complex remained stable over time. In vivo verification using a scopolamine-induced zebrafish model of Alzheimer's disease revealed that diosmetin administration notably enhanced learning and memory abilities in zebrafish. Various behavioral paradigms, including the light/dark preference test, novel tank diving test, T-maze test, and novel object recognition test, have been used to assess cognitive function. Biochemistry revealed that diosmetin counteracted the scopolamine-induced increase in AChE activity, increased oxidative stress, increased myeloperoxidase inflammatory markers, decreased antioxidant activity, and restored normal histology in the brains of the zebrafish. Most importantly, high-dose diosmetin demonstrated comparable neuroprotective efficacy to donepezil in behavioral and biochemical assays while exhibiting weaker molecular binding affinity toward AChE, as indicated by MM-PBSA analysis, underscoring that similar in vivo outcomes do not necessarily imply molecular equivalence at the binding level.},
}

@article {pmid41787100,
year = {2026},
author = {Fieldhouse, R},
title = {These brain cells clear proteins that contribute to Alzheimer's.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41787100},
issn = {1476-4687},
}

@article {pmid41787076,
year = {2026},
author = {Mummery, CJ and Mayorga, AJ and Simmons, A and Chow, TW and Burgess, B and Nguyen, T and Gao, J and Budda, B and Park, LQ and Gupta, R and Li, C and Shi, L and Kenkare-Mitra, S and Rosenthal, A and Paul, R and Ward, M and Purcell, DD and Salloway, S and Grundman, M and Romano, G and Salvadore, G},
title = {The TREM2 agonistic antibody AL002 in early Alzheimer's disease: a phase 2 randomized trial.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41787076},
issn = {1546-170X},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial function and is implicated in Alzheimer's disease (AD) pathogenesis. Here we conducted a phase 2, randomized, double-blind, placebo-controlled trial of a humanized TREM2 agonistic monoclonal antibody in 381 participants with early AD. Participants were randomized (1:1:1:1) to receive AL002 (15 mg kg[-1], 40 mg kg[-1] or 60 mg kg[-1]) or placebo intravenously every 4 weeks for 48-96 weeks. AL002 demonstrated sustained target engagement and pharmacodynamic responses in the central nervous system, as demonstrated by reductions in soluble TREM2 and increases in osteopontin in cerebrospinal fluid, respectively. The study did not meet the primary endpoint of change from baseline in the Clinical Dementia Rating-Sum of Boxes score (versus placebo) (least squares mean difference versus placebo (95% confidence interval) at week 96: 15 mg kg[-1] -0.31 (-1.61 to 0.98), 40 mg kg[-1] 0.13 (-1.18 to 1.43) and 60 mg kg[-1] -0.17 (-1.49 to 1.15); P > 0.05 from mixed-effects model for repeated measures). The most frequent treatment-emergent adverse events were magnetic resonance imaging changes resembling amyloid-related imaging abnormalities (ARIA). This first trial of a TREM2 agonistic antibody in early AD was negative but provides findings relevant to the study of TREM2 therapeutics and ARIA. ClinicalTrials.gov: NCT04592874 .},
}

@article {pmid41787071,
year = {2026},
author = {Haapala, EA and Heinonen, S and Mykkänen, J and Niinikoski, H and Lagström, H and Salo, P and Jula, A and Rönnemaa, T and Viikari, JS and Raitakari, OT and Pahkala, K and Rovio, S},
title = {Genetic susceptibility to Alzheimer's disease and cardiometabolic risk from childhood.},
journal = {Pediatric research},
volume = {},
number = {},
pages = {},
pmid = {41787071},
issn = {1530-0447},
abstract = {BACKGROUND: We investigated the associations of genetic risk score for Alzheimer's disease (GRS-AD) with cardiometabolic risk from early childhood over a 20-year follow-up.

METHODS: The STRIP study included 1062 children at baseline. GRS-AD was calculated for 631 participants using 22 independent genetic risk variants, including APOE ε2 and ε4 alleles, and excluding them (non-APOE-GRS-AD). We repeatedly measured waist circumference, high-density (HDL-C) and low-density (LDL-C) lipoprotein cholesterol, triglycerides, glucose, insulin, and blood pressure. The data were analysed with generalised additive mixed models.

