@article {pmid41975517,
year = {2026},
author = {Raghavan, S and Przybelski, SA and Gebre, RK and Low, A and Hu, M and Reid, RI and Windham, BG and Wiste, HJ and Fought, AJ and Kamykowski, MG and Nguyen, AT and Murray, ME and Lowe, VJ and Jack, CRJ and Petersen, RC and Graff-Radford, J and Vemuri, P and , },
title = {Regional diffusion imaging measures to disentangle SVD-related hypertensive arteriopathy versus cerebral amyloid angiopathy.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {41975517},
issn = {1750-1326},
support = {R37 AG011378/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG056366/AG/NIA NIH HHS/United States ; R37 AG011378/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG056366/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Detecting and distinguishing early changes due to the two key subtypes of cerebral small vessel disease (SVD), hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA), has significant clinical implications. Our goal was to develop and validate dMRI signatures associated with HA-SVD and CAA-SVD proxies and assess their clinical utility using Alzheimer’s disease and SVD biomarkers, pathology, and cognition.

METHODS: Two independent cohorts with baseline dMRI scans, T2* gradient-echo MRI, and vascular risk measures were analyzed: Mayo Clinic Study of Aging (MCSA, N = 1080) and Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 549). In MCSA, regional dMRI measures associated with proxies of HA-SVD (hypertension) and CAA-SVD (lobar cerebral microbleeds) were identified using logistic regression models. The top regional features were then used to compute composite dMRI indices for HA-SVD and CAA-SVD. These dMRI indices were validated in ADNI and in an independent pathology sample of MCSA (N = 147). In MCSA, we also computed standard global SVD indices from diffusion and FLAIR MRI and compared them with dMRI indices to reflect SVD subtypes. Next, we evaluated the association of these indices with cognitive performance (global, attention, and memory) using regression models, after adjusting demographics, white matter hyperintensities (WMH) and amyloid.

RESULTS: Hypertension was associated with reduced microstructural integrity predominantly in fronto-parieto-projection pathways, whereas lobar microbleeds were associated with occipito-parietal damage. These differential tract association patterns with HA-SVD and CAA-SVD proxies were less pronounced in ADNI. In the community-dwelling MCSA cohort with higher prevalence of vascular disease, dMRI indices provided more differentiated associations with both proxies of SVD than global SVD indices, underscoring added value for etiology-specific identification. As expected, CAA-SVD indices were more strongly associated with occipital WMH and amyloid burden and were linked to CAA pathology scores. CAA-SVD indices also had greater association with memory performance, independent of amyloid and WMH. Conversely, HA-SVD indices were robustly associated with post-mortem Kalaria scales and attention scores.

CONCLUSIONS: Using three datasets, (population-based sample, independent cohort, pathology sample), we found that regional dMRI signatures can capture distinct SVD processes of HA and CAA. These dMRI signatures offer potential for early differential identification of SVD subtypes and can aid in guiding clinical decision making and prevention.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-026-00942-4.},
}

@article {pmid42156124,
year = {2026},
author = {Jaswal, S and Ghaderi Yazdi, B and Khalafi, M and Ozoria, S and Chernek, P and Calimag, J and Wang, XH and Razlighi, QR and Chiang, GC},
title = {In Vivo [18F]MK6240 PET Reveals Atypical Patterns of Early Tau Deposition and Evidence for Primary Age-Related Tauopathy in Community-Residing Adults.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9420},
pmid = {42156124},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: [18F]MK-6240, a second-generation tau PET tracer, enables in vivo detection of tau neurofibrillary tangles-one of the key pathologic hallmarks of Alzheimer's disease (AD). Building on prior work demonstrating the utility of [18F]MK-6240 for in vivo Braak staging, this study assessed the frequency of typical and atypical tau deposition patterns in a cognitively unimpaired, community-residing cohort and associations with early memory changes.

MATERIALS AND METHODS: One hundred seventy-three older adults (aged 69 +/- 5.7 years, 49% female) were recruited prospectively from the community to undergo [18F]MK-6240 tau PET, [18F]florbetaben amyloid PET, and clinical and neuropsychological evaluations. Images were analyzed qualitatively and quantitatively to determine amyloid and tau positivity, and participants were subsequently classified according to Braak stage. Associations with cognitive measures were assessed using linear regression models.

RESULTS: Fifty-nine participants (34%) were found to be tau positive on PET: 32 were Braak stages I-II, 7 Braak stages III-IV, 19 Braak stages V-VI, and 1 had tau localized to the right thalamus. Notably, thirty participants (17%) were tau positive on PET but amyloid negative, suggestive of primary age-related tauopathy. Five had atypical tau deposition in cortical/subcortical regions without deposition in the medial temporal lobe, a departure from typical Braak staging, suggestive of hippocampal-sparing AD. Amyloid-positive, tau-positive participants had slightly lower cognition on the Montreal Cognitive Assessment (p=0.02) and Craft Story delayed recall (p=0.03). Amyloid-negative, tau-positive participants had lower Craft Story immediate recall scores (p=0.03).

CONCLUSION: A significant proportion of older adults in the community have tau deposition in the brain, including those who are amyloid negative on PET, allowing for a critical therapeutic window before symptoms onset. Tau deposition patterns are heterogeneous and can deviate from traditional Braak staging, even in the preclinical stage, which underscores the need for an individualized, spatially-based approach to disease monitoring.},
}

@article {pmid42156213,
year = {2026},
author = {Nalepa, M and Skweres, A and Węgrzynowicz, M},
title = {Dysregulation of arginase and arginine pathways in neurodegenerative diseases: Metabolic and cellular dysfunction and therapeutic implications.},
journal = {Free radical biology & medicine},
volume = {252},
number = {},
pages = {559-579},
doi = {10.1016/j.freeradbiomed.2026.05.285},
pmid = {42156213},
issn = {1873-4596},
abstract = {Neurodegenerative diseases are increasingly recognized as disorders associated with metabolic dysfunction with arginine metabolism emerging as a significant contributor. Arginase, by regulating the balance between arginine and ornithine, is positioned at the crossroads of multiple arginine metabolic pathways, thereby controlling a variety of cellular processes essential for proper brain homeostasis. Chronic disruption of these pathways may lead to dysfunction of neurons and glia ultimately resulting in the induction of neurodegenerative processes. In this review, based on data from patients and experimental models, we synthesize and critically evaluate evidence demonstrating alterations in arginase isoenzymes and associated metabolic pathways in Alzheimer's Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. We discuss mechanisms through which dysregulation of arginase and arginine metabolism may contribute to neurodegeneration, including disturbances in nitrogen metabolism, oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Based on this body of evidence, we propose therapeutic strategies targeting arginase-related pathways, with the aim of preserving cellular metabolic homeostasis to ameliorate disease progression. Finally, we outline directions for future research, emphasizing that a proper understanding of the physiological roles of arginase isoenzymes and their disease-, stage-, and cell-specific dysregulation will be essential for the development of effective metabolically targeted therapies against neurodegenerative diseases.},
}

@article {pmid42156588,
year = {2026},
author = {Kulatunga, DCM and Ranaraja, U and Kim, EY and Ji, K and Choi, HY and Yoon, J and Park, K and Kim, MK},
title = {Engineered APP C-terminus Alters Its Native Transcript Dynamics in Differentiated SH-SY5Y-Derived Neurons.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42156588},
issn = {1559-1182},
mesh = {Humans ; *Neurons/metabolism/cytology ; *Amyloid beta-Protein Precursor/genetics/metabolism/chemistry ; *Cell Differentiation/genetics ; Cell Line, Tumor ; RNA, Messenger/metabolism/genetics ; *Protein Engineering/methods ; Alternative Splicing/genetics ; *Transcription, Genetic ; },
abstract = {Alzheimer's disease (AD) pathology is deeply connected with the processing of amyloid precursor protein (APP) and its cleavage products. APP processing generates functional fragments, such as the APP intracellular domain (AICD) and the APP carboxy-terminal fragment (CTF), which have been implicated in transcriptional regulation. However, their potential role in modulating endogenous APP splicing and expression remains unclear. This study investigates the self-regulatory potential of APP through its C-terminal fragments. Stable transgenic SH-SY5Y lines overexpressing APP695, its Swedish mutant form, and truncated and engineered C-terminal constructs were generated. They were differentiated over 24 days to get mature neuron-like cells and analyzed for APP transcript variants. The overexpression of APP fragments altered total APP levels and specific transcript variants, especially APPv3 and APPv11, predominantly in differentiated neurons. Differential splicing patterns were further confirmed through specific transcript fragment-size analysis. These findings highlight that APP derivatives actively influence transcriptional regulation and alternative splicing of native APP. This research advances our understanding of APP biology by revealing its self-regulatory complexity, suggesting that APP fragments could serve as transcription modulators of APP itself, providing insights into disease pathogenesis and novel therapeutic strategies in AD.},
}

Humans
*Neurons/metabolism/cytology
*Amyloid beta-Protein Precursor/genetics/metabolism/chemistry
*Cell Differentiation/genetics
Cell Line, Tumor
RNA, Messenger/metabolism/genetics
*Protein Engineering/methods
Alternative Splicing/genetics
*Transcription, Genetic

@article {pmid42156706,
year = {2026},
author = {Hokett, E and Brickman, AM and Adkins-Jackson, PB},
title = {Anticipating Racism is Associated with Poorer Sleep Among Adults Racialized as Black.},
journal = {Journal of racial and ethnic health disparities},
volume = {},
number = {},
pages = {},
pmid = {42156706},
issn = {2196-8837},
support = {R01AG054070-S1/AG/NIA NIH HHS/United States ; L60AG079481/AG/NIA NIH HHS/United States ; K01AG081454/AG/NIA NIH HHS/United States ; AARFD-22-924391/ALZ/Alzheimer's Association/United States ; },
abstract = {INTRODUCTION: Racism has deleterious effects on sleep. Higher interpersonal discrimination is associated with lower sleep duration and poorer sleep quality (i.e., poor sleep) in adults who are racialized as Black, but this association is understudied across the age range of the adult lifespan. Here, we hypothesized higher racism-related vigilance is associated with poorer sleep quality and lower sleep duration in women and men.

METHOD: We used a subsample of the Offspring Study of Racial and Ethnic Disparities of Alzheimer's Disease, a community-based cohort study. In adults across the lifespan racialized as Black (n = 258, 62% women, mean age = 56, SD = 11, range: 27-89), we measured the frequency of racism-related vigilance with a questionnaire on a scale from (1) at least once a week to (6) never. We measured sleep duration and sleep quality with a modified version of the Pittsburgh Sleep Quality Index and evaluated associations between vigilance and sleep with linear regression models.

RESULTS: Higher racism-related vigilance was associated with poorer sleep quality. We observed associations between higher vigilance and lower sleep duration across the full sample, and these associations were similar among women and men.

CONCLUSION: Anticipatory experiences of racism are associated with poorer sleep quality. Specifically, the threat of racist experiences is associated with poorer sleep quality in women and men. Future research and policies should aim to reduce racism-related vigilance by intervening on negative environments that trigger vigilance responses to improve sleep quality in adults racialized as Black.},
}

@article {pmid42156845,
year = {2026},
author = {Sheng, J and Chen, Z and Zhang, Q and Zhang, R and Zhang, X and Zhong, H and Lin, J and Huang, R},
title = {A novel diagnosis method based on multimodal-aware bi-objective competitive mechanism for Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52922-9},
pmid = {42156845},
issn = {2045-2322},
support = {LZ24F010007//Natural Science Foundation of Zhejiang Province/ ; 62271177//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. Recent statistical surveys and studies indicate that AD is poised to become a major global health burden in the coming decades. Among current strategies, leveraging multimodal imaging data for early diagnosis and classification of AD has emerged as a promising approach. However, most existing methods primarily focus only on improving classification accuracy, while overlooking the importance of extracted imaging features and the underlying relationships among them. In this study, we propose a novel Multimodal-Aware Bi-Objective Competitive Mechanism Estimation of Distribution Algorithm (MABOC-EDA). The proposed MABOC-EDA incorporates both the individual significance of imaging features and their inter-modality interactions during the evolutionary process, two data structures were employed to represent them, which were updated according to a predefined update strategy. These structures were then used to construct a probabilistic model, from which the optimal feature subset was derived. The proposed method achieved classification accuracies and area under the ROC curve of 95.74%/97.25%,87.23%/89.93%, and 86.54%/88.76% for the AD vs. CN, AD vs. MCI, and CN vs. MCI classification tasks, respectively. Moreover, the brain regions that contribute most significantly to classification and those exhibiting strong correlations in the context of AD diagnosis. The correlated brain regions identified by proposed method provide insights that may facilitate the discovery of complementary biomarkers across different imaging modalities.},
}

@article {pmid42156857,
year = {2026},
author = {Shafik, RA and Afify, YM and Badr, N and Mounir, M},
title = {Robust transcriptomic signatures of Alzheimer's disease progression: validated explainable AI approach.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42156857},
issn = {2045-2322},
mesh = {*Alzheimer Disease/genetics/pathology/metabolism ; Humans ; Disease Progression ; *Transcriptome ; *Gene Expression Profiling ; Machine Learning ; Biomarkers/metabolism ; Male ; Female ; Aged ; },
abstract = {The lack of validated stage-specific biomarkers hampers the understanding of Alzheimer's disease (AD) progression and clinical translation. Current transcriptomic methods often produce unstable results with limited stage discrimination. We aimed to develop an explainable machine learning pipeline to identify robust, interpretable gene signatures linked to distinct AD neuropathological stages. We analyzed multi-region transcriptomic data from the MSBB cohort using a multi-class XGBoost-SHAP-driven framework. Class imbalance was addressed using SMOTE, and model robustness was assessed through cross-validation and permutation-based validation. Our pipeline accurately classified Early, Mid, and Late Braak stages and achieved accurate Braak stage classification (regional ROC AUCs up to 0.76). The method identified a concise set of high-confidence, stage-specific genes, showing minimal signature overlap (~ 1.7%). Key validated novel candidate biomarkers included ARX (Early), MKNK2 (Mid), and SLC25A16/NEURL1B (Late), linked to GABAergic, inflammatory, mitochondrial, and synaptic pathways. This explainable framework overcomes key limitations of conventional analyses, providing a stable, interpretable gene signature for AD staging. It establishes a robust method for transcriptional biomarker discovery and offers new biological insight into AD progression, highlighting potential stage-specific therapeutic targets.},
}

*Alzheimer Disease/genetics/pathology/metabolism
Humans
Disease Progression
*Transcriptome
*Gene Expression Profiling
Machine Learning
Biomarkers/metabolism
Male
Female
Aged

@article {pmid42156936,
year = {2026},
author = {Young, VM and Wiedner, C and Baril, AA and Pase, MP and Ruiz, A and Salardini, A and Frei, CR and Kautz, T and Bernal, R and Yiallourou, S and Cribb, L and Beiser, A and Teixeira, AL and Himali, JJ and Seshadri, S},
title = {Non-linear associations between sleep duration and plasma p-tau181 in the Framingham Heart Study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71499},
doi = {10.1002/alz.71499},
pmid = {42156936},
issn = {1552-5279},
support = {N01-HC-25195/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; R01 AG054076/AG/NIA NIH HHS/United States ; R01 AG049607/AG/NIA NIH HHS/United States ; U01 AG052409/AG/NIA NIH HHS/United States ; R01 AG059421/AG/NIA NIH HHS/United States ; RF1 AG063507/AG/NIA NIH HHS/United States ; RF1 AG066524/AG/NIA NIH HHS/United States ; U01 AG058589/AG/NIA NIH HHS/United States ; P30 AG066546/NH/NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Sleep Research Society Foundation/ ; //Fonds de recherche du Québec en Santé/ ; //CIHR/Canada ; //Alzheimer Society of Canada/ ; GTN2009264//National Health and Medical Research Council of Australia Investigator/ ; //Alzheimer Society of B.C./ ; },
mesh = {Humans ; Female ; Male ; *tau Proteins/blood ; *Sleep/physiology ; Aged ; Biomarkers/blood ; Middle Aged ; *Alzheimer Disease/blood ; Phosphorylation ; Longitudinal Studies ; Neurofilament Proteins/blood ; Sleep Duration ; },
abstract = {INTRODUCTION: Both short and long sleep duration have been associated with Alzheimer's disease (AD) risk, yet the nature of the non-linear associations between sleep quantity and blood-based biomarkers of AD and neurodegeneration remains understudied.

METHODS: Among 2410 Framingham Heart Study participants (mean age: 70.0 ± 8.45 years; 55.2% female), we examined associations between self-reported sleep duration and plasma phosphorylated tau (p-tau)181, total tau, neurofilament light chain, and glial fibrillary acidic protein using restricted cubic splines (RCS) and categorical comparisons (≤ 6, > 6-< 9 reference; ≥ 9 hours).

RESULTS: RCS revealed non-linear associations between sleep duration and p-tau181 (overall p = 0.005; non-linearity p = 0.002), with higher levels at ≥ 8.5 hours, after adjusting for age, sex, apolipoprotein E ε4 genotype, sleep apnea, depression, and kidney function. Categorical comparisons showed no association in adjusted models.

DISCUSSION: Sleep duration exhibits robust non-linear associations with p-tau181. Findings underscore the importance of non-linear modeling in relating sleep to blood-based biomarkers. Longitudinal studies are needed to clarify temporal relationships and mechanistic pathways.},
}

Humans
Female
Male
*tau Proteins/blood
*Sleep/physiology
Aged
Biomarkers/blood
Middle Aged
*Alzheimer Disease/blood
Phosphorylation
Longitudinal Studies
Neurofilament Proteins/blood
Sleep Duration

@article {pmid42157001,
year = {2026},
author = {Deng, F and Henson, RN and Muniz-Terrera, G and Malhotra, P and O'Brien, JT and Ritchie, CW and Lawlor, B and Naci, L},
title = {Genetic risk of Alzheimer's disease is associated with loss of brain network segregation in midlife.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10282-0},
pmid = {42157001},
issn = {2399-3642},
support = {ILP-POR-2024-057//Health Research Board (HRB)/ ; 32400902//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Alzheimer's disease (AD) neuropathology starts decades before clinical manifestations, but the early indicators of AD in midlife remain unclear. Functional segregation of brain networks is a key marker of brain health. It remains unknown, however, whether inherited risk of AD impacts network segregation from midlife in individuals who are cognitively healthy but carry inherited risk for late-life AD. To address this question, we investigate which brain networks show the strongest age-related segregation loss in the Cam-CAN lifespan cohort (18-88 years, N = 652), and whether APOE ε4 genotype impacts segregation of age-vulnerable networks in the midlife PREVENT cohort (40-59 years, N = 210), cross-sectionally and longitudinally. Higher-order networks showing the most significant age-related decline are the default mode (DMN), frontal-parietal control (FPN) and salience (SN) networks. Cognitively healthy midlife APOE ε4 carriers have higher segregation across the brain cross-sectionally, accompanied by greater longitudinal decline in the DMN over two years, relative to non-carriers. Higher DMN segregation is associated with better episodic and relational memory across the PREVENT cohort. These findings suggest that functional segregation may serve as a potential biomarker, providing insights into the mechanisms through which APOE influences brain function and cognition from healthy midlife, on average 23 years before dementia onset.},
}

@article {pmid42157020,
year = {2026},
author = {Benge, JF and Werry, AE and Hromas, G and Aguirre, A and Zuniga, C and Hilsabeck, RC and González, DA},
title = {The Lawton and Brody a half century later: A case for contemporary revision.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/13854046.2026.2670535},
pmid = {42157020},
issn = {1744-4144},
abstract = {Objective: To reevaluate the psychometric properties and contemporary relevance of the 1969 Lawton and Brody Instrumental Activities of Daily Living (iADL) Scale in older adults. Methods: Data from 3552 participants and co-participants in the Texas Alzheimer's Research and Care Consortium cohort were analyzed. Lawton and Brody iADL Scale items were analyzed in a sample with no cognitive disorder, mild cognitive impairment, and dementia. Graded response models assessed item discrimination and difficulty, with differential item functioning (DIF) analyses examining demographic effects. Expert reviewers evaluated item content for cultural and technological relevance. Results: Items assessing shopping, food preparation, and transportation were most sensitive to mild functional impairment, while the total scale had limited detection of subtle functional decline. Statistical DIF emerged on 75% of items, whereas clinically meaningful DIF for several demographic groupings emerged on the transportation item. Expert reviewers identified outdated content, particularly for telephone and financial items, reflecting technological shifts. Broader changes in normative behaviors and sample demographics may further challenge scale applicability. Conclusions: The Lawton and Brody iADL Scale remains foundational but shows limited sensitivity for early functional decline. Outdated items and evolving socioeconomic and technological contexts underscore the need for refinement to enhance unbiased early detection and maintain longitudinal comparability. Updating the instrument to reflect modern demands could strengthen functional assessment in Alzheimer's disease and related disorders research and clinical trials.},
}

@article {pmid42157022,
year = {2026},
author = {Reimer, CJ and Jenson, TE and Tripodis, Y and Shiba, K and James, P and Kirwa, K and Heckbert, SR and Hirsch, JA and Besser, L and Hughes, T and Kaufman, JD and Coull, BA and Pescador Jimenez, M},
title = {Mixtures of key components of the external exposome in association with MRI biomarkers of brain structure: Multi-Ethnic Study of Atherosclerosis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71459},
doi = {10.1002/alz.71459},
pmid = {42157022},
issn = {1552-5279},
support = {R01AG087199//National Institute on Aging (NIA)/ ; R00AG066949//National Institute on Aging (NIA)/ ; R01NS139186/NS/NINDS NIH HHS/United States ; UL1-TR-000040/TR/NCATS NIH HHS/United States ; UL1-TR-001079/TR/NCATS NIH HHS/United States ; UL1-TR-001420/TR/NCATS NIH HHS/United States ; R01 HL127659/HL/NHLBI NIH HHS/United States ; R01AG049970/AG/NIA NIH HHS/United States ; R01AG049970-04S1/AG/NIA NIH HHS/United States ; R01AG072634/AG/NIA NIH HHS/United States ; R01AA028552/AA/NIAAA NIH HHS/United States ; //Commonwealth Universal Research Enhancement/ ; 4100072543//Pennsylvania Department of Health - 2015 Formula award/ ; },
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Brain/diagnostic imaging/pathology ; *Atherosclerosis/diagnostic imaging/ethnology ; Risk Factors ; Biomarkers ; White Matter/diagnostic imaging/pathology ; Ethnicity ; Gray Matter/diagnostic imaging/pathology ; *Environmental Exposure/adverse effects ; Aged, 80 and over ; },
abstract = {INTRODUCTION: There is a critical need to identify risk factors of Alzheimer's disease and related dementias (ADRD).

METHODS: We included 1227 participants (mean age [standard deviation]: 74.1 [7.9] years) from the Multi-Ethnic Study of Atherosclerosis with brain MRI scans. We investigated joint associations of 13 natural, social, and built-environment exposures with gray matter volume (GMV) (n = 1219), white matter fractional anisotropy (WM FA) (n = 1102), and white matter hyperintensity volume (n = 1210) using weighted quantile sum regression.

RESULTS: A one-decile increase in all harmful exposures was associated with lower GMV and WM FA; however, associations were null when adjusting for study site.

DISCUSSION: Examining the impact of many environmental factors simultaneously may provide insight into important modifiable risk factors for ADRD, capturing concomitant exposures as they are experienced.},
}

Humans
Male
Female
Magnetic Resonance Imaging
Aged
*Brain/diagnostic imaging/pathology
*Atherosclerosis/diagnostic imaging/ethnology
Risk Factors
Biomarkers
White Matter/diagnostic imaging/pathology
Ethnicity
Gray Matter/diagnostic imaging/pathology
*Environmental Exposure/adverse effects
Aged, 80 and over

@article {pmid42157023,
year = {2026},
author = {Rybicki-Kler, CI and Brooks, IAW and Jedrasiak-Cape, I and Deng, T and Avila, C and Brouns, E and Lekander, A and Ahmed, OJ},
title = {Reciprocal molecular and cellular cholinergic working memory impairments in Alzheimer's disease model mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71490},
doi = {10.1002/alz.71490},
pmid = {42157023},
issn = {1552-5279},
support = {R01MH129282/MH/NIMH NIH HHS/United States ; R34NS127101/NS/NINDS NIH HHS/United States ; P50NS123067/NS/NINDS NIH HHS/United States ; T32NS007222/NS/NINDS NIH HHS/United States ; T32NS076401/NS/NINDS NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; F31AG087629/AG/NIA NIH HHS/United States ; AARG-NTF-21-846572/ALZ/Alzheimer's Association/United States ; T32DC000011/DC/NIDCD NIH HHS/United States ; G102865/321033//Berger Endowment/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; Disease Models, Animal ; Mice ; *Memory, Short-Term/physiology ; Mice, Transgenic ; *Cholinergic Neurons/metabolism ; Receptor, Muscarinic M1/metabolism/genetics ; Humans ; Cerebral Cortex/metabolism ; Acetylcholine/metabolism ; *Memory Disorders ; },
abstract = {INTRODUCTION: The degeneration of basal forebrain cholinergic neurons is a key pathophysiological feature of Alzheimer's disease (AD). These cholinergic neurons target cortical neurons including those in the granular retrosplenial cortex (RSG) to facilitate essential cognitive functions. At the cellular level, acetylcholine supports working memory by inducing persistent firing that outlasts the stimulus, but how such cholinergic-induced persistent firing is altered in AD remains unknown.

METHODS: Using multiscale molecular and cellular analyses, we investigated neuron type-specific transcriptomic and physiological impairments of cholinergic persistent signaling in the RSG of 5xFAD mice.

RESULTS: Cholinergic inputs to RSG were reduced in 5xFAD mice. Expression of the Chrm1 gene encoding M1 muscarinic receptors was also reduced in RSG neurons, coupled with impaired cellular persistent firing.