RESULTS: GRS-AD was directly associated with serum LDL-C (unstandardised β = 0.140, 95% CI = 0.084 to 0.195) and inversely with HDL-C (β = -0.026, 95% CI = -0.044 to -0.009). GRS-AD was inversely associated with serum HDL-C in males (β = -0.044, 95% CI = -0.070 to -0.018) but not in females (β = -0.010, 95% CI = -0.032 to 0.012). The associations were diluted when the non-APOE-GRS-AD was applied.

CONCLUSION: A genetic predisposition to AD may alter lipid metabolism from early childhood.

IMPACT: While Alzheimer's disease and cardiometabolic diseases may have shared genetic determinants, the associations between genetic susceptibility for Alzheimer's disease and increased cardiometabolic risk from childhood to young adulthood are poorly understood. We investigated the associations of genetic risk score for Alzheimer's disease with cardiometabolic risk from early childhood over a 20-year follow-up. We found that a higher genetic risk score for Alzheimer's disease was associated with higher LDL cholesterol, non-HDL cholesterol, and ApoB, and with lower serum HDL cholesterol and ApoA1. These findings suggest that a genetic predisposition to Alzheimer's disease may alter lipid metabolism from early childhood.},
}

@article {pmid41787066,
year = {2026},
author = {Colombo, G and Minta, K and Taylor, WR and Grübel, J and Chong, E and Chong, JR and Lim, MJH and Gonzales, PNG and Lai, MKP and Chen, CP and Schinazi, VR},
title = {Spatial navigation as a digital marker for clinically differentiating cognitive impairment severity.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01484-y},
pmid = {41787066},
issn = {2730-664X},
abstract = {BACKGROUND: Spatial navigation impairments emerge early in Alzheimer's disease, but assessments targeting these deficits remain underutilised or impractical for cognitive screening. The Spatial Performance Assessment for Cognitive Evaluation (SPACE) is a newly developed digital tool that evaluates spatial navigation deficits associated with cognitive impairment.

METHODS: We assessed spatial navigation ability using SPACE in 300 older adults recruited from memory clinics and the general community. Participants were classified across different levels of cognitive impairment using the Clinical Dementia Rating (CDR) scale. Performance in SPACE was compared with clinical diagnosis, standard cognitive assessments, and demographic models using Area Under the ROC Curve (AUC), sensitivity, and specificity.

RESULTS: We show that SPACE reliably distinguishes CDR levels, exceeding the accuracy of demographic models and matching or surpassing most traditional neuropsychological tests. Including SPACE significantly increases the AUC for distinguishing between no dementia from mild dementia (0.76 to 0.94), no dementia from moderate dementia (0.79 to 0.95), and questionable dementia from mild dementia (0.70 to 0.91), all with consistently high sensitivity and specificity. A shortened version of SPACE, lasting less than 11 minutes, reduces administration time by 40% while maintaining high diagnostic accuracy. Cross-validation analyses confirm the reliability and robustness of these models.

CONCLUSIONS: These findings highlight the potential of digital spatial navigation assessments to advance early detection, contributing to scalable and accessible healthcare.},
}

@article {pmid41786925,
year = {2026},
author = {Iqbal, S and Nisar, H and Yeap, KH},
title = {Quantitative EEG signatures of power and functional connectivity alterations in Alzheimer's disease and frontotemporal dementia.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-42452-9},
pmid = {41786925},
issn = {2045-2322},
support = {IPSR/RMC/UTARRF/2023-C2/H01//Universiti Tunku Abdul Rahman/ ; },
abstract = {Dementia is a common neurodegenerative disease in the elderly, which affects the structural and functional connectivity of the brain. Recent studies indicate that electrophysiological measures, such as power spectral features and functional connectivity (FC), show promise for the diagnosis and classification of dementia. However, findings across studies remain inconsistent, and distinct electrophysiological patterns separating dementia subtypes, as well as Frontotemporal Dementia (FTD) and cognitively normal (CN) individuals, are not yet well established. This study focuses on spectral power and functional connectivity (FC) analyses of the Electroencephalography (EEG) frequency bands (delta, theta, alpha, beta, and gamma) in Alzheimer's Disease (AD) and FTD. A publicly available eyes-closed (EC), resting-state (RS) EEG dataset comprising 88 age-matched participants, 36 with AD, 29 CN, and 23 with FTD, was used in this study. Absolute power was computed using Welch's method, while FC within each frequency band was assessed using Inter-Site Phase Clustering (ISPC) and network-based statistics, edge and node strength. The global power analysis revealed a significantly higher alpha power in CN compared to both AD and FTD. Regional analysis revealed a significantly lower temporal and parietal alpha in AD relative to CN and a significantly lower occipital alpha and beta in both AD and FTD compared to CN. Topographical power analysis showed unique significant differences within lobes in delta, theta, alpha, and gamma bands in AD and FTD, with AD illustrating a relatively more heterogeneous power distribution than FTD. Furthermore, FC analysis indicated that compared with CN, AD exhibited significantly lower edge strength in delta, theta, beta, and gamma bands, while significantly lower node strength in delta, theta, and gamma bands. Likewise, compared with CN, FTD showed significantly lower edge and node strength in the delta and theta bands, while significantly higher in the beta band. Furthermore, when compared to FTD, AD revealed a significantly lower edge and node strength in the delta, beta, and gamma bands. In conclusion, AD was associated with widespread FC disruptions, while FTD retained partially preserved connectivity, with the temporal lobe more affected than the frontal lobe. These findings suggest that band power and FC alterations may serve as potential biomarkers for diagnosing and classifying dementia into AD and FTD.},
}