DISCUSSION: The loss of M1 receptors suggests that allosteric M1 modulators being considered for treatment of AD symptoms may not be as effective on key cell types, necessitating further multiscale investigation.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology
Disease Models, Animal
Mice
*Memory, Short-Term/physiology
Mice, Transgenic
*Cholinergic Neurons/metabolism
Receptor, Muscarinic M1/metabolism/genetics
Humans
Cerebral Cortex/metabolism
Acetylcholine/metabolism
*Memory Disorders

@article {pmid42157196,
year = {2026},
author = {Zhang, P and Zhu, Q and Zhang, K and Qi, S},
title = {Porphyromonas gingivalis outer membrane vesicles drive neuroinflammation via TGM2-mediated mitochondria-associated endoplasmic reticulum membranes.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-026-08458-5},
pmid = {42157196},
issn = {1472-6831},
support = {SSH-2022-KJCX-B05//Shanghai Stomatological Hospital, Fudan University/ ; },
abstract = {BACKGROUND: Porphyromonas gingivalis (P.g), a key periodontal pathogen, is implicated in Alzheimer's disease (AD). Given that mitochondrial dysfunction is a common event happened in neurodegenerative diseases, mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) play a potential role in AD pathology. This study aimed to investigate the impact of P.g derived outer membrane vesicles (P.g-OMVs) on neuroinflammation in the onset and progression of AD, and to elucidate the underlying mechanism.

METHODS: Eight-week-old male C57BL/6 mice received bilateral gingival injections of P.g-OMVs (4 × 10⁸ particles) 3 times weekly for 8 weeks to assess cognitive impairment and neuroinflammation. RNA-seq identified differentially expressed genes (DEGs) and enriched pathway in brain tissues. In vitro, HT22 cells were treated with P.g-OMVs (5 µg/mL), and the expressions of inflammatory cytokines, transglutaminase 2 (TGM2) and ferroptosis markers were quantified. MAM formation and mitochondrial function regulated by TGM2, including mitochondrial Ca[2+] accumulation and membrane potential, were assessed, which further elucidated after knocking down TGM2 by siRNA.

RESULTS: P.g-OMVs induced significant cognitive impairment and​ neurodegeneration in mice, evidenced by escape latency in the MWM (p < 0.001) and accumulation of amyloid β plaques and hyperphosphorylated tau. RNA-seq highlighted DEGs enriched in mitochondrial pathways, notably targeting TGM2. In vitro, P.g-OMVs triggered inflammation evidenced by increased pro-inflammatory cytokines (IL-1β, IL-17, etc.) and reduced levels of IL-10 (p < 0.05), and led to the upregulation of TGM2 (p < 0.05). Crucially, co-localization of mitochondria and ER suggested that P.g-OMVs promoted MAM formation in neurons, accompanied by ​aberrant mitochondrial Ca[2+] levels​ and membrane potential. Additionally, altered expressions of ferroptotic markers were observed, including increased level of ACSL4 (p < 0.01) and decreased levels of GPX4 and xCT (p < 0.01). TGM2 knockdown reversed the inflammation, ferroptosis, mitochondrial dysfunction and MAM formation.

CONCLUSIONS: Our findings demonstrate that P.g-OMVs drive​ neuroinflammation and neuronal ferroptosis through a MAMs-associated mechanism. TGM2 acts as a key mediator, promoting MAM formation and subsequent mitochondrial dysfunction. These findings highlight TGM2 represents a potential therapeutic target for neuroinflammatory conditions linked to oral pathogens.},
}

@article {pmid42157213,
year = {2026},
author = {Lovró, Z and Sandberg, A and Zetterberg, H and Pierrou, S and Parkkola, R and Sjögren, N and Scheinin, M and Rinne, JO},
title = {Safety, tolerability and immunogenicity of vaccine ALZ-101 in patients with early Alzheimer's disease: randomised, controlled trial.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02082-9},
pmid = {42157213},
issn = {1758-9193},
abstract = {BACKGROUND: ALZ-101 is a therapeutic vaccine comprised of a stabilised oligomeric derivative of amyloid-β42 (Aβ42), denoted Aβ42CC, that elicits antibodies targeting a low-abundance, neurotoxic Aβ oligomer species. This first-in-human, single-center Phase 1b trial evaluated the safety, tolerability, and immunogenicity of ALZ-101, with exploratory biomarker and clinical outcomes, in participants with early Alzheimer's disease (AD).

METHODS: Thirty‑two participants with biomarker‑confirmed early AD (mean age ∼69 years, ∼30% female, Mini‑Mental State Examination ∼24, Alzheimer's Disease Composite Score [ADCOMS] ∼0.55, Clinical Dementia Rating-Sum of Boxes ∼3.0, ∼70% APOE ε4 carriers) were enrolled in a randomised, double‑blind, placebo‑controlled main study (Part A1) and a semi‑blinded extension (Part B). In Part A1, participants received intramuscular ALZ‑101 125 µg (n = 10) or 250 µg (n = 10) or placebo (n = 6) at Weeks 0, 4, 8, and 16. After ≥ 14 weeks of follow‑up, eligible participants (n = 23) entered Part B and received two or four additional 250 µg doses of ALZ‑101 with partial blinding of original allocation. An open‑label arm (Part A2) explored ALZ‑101 400 µg (n = 6) on the same schedule as Part A1. Primary endpoints were safety and tolerability. Secondary and exploratory endpoints included Aβ‑specific antibody responses, cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive/functional scales.

RESULTS: ALZ-101 was not associated with any clear safety signals, and no serious adverse drug reactions were observed. Sixteen asymptomatic ARIA‑H events, including two superficial siderosis events, occurred in nine participants (two initially on placebo, six on 125 µg, one on 250 µg), and one asymptomatic ARIA‑E occurred in the extension phase in a participant originally randomised to placebo; no ARIA was observed in the 400 µg arm. ALZ‑101 induced robust Aβ‑specific IgG responses in nearly all vaccinated participants, with classical primary/booster kinetics and high responder rates at all dose levels. No statistically significant between‑group differences were detected for pre‑specified CSF biomarkers or cognitive and functional outcomes versus placebo in the randomised phase. Over longer follow‑up in Part B, participants initially randomised to ALZ‑101 showed numerically smaller increases in CSF neurofilament light (NfL) and tau and a flatter ADCOMS trajectory than those initially on placebo, but these differences were not statistically significant. For CSF tau, attenuation of the increase seemed to be present already in Part A1, whereas for the more slowly changing NfL, potential attenuation emerged only over the longer Part B.

CONCLUSION: In this small Phase 1 study in early AD, ALZ‑101 was not associated with clear safety signals and elicited strong, durable Aβ‑specific antibody responses. Exploratory biomarker and ADCOMS findings are compatible with a possible disease‑modifying effect, but formal evidence of clinical efficacy is lacking, and all non‑primary analyses should be interpreted with caution. These results support further evaluation of ALZ‑101 in larger, adequately powered trials. Registered at clinicaltrials.gov: NCT05328115, 14 April 2022.},
}

@article {pmid42157271,
year = {2026},
author = {Crincoli, E and Savastano, MC and Savastano, A and Carlà, MM and Giannuzzi, F and Catania, F and Kilian, R and Rizzo, C and Rizzo, S},
title = {Artificial intelligence and neurodegeneration: state of the art and explainability.},
journal = {International journal of retina and vitreous},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40942-026-00807-4},
pmid = {42157271},
issn = {2056-9920},
abstract = {BACKGROUND: Alzheimer disease (AD) and Parkinson disease (PD) are an increasing healthcare concern and growing cause of disability in our century. The advent of the artificial intelligence (AI) era and the early changes in retina and optic nerve morphology detected in neurodegenerative diseases by recent literature opened the way to the perspective of a AI-based diagnosis for both conditions.

MAIN BODY: In AD a generalized decrease in macular Ganglion Cells-Inner Plexiform Layer (GC-IPL) and retinal nerve fiber layer (RNFL) and peripapillary RNFL thickness has been documented. Moreover, clinical AD is characterized by a lower choroidal thickness and higher choroidal vascularity index. AI can be predicted with around 80% accuracy based on small fundus vessels characteristics. Similarly, AI based on Optical Coherence Tomography (OCT) images showed very good performance in detecting AD, especially based on total macular volume (TVM) and GCL thickness. A combination of OCT and color fundus photographs (CFP) imaging reached 85% accuracy in detecting MCI. In PD typical retinal anomalies include a generalized thinning of the peripapillary RNFL with a degeneration pattern similar to the one of mitochondrial optic neuropathies, foveal pit widening, generalized retinal and retinal pigmented epithelium thinning and outer plexiform layer thickening. AI CFP-based detection of PD showed only 65% accuracy due to a low specificity, while multimodal imaging-based AI was the best approach, reaching a 100% sensitivity and 85% specificity.

CONCLUSION: In consideration of the overall very good performance, AD and PD are likely to benefit from the support of retinal-imaging based AI for early diagnosis. To optimize the performance, especially in terms of specificity, the use of multimodal imaging and possible integration with meta-data has been demonstrated to be the best technique, especially for PD diagnosis. However, training and testing on a larger sample size and longitudinal evaluation of the chosen models will be needed before application on general population. So far, explainability of the proposed models seems robust and coherent with the corresponding central nervous system damage.},
}

@article {pmid42157276,
year = {2026},
author = {Krick, KE and Chalk, JL and Lykins, JT and Wang, HP and Ferguson, CA and Shahid, SS and Weekman, EM and Wilcock, DM},
title = {TNF inhibition differentially impacts regional Abeta immunotherapy efficacy in the humanized hAb[SAA] mouse model.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02084-7},
pmid = {42157276},
issn = {1758-9193},
support = {1RF1NS130834//Foundation for the National Institutes of Health/ ; },
abstract = {BACKGROUND: The FDA approval of amyloid beta (Aβ) targeting immunotherapies offered the first opportunity to clinically modify Alzheimer's disease progression and give patients back precious months in the course of disease progression. The administration of these therapeutics has uncovered a common side effect called Amyloid Related Imaging Abnormalities (ARIA). While often asymptomatic, these adverse events have potential to escalate, and their commonality has encouraged further studies to mitigate their incidence. Increases in immune activation are important in immunotherapy action, though heightened release of cytokines have also been shown in ARIA development. TNF has been shown in early studies to increase with immunotherapy administration and subsequent ARIA development and TNF itself has been implicated in blood brain barrier dysfunction which could contribute to hemorrhagic ARIA (ARIA-H) development.

METHODS: This study assessed hemorrhage outcomes in an aged mouse model using MRI and Prussian blue histology, explored transcriptomic and protein changes with NanoString nCounter and Meso Scale Discovery, and we performed immunohistochemical stains for microglia/macrophages, astrocytes, and pericyte changes.

RESULTS: In this study, we established ARIA-H pathology in a humanized mouse model (hAβ[SAA]) via chronic Aβ immunotherapy administration. We saw significant hemorrhagic lesions in our model, despite low levels of cortical cerebral amyloid angiopathy (CAA) suggesting a role for CAA as a risk factor for ARIA but potentially not its driver. We also explored the role of TNF in ARIA progression by inhibiting soluble TNF alongside immunotherapy administration as a potential combination therapeutic to address ARIA. With TNF inhibition, we saw a reduction of hemorrhages in the hippocampus, but not in the cortex, suggesting a regional effect. Further, we saw additional regional differences between the cortex and hippocampus with TNF inhibition including macrophage activation markers and amyloid levels, suggesting a differential role for TNF signaling in these areas and a potential heterogeneity of cellular responses in each region.

CONCLUSION: We induced ARIA without significant cortical CAA pathology and identified regional differences with TNF inhibition including a potential benefit of treatment in the hippocampus and possible detriment to pathology in the cortex.},
}

@article {pmid42157283,
year = {2026},
author = {Jannati, A and Tobyne, S and Pascual-Leone, A},
title = {Re: Clarifying comparative claims in digital cognitive assessment: Assessing concurrent validity in a shared cohort.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42157283},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Neuropsychological Tests/standards ; Cohort Studies ; Reproducibility of Results ; *Cognition ; Male ; },
abstract = {In response to correspondence from Cognivue, Inc. regarding our publication (Jannati et al., 2025), we clarify that our analysis employed a rigorous paired-sample design using the same 930 participants from the Bio-Hermes-001 study for both the Digital Clock and Recall[®] (DCR) and Cognivue Clarity[®] assessments. The assertion that our findings rely on "nonequivalent cohorts" or "outdated regulatory data" is factually incorrect; performance metrics were calculated de novo using the harmonized study dataset. Furthermore, we address the omission of the Cognivue Amyloid Risk Measure (CARM), noting that comparing a cross-validated predictive model (DCR) with a post hoc metric derived from the same dataset (CARM) would introduce significant bias due to overfitting. We conclude by highlighting how head-to-head comparisons in diverse cohorts align with the recently published Global CEO Initiative on Alzheimer's Disease (CEOi) recommendations for digital cognitive assessment standards.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
*Neuropsychological Tests/standards
Cohort Studies
Reproducibility of Results
*Cognition
Male

@article {pmid42157320,
year = {2026},
author = {Estes, PW},
title = {Clarifying comparative claims in digital cognitive assessment: a matters arising on multimodal detection of cognitive impairment and amyloid positivity.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42157320},
issn = {1758-9193},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/psychology ; *Neuropsychological Tests ; *Alzheimer Disease/diagnosis ; *Amyloid beta-Peptides/metabolism ; },
abstract = {Digital cognitive assessments represent an important and rapidly evolving approach to detecting cognitive impairment and Alzheimer's disease-related pathology. Jannati et al. report promising findings using a multimodal digital clock and recall assessment to identify cognitive impairment and amyloid positivity. While this contribution is welcomed, several comparative statements regarding Cognivue[®] rely on historical regulatory data and do not reflect the contemporaneous peer-reviewed evidence base available at the time of manuscript preparation. This Matters Arising article clarifies the limitations of cross-study performance comparisons, addresses selective citation of a single early Cognivue publication, and summarizes subsequent peer-reviewed findings demonstrating Cognivue's psychometric validity, biomarker associations, and generalizability across diverse populations. These considerations highlight the importance of harmonized, contemporaneous comparisons when asserting relative performance among digital cognitive assessment tools.},
}

Humans
*Cognitive Dysfunction/diagnosis/psychology
*Neuropsychological Tests
*Alzheimer Disease/diagnosis
*Amyloid beta-Peptides/metabolism

@article {pmid42157525,
year = {2026},
author = {Aware, C and Woods, C and Khodakivskyi, P and Dwivedi, AK and Zuckerman, A and Govindarajan, M and Ivanich, K and Yu, W and Cui, J and Gu, Z and Goun, E and Ericsson, AC and Zafonte, R and Balchandani, P and Lin, AL},
title = {Stroke-induced gut microbiome dysbiosis accelerates Alzheimer's disease progression.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261449017},
doi = {10.1177/0271678X261449017},
pmid = {42157525},
issn = {1559-7016},
abstract = {Stroke survivors face an elevated risk of developing Alzheimer's disease (AD), yet the biological mechanisms linking these conditions remain poorly defined. Here, we show that a stroke-induced gut microbiome is a key driver of AD-related pathology. Fecal microbiota transplantation (FMT) from stroke patients into young triple-transgenic Alzheimer's disease (3xTg-AD) mice accelerated tau phosphorylation, increased neuroinflammation, and disrupted metabolic homeostasis in both the brain and gut, compared with FMT from healthy donors. Mice receiving stroke-derived microbiota exhibited persistent, donor-specific dysbiosis and broad metabolic reprogramming involving redox balance, nucleotide metabolism, and energy pathways in cecal contents and brain tissue. These metabolic disturbances were accompanied by widespread and region-specific transcriptional changes revealed by single-cell spatial transcriptomics, including glial activation, impaired neuron-glia communication, and dysregulation of mitochondrial, amyloid-processing and inflammatory pathways across cortical and hippocampal regions. Collectively, these findings identify post-stroke gut dysbiosis as a mechanistic contributor to heightened neurodegenerative vulnerability and AD risk, highlighting the gut-brain axis as a potentially modifiable target for preventing post-stroke dementia.},
}

@article {pmid42157534,
year = {2026},
author = {Xin, Y and Gardner, M and Tustison, NJ and Cook, P and Gee, J and Benitez, A and Jensen, JH and , and , and Bethlehem, R and Seidlitz, J and Alexander-Bloch, AF and Chen, AA},
title = {ComBat-Predict Enhances Generalizability of Neuroimaging Models to New Sites.},
journal = {Human brain mapping},
volume = {47},
number = {8},
pages = {e70546},
doi = {10.1002/hbm.70546},
pmid = {42157534},
issn = {1097-0193},
support = {R01MH123550/NH/NIH HHS/United States ; R01MH132934/NH/NIH HHS/United States ; R01MH133843/NH/NIH HHS/United States ; R01MH134896/NH/NIH HHS/United States ; },
mesh = {Humans ; *Neuroimaging/methods/standards ; *Magnetic Resonance Imaging/methods ; *Alzheimer Disease/diagnostic imaging/pathology ; Aged ; Male ; Female ; *Brain/diagnostic imaging ; *Multicenter Studies as Topic ; *Cerebral Cortex/diagnostic imaging/pathology ; Atrophy/pathology ; Middle Aged ; Aging/pathology ; Aged, 80 and over ; },
abstract = {Neuroimaging is vital in quantifying brain atrophy due to typical aging and due to neurodegenerative diseases. To collect large samples necessary to model lifespan brain development, research consortiums aggregate images acquired across multiple study sites. Previous studies have demonstrated that this multi-site study design can lead to site-related bias, necessitating harmonization of these "site effects." However, current methodologies are unable to generalize to new sites outside the original harmonized sample, limiting translation to new sites or clinical practice. Here, we propose a method called ComBat-Predict (CB-Predict) building upon the ComBat method for site effect adjustment, which extends to data from a new site with smaller sample sizes and unknown site effects. In data from the Alzheimer's Disease Neuroimaging Initiative, our proposed method mitigates bias and yields high accuracy in predicting cortical thickness measures when generalizing the model to new data. Furthermore, we demonstrate that our proposed harmonization method can reduce site-related variance in centile scores estimated using data from the Lifespan Brain Chart Consortium. Altogether, our results demonstrate that CB-Predict effectively harmonizes new sites and thereby enables effective translation of neuroimaging models to additional samples.},
}

Humans
*Neuroimaging/methods/standards
*Magnetic Resonance Imaging/methods
*Alzheimer Disease/diagnostic imaging/pathology
Aged
Male
Female
*Brain/diagnostic imaging
*Multicenter Studies as Topic
*Cerebral Cortex/diagnostic imaging/pathology
Atrophy/pathology
Middle Aged
Aging/pathology
Aged, 80 and over

@article {pmid42157556,
year = {2026},
author = {Abozaid, YM and Khalaf, MM and Abdel-Fattah, MM and Khattab, MA and Shehata Messiha, BA},
title = {Targeting alpha 7 nicotinic acetylcholine receptors by galantamine alleviates doxorubicin-induced cardiotoxicity via modulation of PI3K/AKT, Bax/Bcl-2, and NF-κB/TNF-α pathways.},
journal = {Immunopharmacology and immunotoxicology},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/08923973.2026.2673955},
pmid = {42157556},
issn = {1532-2513},
abstract = {BACKGROUND: Doxorubicin is a potent anthracycline employed in the management of several malignant conditions. While it serves as an effective anticancer agent, its therapeutic application is constrained by dose-dependent cardiotoxicity. Galantamine is a reversible competitive antagonist of cholinesterase utilized in the management of Alzheimer's disease.Aim of the workThis work sought to ascertain the cardioprotective benefits of GALA versus cardiotoxicity triggered by DOX and elucidate the fundamental molecular pathways.

MATERIALS AND METHODS: Rats were randomized to four groups, as follows: control, GALA (5 mg/kg, P.O.), DOX single dose (20 mg/kg, I.P), and DOX + GALA.

RESULTS: Unlike the DOX group, GALA pretreatment mitigated cardiotoxicity, as revealed by a notable drop in serum CK-MB and CTnI, along with marked improvement in the histopathological features of heart tissues. GALA also diminished oxidative damage, as recognized by reduced MDA and elevated GSH and SOD. Moreover, GALA pretreatment reduced DOX-induced inflammation, as revealed by a decline in NF-κB, along with TNF-α and IL-6. Furthermore, GALA pretreatment mitigated DOX's apoptotic effects, as revealed by reduced Bax and caspase-3, alongside an elevation in Bcl-2 and its upstream signaling pathway PI3K/AKT.

CONCLUSION: These findings indicated that GALA's protective impact versus DOX-induced cardiotoxicity is attributed to its capability to modulate PI3K/AKT, Bax/Bcl-2, and NF-κB/TNF-α pathways.},
}

@article {pmid42157624,
year = {2026},
author = {Granberg, T and Blystad, I and Fällmar, D and Savitcheva, I and van Westen, D and Westman, E},
title = {[Brain imaging in cognitive disorders - from diagnosis to treatment and monitoring].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42157624},
issn = {1652-7518},
mesh = {Humans ; Magnetic Resonance Imaging ; *Neuroimaging/methods ; Tomography, X-Ray Computed ; *Cognition Disorders/diagnostic imaging/therapy/diagnosis ; *Brain/diagnostic imaging/pathology ; Alzheimer Disease/diagnostic imaging/therapy ; Positron-Emission Tomography ; },
abstract = {Brain imaging is essential in the diagnostic workup of cognitive disorders. Computed tomography (CT) is usually the first-line method due to accessibility and patient comfort, whereas magnetic resonance imaging (MRI) offers higher diagnostic precision and is required before anti-amyloid therapy. MRI adds value by detecting microvascular pathology, enabling volumetric analysis, and ensuring safe monitoring of amyloid-related imaging abnormalities (ARIA). National Swedish MRI protocols and structured reporting templates support harmonized diagnostics and follow-up. Nuclear medicine methods are useful for complex cases to assess glucose metabolism, amyloid burden or dopamine transport function. With emerging treatment options for Alzheimer's disease, standardized imaging and close collaboration across specialties are essential for upscaling diagnostic routines and for safe and efficient care.},
}

Humans
Magnetic Resonance Imaging
*Neuroimaging/methods
Tomography, X-Ray Computed
*Cognition Disorders/diagnostic imaging/therapy/diagnosis
*Brain/diagnostic imaging/pathology
Alzheimer Disease/diagnostic imaging/therapy
Positron-Emission Tomography

@article {pmid42157700,
year = {2026},
author = {Rix, T and Sands, CJ and Villaseñor, A and Gradillas, A and Barbas, C and Chekmeneva, E and Want, EJ and Ebbels, TMD},
title = {Lipid Class Prediction from MS1 Data using Gaussian Graphical Models.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c08067},
pmid = {42157700},
issn = {1520-6882},
abstract = {Liquid chromatography-mass spectrometry (LC-MS) untargeted analysis enables comprehensive lipid profiling of biological samples. However, system-level interpretation is often limited by the large number of unannotated features. Assigning features to lipid classes provides a higher-level, yet informative, overview that complements detailed structural analysis and supports biological interpretation at the class level. Recent advances in the systematic prediction of chemical class using tandem mass spectrometry (MS2) help address this; however, a substantial proportion of features in untargeted LC-MS data sets are typically characterized only at the MS1 level. Here, we present a workflow to systematically predict the lipid class from MS1-only data in untargeted LC-MS, without requiring prior annotations or MS2. Motivated by previous research showing that Gaussian graphical models (GGMs) estimated from feature intensities can encode the lipid class structure, our method, GgmLipidClassifier (GLC), combines conventional accurate-mass database searching with a GGM-derived network structure in a unified scoring framework to predict lipid class according to the LIPID MAPS Structure Database (LMSD) ontology. Across three human serum and plasma data sets, GLC achieved overall accuracies of 82-90% at the LMSD main class-level and 72-86% at the lipid subclass level, with improved accuracy and reduced uncertainty compared to closest-m/z matching. GLC provides class predictions for most detected features and also generates prediction quality scores to support downstream interpretation. Applied to serum samples from an Alzheimer's disease study, lipid class enrichment based on GLC predictions was highly consistent with class enrichment derived from ground-truth lipid annotations. Importantly, GLC extended coverage to classes missing from the annotation set, revealing biologically plausible associations with Alzheimer's disease, including cholesterol and derivatives, vitamin D3 and derivatives, and plasmalogen glycerophosphoethanolamines. Overall, GLC provides robust lipid class predictions from MS1-only data, generating lipid class assignments for most detected features and complementing conventional analysis to support broader system-level interpretation.},
}

@article {pmid42157845,
year = {2026},
author = {Bouton, J and Bretteville, A and Tresadern, G and Shaffer, P and Austin, N and Buijnsters, P and Cedervall, EP and Darville, N and Fonteyn, I and Leenaerts, J and Lamenca, CM and Mertens, L and Peeters, D and Velter, AI and Roosbroeck, YV and Ebneth, A and Bartolomé, JM and Trabanco, AA and Oehlrich, D},
title = {Discovery of 5‑Azaindole Inhibitors of O‑GlcNAcase for the Treatment of Alzheimer's Disease and Related Tauopathies.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {5},
pages = {1096-1105},
pmid = {42157845},
issn = {1948-5875},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid-β plaque accumulation and intracellular tau neurofibrillary tangles, with tau pathology correlating more closely with cognitive decline. Modulation of tau phosphorylation through the regulation of O-GlcNAcylation, a post-translational modification controlled by O-GlcNAcase (OGA), represents a promising therapeutic strategy. In this study, we report the optimization of a pyrimidine hit identified by high-throughput screening, leading to the discovery and optimization of a novel series of 5-azaindole-based OGA inhibitors. From this series, compound 24 was identified as an in vivo tool candidate that demonstrated a favorable pharmacokinetic profile and measurable brain exposure. Pharmacodynamic studies in murine models demonstrated that compound 24 induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the in vivo target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation.},
}

@article {pmid42157856,
year = {2026},
author = {Blazquez-Folch, J and Calm, B and Hinojosa-Calleja, A and García-Gutiérrez, F and Alegret, M and Muñoz, N and Cano, A and Fernández, MV and Miguel, A and Solivar, A and De Rojas, I and Valenzuela-Seba, A and García-González, P and Puerta, R and Olivé, C and Capdevila-Bayo, M and Muñoz-Morales, Á and Bayón-Buján, P and Montrreal, L and Orellana, A and Ortega, G and Sanz-Cartagena, P and Rosende-Roca, M and Cantero-Fortiz, Y and Gurruchaga, MJ and Tarraga, L and Butler, C and Montalban, X and Boada, M and Ruiz, A and Marquié, M and Valero, S},
title = {Listening for Alzheimer's clues: machine learning analysis of multidomain speech features for cognitive impairment screening.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1816747},
pmid = {42157856},
issn = {1663-4365},
abstract = {INTRODUCTION: Early detection of Alzheimer's disease (AD) is critical for timely intervention, particularly during the mild cognitive impairment (MCI) stage. This study aimed to develop and evaluate a multidomain speech analysis framework to support cognitive screening, biomarker prediction within the amyloid, tau and neurodegeneration (ATN) framework, and estimation of cognitive function across the AD continuum.