@article {pmid41786890,
year = {2026},
author = {Brossaud, R and Oullier, T and Bessard, A and Aubert, P and Brossard, L and Mahé, MM and Caillaud, M and Delfino, G and Paillusson, S and Falentin, H and Naveilhan, P and Le-Loir, Y and Paillé, V and Neunlist, M and Cissé, M},
title = {The short-chain fatty acid butyrate prevents gut-brain amyloid-β pathology and neuroinflammation in an Alzheimer mouse model.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41786890},
issn = {1476-5578},
abstract = {Amyloid-β (Aβ) plays a critical role in Alzheimer's disease (AD) and its accumulation in the brain is pivotal to disease progression and precedes memory and neuronal loss. Besides the severely handicapping brain symptoms, AD patients display early gastro-intestinal (GI) manifestations such as upper and lower GI dysmotility, in particular constipation. Although there is increasing evidence of Aβ accumulation in the gut, its pathogenic effects on enteric nervous system (ENS) connectivity and gut function as well as underlying pathophysiological mechanisms are poorly understood. Furthermore, studies have reported a gut to brain transmission of Aβ that causes memory deficits in mice. Therefore, identifying therapeutics which can reduce Aβ accumulation in the gut at an early stage of the disease could have the advantage of slowing or even reversing disease progression before severe alterations or irreversible damages at both intestinal and brain levels. Hence, in this study, we investigated the capacity of the short-fatty acid butyrate to restore Aβ-driven alteration of ENS connectivity and gut-brain functions in the SAMP8 mouse model of AD. Here we show that SAMP8 mice display a gut amyloid pathology, an alteration of ENS connectivity and gut defects prior to memory decline. BACE1, an Aβ-producing enzyme, expression and activity are increased whereas neprilysin, an Aβ-degrading enzyme, is decreased in the gut of SAMP8 mice, indicating a rise in the Amyloid Precursor Protein (APP) holoprotein processing and a reduction of Aβ clearance which promote an amyloidosis. In primary ENS cultures, Aβ causes a degradation of synaptic-associated proteins EphB2 and synaptophysin, leading to an alteration of ENS connectivity. In wild-type mice, intra-colon delivery of Aβ alters ENS connectivity and causes subsequent GI symptoms, recapitulating the phenotype of the SAMP8 mouse model of aging and AD. Moreover, Aβ impairs ENS connectivity in human induced pluripotent stem cell (iPSC)-derived intestinal organoids and explant cultures of human colon, indicating that Aβ causes ENS lesions in models of the human gut. Butyrate, a short-chain fatty acid derived from bacterial metabolism, reduces Aβ secretion and preserves enteric neuronal connectivity in vitro and in vivo, and blocks Aβ accumulation in the gut, brain and plasma in SAMP8 mice. In addition, butyrate ameliorates neuroinflammation and prevents gut dysfunction and memory deficit. Collectively, these findings suggest that Aβ promotes gut symptoms through alteration of ENS connectivity and butyrate counteracts these impairments with an amelioration of neuroinflammation and memory function in AD model.},
}

@article {pmid41786716,
year = {2026},
author = {Jara, C and Venegas-Zamora, L and Park-Kang, HS and Lira, M and Ricca, M and Valenzuela, S and Tapia-Rojas, C},
title = {Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-026-00351-3},
pmid = {41786716},
issn = {2731-6068},
support = {11241376//Agencia Nacional de Investigación y Desarrollo/ ; 1221178//Agencia Nacional de Investigación y Desarrollo/ ; },
abstract = {The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.},
}