METHODS: This study analyzed speech from 2,320 individuals spanning the cognitive spectrum-including those with subjective cognitive decline (SCD), MCI, and Alzheimer's disease dementia (ADD)-using three spoken tasks (∼3 min) and extracted multidomain features including acoustic, lexical, syntactic, and semantic features. Machine learning models were trained to classify cognitive status, predict amyloid, tau and neurodegeneration (ATN) biomarker positivity, and estimate scores across six neuropsychological domains.

RESULTS: Multidomain speech models achieved high performance in differentiating cognitive stages, with AUC values of up to 0.94 for SCD vs. ADD and 0.82 for SCD vs. MCI classifications. In biomarker prediction, the models yielded AUCs of 0.71, 0.74, and 0.73 for ATN classification, respectively. Speech-based models also showed strong correlations (up to 0.83) with cognitive function scores. Feature importance analysis revealed that verbal fluency measures were the most predictive. Explainability analyses indicated minimal dependency on age, sex, or education, supporting model fairness.

DISCUSSION: These findings show that multidomain speech features capture clinically and biologically relevant information across the AD continuum, enabling cognitive classification, biomarker prediction, and cognitive estimation. These results underscore the potential of speech analysis as a non-invasive, accessible tool for scalable cognitive screening and early detection of AD. These results underscore the potential of speech analysis as a non-invasive, accessible tool for scalable cognitive screening and early detection of AD.},
}

@article {pmid42157881,
year = {2026},
author = {Jabbari, S and Zakaria, ZA and de Menezes, IRA and Mohammadi, S},
title = {Rhamnazin attenuates Amyloid β-Peptide (1-42) induced spatial memory impairments by modulation of BDNF-ERK signaling pathway.},
journal = {3 Biotech},
volume = {16},
number = {6},
pages = {200},
pmid = {42157881},
issn = {2190-572X},
abstract = {Rhamnazin (Rham), a natural flavonoid, possesses various medicinal benefits including anti-inflammatory, antioxidant, antiangiogenic, and antibacterial activities. Additionally, Rham showed neuroprotective effects when assessed using the chronic stress-induced cognitive impairment assay. In this intriguing investigation, researchers delved into the working memory and spatial reference memory of Rham, utilizing a rat model of Alzheimer's disease (AD) induced by amyloid β1-42 (Aβ1-42). Administering Aβ1-42 directly into the ventricles led to notable cognitive impairments in behavioral assessments of rats with AD. However, chronic treatment of Rham (30, 60, and 120 mg/kg) once per day during five consecutive days improved the cognitive functions of AD-induced rats in a dose-dependent manner which was not observed following the acute Rham treatment. Concurrently, Rham administration also increased the levels of BDNF and phosphorylated ERK in the hippocampus. Moreover, the cognitive boost triggered by Rham was replicated through the overproduction of BDNF in the hippocampus. However, this effect was thwarted by either the bilateral delivery of lentiviruses expressing BDNF shRNA into the hippocampus or by a targeted injection of an ERK inhibitor. In conclusion, chronic treatment with Rham improves the cognitive deficits in AD-induced rats possibly via the upregulation of BDNF/ERK signaling pathway in hippocampus.},
}

@article {pmid42157911,
year = {2025},
author = {Waqar, Z and Sethi, P and Jain, D and Singh, K and Alsaidan, OA and Alzarea, SI and Gupta, JK and Saxena, S and Sharma, MC},
title = {Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.},
journal = {Current genomics},
volume = {26},
number = {6},
pages = {469-494},
pmid = {42157911},
issn = {1389-2029},
abstract = {Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by the pathological aggregation of proteins such as amyloid-β, tau, and alpha-synuclein. These hallmark proteins play central roles in disease progression and represent promising targets for therapeutic intervention. Advances in precision medicine, driven by genomic technologies such as CRISPR-Cas systems, RNA-based therapies, and high-throughput sequencing, have enabled the development of tailored strategies to modulate these pathological pathways. This review examines the integration of genomic approaches in targeting amyloid-β, tau, and alpha-synuclein, emphasizing their potential to mitigate disease progression and improve patient outcomes. We highlight current progress in preclinical and clinical studies, discuss challenges associated with translating these therapies into clinical practice, and explore future directions for achieving therapeutic precision in neurodegenerative disorders. By examining the interplay of genetic, molecular, and therapeutic innovations, this review underscores the transformative potential of genomic medicine in addressing the unmet needs of neurodegenerative disease treatment.},
}

@article {pmid42157943,
year = {2026},
author = {Li, R and Yao, J and Peng, W and Zheng, L and Wu, X and Shui, X and Zheng, X and Tian, W and Wang, L and Zhou, Y and Ruan, X and Pan, X and Zhang, T and Liu, Y and Lee, TH and Chen, D},
title = {A Novel PROTAC Confers a Dual Benefit Against Amyloid and Tau Pathology in Alzheimer's Disease via DAPK1 Degradation.},
journal = {International journal of biological sciences},
volume = {22},
number = {9},
pages = {4724-4746},
pmid = {42157943},
issn = {1449-2288},
mesh = {*Death-Associated Protein Kinases/metabolism/genetics ; Animals ; *Alzheimer Disease/metabolism/drug therapy ; Mice ; Female ; Humans ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Proteolysis ; Phosphorylation ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that is caused by multiple factors, characterized by a progressive decline in cognitive ability, extracellular amyloid-β (Aβ) plaques, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Current treatment strategies can provide only symptomatic treatment or limited efficacy, highlighting the need to intervene in the upstream regulatory factors that drive both amyloid and tau pathologies. Death-associated protein kinase 1 (DAPK1) is a key driver upstream of both amyloid precursor protein processing and tau phosphorylation, simultaneously promoting amyloidogenesis and tau-mediated pathology in AD. In this study, we developed CP1, a bifunctional proteolysis-targeting chimera (PROTAC), to recruit E3 ubiquitin ligase to DAPK1, thereby inducing the ubiquitination and proteasomal degradation of DAPK1. CP1 efficiently eliminated the DAPK1 protein in primary cortical neurons without affecting its mRNA level, resulting in reduced Aβ generation and tau hyperphosphorylation. In vivo, upon systemic administration, CP1 effectively crossed the blood-brain barrier, degraded DAPK1, and consequently reduced the Aβ plaque burden and mitigated neuroinflammation in female 5xFAD mice. In a AAV-hTau-P301L tauopathy model, CP1 treatment suppressed tau hyperphosphorylation, preserved NeuN- and MAP2-positive neurons, attenuated astrocytic and microglial activation, and ultimately restored learning and memory abilities in both male and female mice. In summary, these findings demonstrate that degrading DAPK1 via a PROTAC strategy simultaneously mitigates both amyloid and tau pathology, indicating that CP1 is an effective candidate for disease-modifying therapy.},
}

*Death-Associated Protein Kinases/metabolism/genetics
Animals
*Alzheimer Disease/metabolism/drug therapy
Mice
Female
Humans
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
Proteolysis
Phosphorylation

@article {pmid42158001,
year = {2026},
author = {Torossian, T and Abla, KK and Dakour, J and Assi, S and Karam, M and Mhanna, R},
title = {Comparative evaluation of donepezil-loaded polymeric and liposomal nanoparticles for Alzheimer's disease: biocompatibility, drug release kinetics, and cellular uptake study.},
journal = {RSC advances},
volume = {16},
number = {29},
pages = {26222-26237},
pmid = {42158001},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition that accounts for approximately 65% of all dementia cases worldwide. Donepezil (DNP) is an acetylcholinesterase inhibitor that is widely prescribed for AD patients. However, extensive first-pass metabolism and the presence of the blood-brain barrier (BBB) significantly restrict its therapeutic efficacy. To address these challenges, two nanocarrier systems were developed: biodegradable polycaprolactone (PCL) and polyvinyl alcohol (PVA)-based polymeric nanoparticles, and dipalmitoylphosphatidylcholine (DPPC)-based liposomes. DNP-loaded PCL/PVA double emulsion nanoparticles and DPPC liposomes were prepared and characterized based on their particle sizes, uniformity, zeta potential, entrapment efficiency, Fourier transform infrared spectroscopy (FTIR), and in vitro drug release kinetics. Their safety profiles and cellular uptake potential were evaluated using the trypan blue exclusion assay and qualitative and quantitative cellular uptake assays with the human endothelial-like ECV-304 and neuronal PC-12 cell lines. The mean particle sizes of polymeric nanoparticles and liposomes were 175.97 ± 11.72 nm and 115.18 ± 4.63 nm, respectively, with low polydispersity indices (<0.3) and negative zeta potentials. FTIR analysis confirmed the absence of chemical interactions between DNP and formulation components. In addition, both nanocarrier systems demonstrated favorable biocompatibility, with cell viability exceeding 80%. Liposomes exhibited a more controlled drug release profile over 48 hours compared to polymeric nanoparticles. In contrast, both formulations exhibited significantly higher cellular uptake compared to their respective controls, with polymeric nanoparticles showing significantly higher cellular uptake than liposomes in ECV-304 cells (27.41 ± 2.38%, p < 0.05), demonstrating that carrier composition is a key determinant of nanoparticle-cell interactions independent of targeting ligands or surface modifications. This suggests that polymeric nanoparticles enhance in vitro cellular uptake in endothelial-like cells, warranting further in vivo investigation for their brain delivery potential.},
}

@article {pmid42158156,
year = {2026},
author = {Li, R and Chen, Z and Jiang, Y and Yan, S and He, J and Yan, J and Zong, G and Yi, Z and Ren, X and Jia, B},
title = {Electroacupuncture for treating the cognitive symptoms of Alzheimer's disease: a randomized controlled trial.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1834514},
pmid = {42158156},
issn = {1664-0640},
abstract = {INTRODUCTION: The long-term efficacy of electroacupuncture (EA) in treating cognitive symptoms of Alzheimer's disease (AD) remains unclear, and its time-dependent relationship requires further investigation.

METHODS: Sixty-six patients were allocated to the EA or sham EA group, with stimulation for 20 minutes, for a 24-week treatment period, and were followed-up at 4 weeks. The primary outcome was the mean change in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score. Activities of daily living and behavioral and psychological symptoms were also assessed.

RESULTS: After 24 weeks of intervention, patients demonstrated significant improvements in ADAS-Cog scores, with sustained benefits observed during the 4-week follow-up period. In addition, improvements were observed in activities of daily living and behavioral and psychological symptoms.

DISCUSSION: The use of EA as a promising nonpharmacological intervention for AD.

CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/showproj.html?proj=151275, identifier (ChiCTR2200056329).},
}

@article {pmid42158158,
year = {2026},
author = {Pozuelo Moyano, B and Orgeta, V and von Gunten, A and Vandel, P and Ma, R and Stewart, R and Mueller, C},
title = {Late-life difficult-to-treat depression and dementia subtypes: a naturalistic cohort study using electronic health records.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1795874},
pmid = {42158158},
issn = {1664-0640},
abstract = {INTRODUCTION: Late-life difficult-to-treat depression (LL-DTD) and dementia frequently coexist in later life, but it remains unclear whether clinical and sociodemographic characteristics, as well as medication exposure patterns, differ across dementia subtypes among older adults with both conditions.

METHODS: We analysed anonymised electronic health records from a south London catchment area. We included patients aged ≥60 years at first recorded depression diagnosis with a dementia diagnosis. LL-DTD was defined as inadequate response to ≥2 antidepressant trials. Dementia diagnoses were classified as Alzheimer's disease (AD), vascular dementia (VD), mixed AD/VD, dementia with Lewy bodies (DLB), or other/unspecified dementia. Around the index depressive episode, we captured sociodemographics, depressive symptoms, physical comorbidity, and medication indicators. We used multivariate logistic regression to examine cross-sectional correlates distinguishing dementia subtypes (with AD as reference) within the LL-DTD and dementia sample. We conducted stratified analyses comparing non-AD versus AD dementia by the temporal order of dementia and depression diagnoses.

RESULTS: Among 890 older adults with LL-DTD and dementia, AD was the most common subtype (33.9%), followed by mixed AD/VD (22.5%), VD (22.2%), other/unspecified dementia (15.2%), and DLB (6.2%). Depressive symptom profiles and psychotropic treatment history were broadly similar across subtypes. Compared with AD, VD was associated with greater functional impairment, while greater physical comorbidity burden was more evident in VD and mixed AD/VD.

DISCUSSION: Somatic multimorbidity and functional impairment provided the clearest clinical separation between subgroups, while depressive symptom patterns and medication exposure appeared largely non-specific across dementia subtypes. This underscores the importance of multimorbidity and physical health burden in understanding heterogeneity of dementia outcomes in LL-DTD.},
}

@article {pmid42158303,
year = {2025},
author = {Safavian, K and Cheki, M and Heydarheydari, S},
title = {Systematic review of curcumin-based optical imaging for amyloid-β detection in Alzheimer's disease models.},
journal = {Current journal of neurology},
volume = {24},
number = {2},
pages = {168-176},
pmid = {42158303},
issn = {2717-011X},
abstract = {Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque accumulation and cognitive decline. Early and precise Aβ detection is vital for effective therapeutic intervention. Curcumin-based fluorescent probes offer high specificity, non-invasive imaging compatibility, and deep tissue penetration, making them promising tools for optical Aβ imaging. This systematic review evaluates preclinical studies on curcumin-based fluorescent probes to assess their photophysical properties, imaging capabilities, and potential applications in detecting Aβ plaques in mouse models of AD. Methods: A comprehensive literature search was performed in PubMed and ScienceDirect (2000-2024). Eligible studies were original English-language articles using curcumin-based probes for optical imaging of Aβ in Alzheimer's mouse models. Data extraction focused on imaging parameters such as binding affinity [dissociation constant (Kd)], emission wavelength, quantum yield, fluorescence enhancement, and delivery methods. Results: Thirteen preclinical studies met the inclusion criteria and were analyzed. CRANAD-102 probe showed the highest binding affinity (Kd = 7.5 nM) while CRANAD-3 achieved the most significant fluorescence intensity (39.5-fold). Emission wavelengths averaged 690 nm, with longer wavelengths facilitating deeper tissue imaging. Quantum yields ranged from 0.011 to 0.40, with the highest yield (20.31) observed in CH2Cl2 and effective doses averaging 2.0 mg/kg. Innovative delivery methods, such as aerosolized formulations and micelle-based probes, expanded diagnostic applications, including non-invasive retinal imaging. Conclusion: Curcumin-based fluorescent probes exhibit high specificity for Aβ aggregates, effective deep tissue imaging, and non-invasive delivery potential, making them promising tools for preclinical Alzheimer's diagnostics. However, their clinical translation requires further validation in standardized preclinical and translational studies.},
}

@article {pmid42158310,
year = {2025},
author = {Jain, SK and Sharma, S and Singh, VK and Matreja, PS},
title = {Transplantation of human glial cells into murine brains: A systematic review of efficacy and safety in neurodegenerative disorders.},
journal = {Current journal of neurology},
volume = {24},
number = {2},
pages = {154-167},
pmid = {42158310},
issn = {2717-011X},
abstract = {Background: Neurodegenerative diseases impact millions of individuals globally. Over the years, brain research has predominantly focused on neurons, but attention is now shifting to glial cells, the brain's support cells, which play a vital role in neurodegenerative disorders. Therefore, glial cell transplantation represents a groundbreaking treatment approach for various neurodegenerative disorders, with the potential to restore neuronal function. We evaluated the evidence on the therapeutic effectiveness of human glial cell transplantation in neurodegenerative disorders. Methods: The literature review was performed in PubMed, Scopus, and Web of Science from 2000 to 2024. The authors independently reviewed the screened articles. The study outcomes on cell differentiation, long survival restoration of neuron function, and adverse outcomes were analyzed. Results: Study results highlight promising findings, including astrocytes improving motor function and slowing disease progression in neurodegenerative animal models through neurotrophic factor secretion and reduced inflammation. Similarly, microglia transplantation has demonstrated effectiveness in reducing α-synuclein toxicity in Parkinson's disease (PD), removing amyloid-β plaques in Alzheimer's disease (AD) models, and enhancing neuronal survival. Additionally, in demyelinating pathologies like multiple sclerosis (MS), oligodendrocyte transplantation promotes remyelination, restoring axonal conduction and enhancing functional outcomes. Cografting astrocytes with neuro progenitor cells significantly improved dopamine neuron engraftment and survival for at least 6 months post-transplantation. Conclusion: The transplantation of human glial cells offers promising therapeutic potential for neurodegenerative disorders, improving neuronal survival, restoring damaged circuits, and reducing disease progression.},
}

@article {pmid42158458,
year = {2026},
author = {Hackett, K and Wurtz, H and Zhu, CW and Loizos, M and Berroa, F and Ramos Espinoza, H and Federman, A and Sano, M},
title = {Older adults' views of passive smartphone monitoring for dementia risk: a multi-method analysis.},
journal = {Innovation in aging},
volume = {10},
number = {6},
pages = {igag034},
pmid = {42158458},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: Functional difficulties are hallmark signs of incident cognitive decline and progression to dementia but are challenging to measure in clinics. Passive smartphone monitoring enables continuous tracking of everyday behaviors and may improve the status quo of dementia risk assessment, but acceptability is understudied. This study evaluated older adults' attitudes toward personal smartphone monitoring for dementia risk and identified barriers and facilitators to acceptability.

METHODS: Seventeen older adults completed a semi-structured interview followed by a Likert-scale rating to measure acceptability. Transcripts were analyzed using hybrid inductive-deductive thematic analysis. Exploratory correlations examined associations between acceptability ratings and participant features.

RESULTS: Participants identified unique benefits of smartphone monitoring, including enhanced scope of measurement, greater ecological validity and personalization, and improved accessibility. Potential disadvantages were confounding variables that threaten validity and concerns about privacy/data security. Preferences for clinical implementation that may improve acceptability included extended monitoring options, assurances of privacy safeguards, control over data, and continued face-to-face interactions with one's medical team. Most participants (13/17) were likely or extremely likely to participate in future smartphone monitoring research; higher likelihood was associated with lower depression (r = -.49, p = .046) and White vs non-White race (U = 57.50, n1 = 10, n2 = 7 p = .025, r = .57).

DISCUSSION AND IMPLICATIONS: Findings offer insights to enhance the acceptability of smartphone monitoring, including transparent review of procedures, privacy safeguards, and existing evidence. Outstanding requirements for clinical implementation include streamlining results to minimize physician burden and accounting for confounders that threaten data integrity. Our small, research-savvy cohort necessitates follow-up in other settings.},
}

@article {pmid42158460,
year = {2026},
author = {Kalesnikava, VA and Madden, B and Vugdalic, N and Lin, P and Mahmoudi, E},
title = {When context matters: social disparities in preventable hospitalizations among Medicare beneficiaries with dementia.},
journal = {Innovation in aging},
volume = {10},
number = {6},
pages = {igag035},
pmid = {42158460},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: We examined geographic variation in the risk of potentially preventable hospitalization (PPH) among individuals with Alzheimer's disease and related dementias.

RESEARCH DESIGN AND METHODS: In this cross-sectional study, we analyzed a 20% random sample of 2017-2018 traditional Medicare claims (n = 67,110), merged with the Area Health Resource File and National Neighborhood Data Archive. Multivariable generalized estimating equation models adjusted for age, sex, frailty index, rurality (metropolitan; micropolitan; rural), and county-level numbers of primary care physicians and hospitals. PPH risk was assessed for the overall cohort, residents of highly disadvantaged areas, and those in rural-or-micropolitan areas.

RESULTS: One-third of hospitalizations were PPHs. Urinary tract infection (33.8%), heart failure (25.7%), and pneumonia (18.6%) accounted for 78% of all PPHs. Unadjusted PPH rates were higher in highly disadvantaged areas (23.9%) compared to low-disadvantaged areas (20.6%). In the overall sample, Black and Hispanic individuals had higher odds of PPH than White individuals, as did those in highly disadvantaged areas compared to low-disadvantaged areas. Among highly disadvantaged urban and rural-or-micropolitan area residents, adjusted PPH rates were 23% and 27%, respectively. Odds of PPH were markedly higher in highly disadvantaged rural-or-micropolitan areas compared with low-disadvantaged areas. Racial/ethnic disparities diminished in these areas, while risk increased for female adults compared with male adults.

DISCUSSION AND IMPLICATIONS: The highest PPH risk occurred in highly disadvantaged rural-or-micropolitan areas. Although racial/ethnic disparities were attenuated in these populations, the overall PPH risk was elevated. Policy efforts should prioritize expanding access to ambulatory care in disadvantaged areas.},
}

@article {pmid42158589,
year = {2026},
author = {Tran, CM and Reddy, N and Thomas, JK and Venugopal, V and Bowser, R},
title = {CHI3L1 (YKL-40) and Chit-1 expressing glia in the white matter of ALS, FTLD and AD: correlations to pathology and disease duration.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001225},
pmid = {42158589},
issn = {2632-6140},
abstract = {BACKGROUND: Chitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1) protein levels are increased in the cerebrospinal fluid (CSF) of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Few studies have examined the spatial expression of chitinase-expressing cells with respect to neuropathologic hallmarks of disease.

METHODS: RNA sequencing was used to examine Chit-1 and CHI3L1 gene expression in the spinal cord and motor cortex. Immunohistochemistry was used to characterise the distribution of Chit-1 and CHI3L1 expressing cells in ALS, C9-ALS, FTLD, AD and non-neurologic disease controls. Immunofluorescence confocal microscopy was used to correlate distribution of Chit-1 and CHI3L1 expressing cells to TDP-43 pathology.

RESULTS: Chit-1 gene expression was increased in the spinal cord, and CHI3L1 expression was increased in both the spinal cord and motor cortex of patients with sALS and C9-ALS when compared with controls. Highest levels of Chit-1[+] glia were in cortical regions that contain hallmark neuropathology for each neurodegenerative disease. CHI3L1[+] glia were only significantly increased in sALS. Neither Chit-1[+] nor CHI3L1[+] glia was in close proximity to phosphorylated TDP-43 (pTDP) containing neurons in the motor cortex grey matter; however, there was a significant co-localisation of glial pTDP with Chit-1 and CHI3L1 in the motor cortex white matter.

CONCLUSIONS: Chit-1 and CHI3L1 expressing cells were most abundant in the white matter of cortical regions affected by each neurodegenerative disease and the spinal cord. Chit-1 or CHI3L1 expressing cells in the white matter often contained pTDP. We also observed correlations between levels of Chit-1 or CHI3L1 expressing cells in the white matter to disease duration.},
}

@article {pmid42158807,
year = {2026},
author = {Kim, D and Ryu, S and Chee, W and Im, EO},
title = {A culturally tailored virtual intervention for Alzheimer's family caregivers: Addressing practical challenges and future directions.},
journal = {Archives of gerontology and geriatrics plus},
volume = {3},
number = {1},
pages = {},
pmid = {42158807},
issn = {2950-3078},
abstract = {BACKGROUND: As interest in virtual care delivery grows, few studies have rigorously explored the real world implementation challenges of culturally tailored, technology-based interventions for Asian American caregivers of persons living with Alzheimer's Disease (PLAD). This study aims to identify and examine key practical barriers to implementing such interventions and to inform the development of more effective and sustainable virtual support programs.

METHODS: This study draws on an ongoing virtual intervention targeting Asian American caregivers of PLAD. Data sources include weekly research diaries maintained by intervention team members and meeting minutes from regular team discussions. A simple content analysis was conducted to identify recurring themes and challenges faced during implementation.

RESULTS: Seven major challenges were identified: (a) difficulties in retention; (b) concerns regarding participant authenticity and fraudulent cases; (c) technological barriers and challenges with virtual reality (VR) features; (d) variability in cultural tailoring needs; (e) stigma and challenges in building rapport; (f) time zone and geographic constraints; and (g) limited resources available for Asian American caregivers. To address these issues, recommended strategies include: flexible and supportive delivery with progress tracking, multilayered participant verification and education, technical support and intuitive design, bicultural perspectives and ongoing training, trust-building and encouragement of help-seeking behaviors, prioritizing time zone compatibility and providing flexible engagement options, and advocacy for expanded caregiver resources.

CONCLUSIONS: Practical and cultural challenges must be addressed when designing and delivering technology-based interventions. Incorporating these considerations can enhance caregiver resilience, improve engagement, and support better outcomes for Asian American families affected by AD.},
}

@article {pmid42158866,
year = {2026},
author = {Li, L and Zhao, X and Zeng, L and Li, Z and Zhao, K and Cai, Z and Liu, R},
title = {Targeting the miR-32533/CREB5 axis: a promising immunomodulatory and therapeutic strategy for Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1780328},
pmid = {42158866},
issn = {1664-3224},
}

@article {pmid42159020,
year = {2026},
author = {Andersen, P and Bonnard, A and Börjesson Hanson, A and Kivipelto, M},
title = {[New therapies and ongoing clinical trials in Alzheimer's disease].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42159020},
issn = {1652-7518},
mesh = {Humans ; *Alzheimer Disease/therapy/drug therapy ; Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Clinical Trials as Topic ; tau Proteins/antagonists & inhibitors ; Immunotherapy/methods ; Antibodies, Monoclonal/therapeutic use ; Alzheimer Vaccines/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Oligonucleotides, Antisense/therapeutic use ; },
abstract = {Clinical trials in Alzheimer's disease focus on disease-modifying therapies with targeted approaches addressing underlying pathology. Immunotherapies against amyloid-beta with monoclonal antibodies such as lecanemab and donanemab have shown promise in reducing amyloid plaque burden and modestly preserving cognition and function in early-stage patients. Tau-targeted therapies, including vaccines, antibodies, and antisense oligonucleotides, have indicated good tolerability in early studies. Additionally, anti-inflammatory strategies and different neurotransmitters are being explored. As of early 2025, over 180 clinical trials are ongoing, targeting various disease mechanisms and stages, including preclinical and at-risk populations. Increased knowledge of pathophysiology, clinical presentation, genetics, and biomarkers has over time provided a broader foundation for the development of Alzheimer's therapy. However, there is still a significant need for better implementation of this knowledge in clinical practice.},
}

Humans
*Alzheimer Disease/therapy/drug therapy
Amyloid beta-Peptides/antagonists & inhibitors/immunology
Clinical Trials as Topic
tau Proteins/antagonists & inhibitors
Immunotherapy/methods
Antibodies, Monoclonal/therapeutic use
Alzheimer Vaccines/therapeutic use
Antibodies, Monoclonal, Humanized/therapeutic use
Oligonucleotides, Antisense/therapeutic use

@article {pmid42159155,
year = {2026},
author = {Cummings, JL and Atri, A and Sano, M and Zetterberg, H and Scheltens, P and Knop, FK and Johannsen, P and Wichmann, CA and Abschneider, RM and Leon, T and Taylor, J and Feldman, HH},
title = {Plain language summary: the evoke(+) studies of semaglutide for early Alzheimer's disease.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/17582024.2026.2666332},
pmid = {42159155},
issn = {1758-2032},
}

@article {pmid42159271,
year = {2026},
author = {Shi, J and Du, Y and Wang, H and Zhang, N and Chen, W and Ni, J and Lu, X and Sun, Y and Wang, G and Liu, J and Zhang, W and Wei, M and Li, T and Zhou, B and Li, F and Wei, C and Yao, L and Xie, H and Tian, J and , },
title = {A paradigm of the diagnosis and treatment for the whole process of Alzheimer's disease.},
journal = {Annals of medicine},
volume = {58},
number = {1},
pages = {2672193},
doi = {10.1080/07853890.2026.2672193},
pmid = {42159271},
issn = {1365-2060},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Medicine, Chinese Traditional/methods ; Biomarkers ; Disease Progression ; Early Diagnosis ; Severity of Illness Index ; Practice Guidelines as Topic ; },
abstract = {INTRODUCTION: The clinical management of Alzheimer's disease (AD) is still constrained by the fact that its incompletely understood pathogenesis, difficulty in early diagnosis and the limited long-term treatment benefits so far. This article summarizes a regional perspective on the diagnosis and treatment of AD from the Alzheimer's Disease Chinese (ADC) guideline working group, aiming to improve the whole-process management of AD.

DISCUSSION: The article presents a comprehensive overview of a proposed diagnostic and therapeutic paradigm for AD, consisting of a three-dimensional diagnostic framework and a sequential therapy concept. Crucially, while biological biomarkers of AD are present at all stages, they may be unrelated to clinical severity. To address this, the diagnostic framework combines core clinical criteria with early-changing biomarkers, syndrome staging and traditional Chinese medicine (TCM)-based pattern phenotyping. This integrated, simplified and practical approach enhances diagnostic certainty and its correlation with clinical severity. This sequential therapy is a stage-adaptive treatment plan adjusted according to the disease progression, utilizing a dynamic, multi-target combination therapy. Unlike the existing unchanging single-target therapies, this approach provides specific mechanistic interventions tailored to each stage to prolong efficacy and delay disease progression.

CONCLUSIONS: This paradigm provides a whole-process, stage-oriented approach to AD diagnosis and management that may improve translational relevance, clinical applicability and continuity of care in real-world settings. Future cohort-based validation studies are needed to confirm its diagnostic performance and clinical benefits, and to refine its implementation.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
*Medicine, Chinese Traditional/methods
Biomarkers
Disease Progression
Early Diagnosis
Severity of Illness Index
Practice Guidelines as Topic

@article {pmid42159313,
year = {2026},
author = {Tajika, A and Omae, K and Sahker, E and Luo, Y and Takekita, Y and Furukawa, TA},
title = {Public acceptance and expectations for Lecanemab: Insights from a Smallest Worthwhile Difference study.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70082},
pmid = {42159313},
issn = {1440-1819},
abstract = {AIM: To determine the smallest worthwhile difference (SWD) for lecanemab, a disease-modifying drug for Alzheimer's disease (AD), among the general Japanese population using a benefit-harm trade-off method.

METHODS: We conducted an online survey with 658 participants to evaluate their preferences for the treatment effect of lecanemab, given its associated risks and high cost. We calculated SWD as the minimum required increase in the possibility of maintaining cognitive function (relative to the 50% without lecanemab) that patients would accept in exchange for the burdens of treatment (adverse effects, costs, other inconveniences). We examined the median SWD for two scenarios: a family member (SWD-families) and others (SWD-others), and analyzed subgroup differences.

RESULTS: The median SWD revealed a 15% increase for SWD-families and SWD-others. This value exceeds the drug's actual efficacy of an 8% increase. Notably, 17% of respondents reported zero SWD, driven by an intense fear of AD and possibly high expectations from media coverage. Including these participants, nearly half of the respondents considered the current effect worthwhile. No noticeable difference was found between the SWD-families and SWD-others.

CONCLUSION: Based on Japanese clinical scenarios, the public's median expectation for lecanemab exceeds its efficacy, though its current benefit remains acceptable to nearly half the population. These findings underscore that the SWD is shaped by psychological drivers, including fear and hope, rather than just reasoned evaluation. Clinicians must manage these expectations, accounting for highly heterogeneous treatment preferences. Future research should account for emotional factors that can overshadow a rational assessment of treatment value.},
}

@article {pmid42159329,
year = {2026},
author = {Sheela, A and Subair, S and Gopalakrishnan, AP and Palollathil, A and Raju, R},
title = {The Phosphoproteomic Landscape of CD2AP: A Comprehensive Review of Kinase Networks and Disease Implications.},
journal = {Omics : a journal of integrative biology},
volume = {},
number = {},
pages = {15578100261451308},
doi = {10.1177/15578100261451308},
pmid = {42159329},
issn = {1557-8100},
abstract = {CD2-associated protein (CD2AP) is a multifunctional adaptor linking membrane receptors to the actin cytoskeleton, ensuring slit diaphragm integrity, regulating synaptic proteostasis, and facilitating cytoskeletal remodeling. Dysregulation of CD2AP contributes to proteinuric kidney disease, Alzheimer's disease, and tumor progression. This review provides a comprehensive overview of the structural and functional characteristics of CD2AP, its phosphorylation landscape, and potential regulatory roles. By integrating 3,825 publicly available phosphoproteomic research articles with data obtained from kinase prediction tools, the study offers information on predominant phosphosites, upstream kinases, binary interactors, and disease associations of CD2AP. We identified 45 class I phosphosites with S224, S233, S256, S458, S510, and S514 being frequently regulated across biological contexts. Predictive kinase-substrate mapping and co-regulation analysis highlighted several upstream kinases whose phosphorylation patterns positively co-regulate with CD2AP modification. Co-regulated proteins associated with Alzheimer's and kidney disease, and several phosphoproteins were associated with cell movement and cancer progression. Overall, these findings position CD2AP as a dynamic signaling hub coordinating disease-related pathways.},
}

@article {pmid42159330,
year = {2026},
author = {Lövestam, S and Wagstaff, JL and Katsinelos, T and Shi, J and Freund, SMV and Goedert, M and Scheres, SHW},
title = {Twelve phosphomimetic mutations induce the assembly of recombinant full-length human tau into paired helical filaments.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.104778},
pmid = {42159330},
issn = {2050-084X},
support = {MC_UP_A025-1013/MRC_/Medical Research Council/United Kingdom ; MC_U105184291/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*tau Proteins/genetics/metabolism/chemistry ; Humans ; *Mutation ; Recombinant Proteins/metabolism/genetics/chemistry ; Phosphorylation ; Alzheimer Disease/metabolism ; Brain/metabolism/pathology ; Cryoelectron Microscopy ; },
abstract = {The assembly of tau into amyloid filaments is associated with more than 20 neurodegenerative diseases, collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of brain-derived tau filaments revealed that specific structures define different diseases, triggering a quest for the development of experimental model systems that replicate the structures of disease. Here, we describe 12 phosphomimetic serine/threonine-to-aspartate mutations in tau, which we term PAD12, that collectively induce the in vitro assembly of full-length three-repeat tau into filaments with the same structure as paired helical filaments extracted from the brains of individuals with Alzheimer's disease. Solution-state nuclear magnetic resonance spectroscopy suggests that phosphomimetic mutations in the carboxy-terminal domain of tau may facilitate filament formation by disrupting an intramolecular interaction between two IVYK motifs. PAD12 tau can be used for both nucleation-dependent and multiple rounds of seeded assembly in vitro, as well as for the seeding of tau biosensor cells. PAD12 tau can be assembled into paired helical filaments under various shaking conditions, with the resulting filaments being stable for extended periods of time. They can be labelled with fluorophores and biotin. Tau filaments extracted from the brains of individuals with Alzheimer's disease have been known to be made of hyperphosphorylated and abnormally phosphorylated full-length tau, but it was not known if the presence of this post-translational modification is more than a mere correlation. Our findings suggest that hyperphosphorylation of tau may be sufficient for the formation of the Alzheimer tau fold. PAD12 tau will be a useful tool for the study of molecular mechanisms of neurodegeneration.},
}

*tau Proteins/genetics/metabolism/chemistry
Humans
*Mutation
Recombinant Proteins/metabolism/genetics/chemistry
Phosphorylation
Alzheimer Disease/metabolism
Brain/metabolism/pathology
Cryoelectron Microscopy

@article {pmid42159347,
year = {2026},
author = {Rabec, M and Bourgeais, A and Gautier, J and Corvaisier, M and Brière, O and Annweiler, C},
title = {Association Between Calcium Supplement Use and Cognitive Impairment in Ageing Women: A Longitudinal Analysis.},
journal = {Australasian journal on ageing},
volume = {45},
number = {2},
pages = {e70186},
doi = {10.1111/ajag.70186},
pmid = {42159347},
issn = {1741-6612},
mesh = {Humans ; Female ; Aged ; *Dietary Supplements/adverse effects ; Prospective Studies ; Longitudinal Studies ; *Cognitive Dysfunction/diagnosis/psychology/chemically induced/epidemiology ; Risk Factors ; Aged, 80 and over ; *Cognition/drug effects ; Time Factors ; Age Factors ; *Aging/psychology ; *Calcium, Dietary/adverse effects ; *Cognitive Aging ; Risk Assessment ; },
abstract = {OBJECTIVE: Calcium supplementation is widely used in older adults, but its long-term effects on cognitive function remain unclear. This study assessed the association between pharmacological calcium supplementation and cognitive decline over 7 years in cognitively healthy older women.

METHODS: This prospective cohort study included 227 women (mean age 79.9 ± 3.6 years) from the Toulouse centre of the EPIDOS study. Cognitive function was assessed using the Short Portable Mental Status Questionnaire (SPMSQ) at baseline and after 7 years. Cognitive decline was defined as a decrease of at least one point in SPMSQ score. Calcium supplement use at baseline was recorded. Multivariable logistic regression was used to evaluate the association between supplementation and cognitive decline, adjusted for age, obesity, physical activity, instrumental activities of daily living (iADL) score, education level, dietary calcium and vitamin D intake, number of comorbidities and selected chronic conditions.

RESULTS: Cognitive decline occurred in 26% of participants. Calcium supplementation was reported by 12% of patients and was independently associated with an increased risk of cognitive decline (OR = 3.64; 95% CI: 1.47-9.01; p = 0.005). Obesity and comorbidity burden were also significant risk factors.

CONCLUSIONS: Calcium supplementation was associated with a threefold increased risk of cognitive decline in older women over a 7-year follow-up. These results suggest caution in prescribing calcium supplements and underscore the need for further research on their neurological safety in ageing populations.},
}

Humans
Female
Aged
*Dietary Supplements/adverse effects
Prospective Studies
Longitudinal Studies
*Cognitive Dysfunction/diagnosis/psychology/chemically induced/epidemiology
Risk Factors
Aged, 80 and over
*Cognition/drug effects
Time Factors
Age Factors
*Aging/psychology
*Calcium, Dietary/adverse effects
*Cognitive Aging
Risk Assessment

@article {pmid42159436,
year = {2026},
author = {Wei, YC and Huang, WY and Lin, C and Chen, CK and Hsu, CH and Ding, CM and Chen, YL and Lin, CP},
title = {Mediation pathways and complementary roles of DTI-ALPS and free water fraction in glymphatic impairment and cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261447822},
doi = {10.1177/13872877261447822},
pmid = {42159436},
issn = {1875-8908},
abstract = {BackgroundGlymphatic system dysfunction is linked to cognitive decline in dementia continuum. Diffusion magnetic resonance imaging markers like the Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) index and whole-brain free water (FW) fraction allow non-invasive evaluation of glymphatic activity.ObjectiveThis study assessed whether DTI-ALPS and FW fraction are associated with cognitive performance and examined the influence of factors such as education on these relationships across dementia stages.MethodsCognitively normal, mild cognitive impairment, and dementia participants were recruited from both the community and the memory clinic at Chang Gung Memorial Hospital, Keelung. Brain MRI and neuropsychological assessments were performed.ResultsA total of 127 individuals (Clinical Dementia Rating 0, 0.5, 1-3; N = 75, 43, 6) completed the study. Both DTI-ALPS index and FW fraction differed among groups (p < 0.001) and correlated with cognitive performance (DTI-ALPS: β = 0.35; FW: β = -0.50; both p < 0.001). Mediation analysis showed that DTI-ALPS was positively associated with Montreal Cognitive Assessment (total effect b = 21.94, p < 0.001), largely mediated by FW fraction (indirect β = 0.22, 95% CI [0.14-0.33]). After adjusting for age, sex, and education, the total effect remained significant (b = 10.93, p = 0.018), while the direct effect was not (b = 8.15, p = 0.080), and the indirect effect via FW persisted (β = 0.05, 95% CI [0.01-0.13]). Education moderated these associations (DTI-ALPS x education: b = -2.07, p = 0.033; FW x education: b = 5.59, p = 0.034). In addition, sleep-medication use interacted with FW fraction in relation to cognitive performance (FW x sleep-medication: b = -58.87, p = 0.044).ConclusionsDTI-ALPS index and FW fraction provided complementary insights into glymphatic dysfunction linked to cognitive decline. Higher DTI-ALPS values were associated with better cognition, mediated by lower whole-brain FW, but with attenuated effects in individuals with higher education.},
}

@article {pmid41870696,
year = {2026},
author = {De Lucia, N and Thayanandan, T and Palomba, S and Komici, K and Maldonato, NM and Rengo, G and Femminella, GD},
title = {Neuropsychiatric and neural correlates of subjective cognitive complaint.},
journal = {Aging clinical and experimental research},
volume = {38},
number = {1},
pages = {},
pmid = {41870696},
issn = {1720-8319},
abstract = {BACKGROUND: Subjective cognitive complaint (SCC) has been reported in normal elderly (NE) and Mild Cognitive Impairment (MCI).

AIMS: We investigated the neuropsychiatric predictors of SCC in NE and MCI, and the biomarkers abnormalities, and neural correlates of SCC in MCI.

METHODS: Clinical, cognitive and imaging data of 233 MCI and 419 NE were obtained from the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI-3) database. SCC was assessed by the Cognitive Change Index (CCI) and Everyday Cognition (ECog). Neuropsychiatric symptoms were evaluated through the Neuropsychiatric Inventory (NPI). Brain amyloid and tau status were obtained from [18 F]Florbetapir-PET and [18 F]Flortaucipir-PET SUVR in predefined target regions, and brain and grey matter volumes from structural MRI.

RESULTS: SCC was significantly correlated with depression, anxiety, apathy, irritability, and sleep disorders, in MCI. Linear regression showed that depression and anxiety were significantly associated to SCC index, in MCI. SCC was neither significantly different in amyloid positive vs. negative, nor in tau positive vs. negative MCI. MCI with SCC showed significantly lower Braak 3–4 region volume and reduced amygdala volume, compared to MCI without SCC. MCI with SCC and NPI showed lower posterior cingulate cortex volume compared to MCI without SCC or NPI, whereas MCI with SCC but without NPI had lower anterior cingulate cortex volume, compared to MCI without SCC or NPI.

CONCLUSIONS: These findings recommend the crucial role of psychological therapies focused on anxiety and depression, to prevent the worsening of the subjective cognitive complaint that represent a strong factor of conversion to objective cognitive disorders.},
}

@article {pmid42151483,
year = {2026},
author = {Sanchez-Molina, P and Rosmus, DD and Brownell, D and Meral, M and Gohlich, C and Pratapa, A and Peymanfar, Y and Whitley, A and Hou, Y and Nikulina, N and Bogachuk, A and Bouchard, EL and Chiot, A and Kuhrt, H and Wieghofer, P and Woltjer, R and Svara, F and Braubach, O and Ajami, B},
title = {Spatial proteomic analysis in human Alzheimer's disease brains enables identification of microenvironment-dependent microglial cell states.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42151483},
issn = {1546-1726},
abstract = {Disease-associated microglial states are thought to contribute to Alzheimer's disease (AD) progression, but characterizing them and their relationships to pathology remains challenging. Here we introduce CODEX-CNS-a multiplexed protein imaging technology with a custom data analysis pipeline for use in human brain samples. We profiled 704,706 cells in samples from the frontal cortex of 8 people with AD and 8 healthy controls and mapped features including blood-brain barrier, meningeal components and cell-cell interactions within the same tissue sections. Amongst the myeloid cell populations we identified, we found a border-associated macrophage-like microglial subset associated with aging. Further classifying myeloid cell subsets based on their spatial neighborhood, we identified a border-associated macrophage-like microglial subpopulation that was associated significantly with dense amyloid-β plaques, which we termed human plaque-associated microglia. This work offers insights into myeloid cell heterogeneity in AD and provides a new spatial approach to characterizing brain cells at the single-cell protein level.},
}

@article {pmid42151567,
year = {2026},
author = {Tandalekar, YB and Kulshreshtha, S and Goyal, A and Jachak, SM},
title = {Physalis minima L.: A comprehensive review on phytochemistry, pharmacology, and food applications.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42151567},
issn = {1432-1912},
abstract = {Physalis minima Linn. (Solanaceae) is a widely recognized plant renowned for its diverse medicinal properties and edible applications. Traditionally, this plant has been used to prevent cancer, inflammation, diabetes, Alzheimer's, microbial growth, and leishmaniasis. It is also utilized as a diuretic and laxative. The species has been identified as having various phytoconstituents, including withanolides, flavonoids, fatty acids, and other compounds. Among these, withanolides are the most prevalent and function as the primary bioactive compounds. A total of 221 withanolides (1980-2025) were documented in this review, among which 81 were newly identified from P. minima. Previous research has identified withanolides as key bioactive constituents with notable potential in the management of inflammatory, neuroinflammatory, and cancer-related conditions, largely due to their distinctive steroidal framework and significant biological activities. Despite these promising pharmacological attributes, only a limited number of withanolides have been studied in depth. Most compounds, especially those discovered more recently, remain insufficiently explored with respect to their therapeutic potential. This knowledge gap highlights the need to further investigate compounds isolated from P. minima to better understand their pharmacological effects. We have tried to extensively appraise the data on phytoconstituents identified from this plant and their associated pharmacological activities. Collectively, the findings presented in this review provide a starting point for future research on P. minima, highlighting its promise as a valuable source of bioactive compounds for drug discovery.},
}

@article {pmid42151616,
year = {2026},
author = {Filippi, M and Ghirelli, A and Cecchetti, G and Samanes Gajate, AM and Rugarli, G and Spinelli, EG and Pisano, S and Panzacchi, A and Pepe, G and Chiti, A and Agosta, F},
title = {Serial amyloid PET as a decision tool for switching anti-amyloid therapy in Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42151616},
issn = {1619-7089},
}

@article {pmid42151661,
year = {2026},
author = {König, A and Tröger, J and Mallick, E and Linz, N and Ritchie, C and Gregory, S and Hunter, M and Johnson, K and Benavides, GS and Grau-Rivera, O and Radoi, A and Porta-Mas, C and Köhler, S and Teipel, S and Hansson, O and Tideman, P and Wuestefeld, A and Palmqvist, S},
title = {Speech-based digital cognitive assessment for clinical trials: Detecting cognitive impairment stages and AD biomarker relations across European cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71462},
doi = {10.1002/alz.71462},
pmid = {42151661},
issn = {1552-5279},
support = {//Alzheimer's Drug Discovery Foundation Diagnostic Accelerator/ ; 201906//Alzheimer's Drug Discovery Foundation (ADDF)/ ; 2018897//Alzheimer's Drug Discovery Foundation (ADDF)/ ; 201809//Alzheimer's Drug Discovery Foundation (ADDF)/ ; 2016862//Alzheimer's Drug Discovery Foundation (ADDF)/ ; //Health Department of the Catalan Government/ ; CP23/00039//Instituto de Salud Carlos III (ISCIII)/ ; //Kamprad Foundation/ ; ERAPERMED2021//ERA PerMed/ ; 184//ERA PerMed/ ; 2022//Knut and Alice Wallenberg foundation/ ; 0231//Knut and Alice Wallenberg foundation/ ; //Strategic Research Area MultiPark/ ; AF-980907//Swedish Alzheimer Foundation/ ; AF-1011949//Swedish Alzheimer Foundation/ ; AF-994075//Swedish Alzheimer Foundation/ ; AF-940046//Swedish Alzheimer Foundation/ ; AF-981132//Swedish Alzheimer Foundation/ ; 1412/22//Parkinson foundation of Sweden/ ; //Cure Alzheimer's fund/ ; FRS-0004//Rönström Family Foundation/ ; FRS-0011//Rönström Family Foundation/ ; 2020//Skåne University Hospital Foundation/ ; O000028//Skåne University Hospital Foundation/ ; 2022//Regionalt Forskningsstöd/ ; 1259//Regionalt Forskningsstöd/ ; 2022//Swedish federal government/ ; Projekt0080//Swedish federal government/ ; 2022//Swedish federal government/ ; 1346//Swedish federal government/ ; },
mesh = {Humans ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Europe ; Cohort Studies ; *Speech ; Neuropsychological Tests ; tau Proteins/cerebrospinal fluid ; Aged, 80 and over ; Middle Aged ; },
abstract = {INTRODUCTION: Early detection of Alzheimer's disease (AD) is critical for timely intervention as disease-modifying treatments emerge. Speech-based digital biomarkers offer scalable options for remotely capturing speech-derived functional changes associated with early cognitive decline, but validation across real-world populations remains limited.

METHODS: We evaluated the speech biomarker for cognition (SB-C), an automated speech-derived measure associated with cognitive status, in 736 participants across five European cohorts (Barcelonaβeta Brain Research Center's Alzheimer's at-risk cohort, European Prevention of Alzheimer's Dementia Scotland, Dementia Study of Cognitive and Biomarker Dynamics, Longitudinal Cognitive Impairment and Dementia Study, and Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably [BioFINDER-Primary Care]). Participants completed verbal learning and semantic fluency tasks via automated phone or app-based platforms. SB-C performance was compared to Mini-Mental State Examination, Clinical Dementia Rating, Preclinical Alzheimer Cognitive Composite 5, and cerebrospinal fluid amyloid beta and phosphorylated tau181 biomarker status.

RESULTS: SB-C significantly differentiated cognitively unimpaired and impaired groups (P < 0.001), correlated with standard cognitive measures, and showed moderate-to-high area under the curve (0.56-0.82) for classifying biomarker positivity, with strongest results in BioFINDER-Primary Care.

DISCUSSION: SB-C is a scalable, remote speech-derived marker associated with cognitive status and AD biomarker group differences.},
}

Humans
Male
Female
Biomarkers/cerebrospinal fluid
*Cognitive Dysfunction/diagnosis/cerebrospinal fluid
*Alzheimer Disease/diagnosis/cerebrospinal fluid
Aged
Amyloid beta-Peptides/cerebrospinal fluid
Europe
Cohort Studies
*Speech
Neuropsychological Tests
tau Proteins/cerebrospinal fluid
Aged, 80 and over
Middle Aged

@article {pmid42151696,
year = {2026},
author = {Zhang, J and Zhang, J and Ding, J and Zhang, X and Wang, Y and Wei, W and Chai, Y and Zhang, S and Chen, X},
title = {Reconstructing cerebral lymphatic clearance: an emerging target in the Alzheimer's disease therapeutic pipeline.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71451},
doi = {10.1002/alz.71451},
pmid = {42151696},
issn = {1552-5279},
support = {82471397//National Natural Science Foundation of China/ ; 82271399//National Natural Science Foundation of China/ ; No.25JCLZJC00280//Joint Funds of the Natural Science Foundation of Tianjin/ ; //Tianjin Health Care Elite Prominent Young Doctor Development Program/ ; //Young and Middle-aged Backbone Innovative Talent Program/ ; //Clinical Talent Training '123' Climbing Plan of Tianjin Medical University/ ; TJYXZDXK-002A//Tianjin Key Medical Discipline (Neurosurgery) Construction Project/ ; },
mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Brain/metabolism ; *Lymphatic Vessels ; Glymphatic System ; Animals ; },
abstract = {Neurotoxic protein accumulation is widely recognized as a key feature of Alzheimer's disease (AD), and increasing evidence indicates that impaired brain clearance associated with dysfunction of the meningeal lymphatic and glymphatic may contribute to this process. Disruption of these pathways may weaken homeostatic mechanisms and facilitate amyloid‑β and tau buildup. This review considers lymphatic reconstruction as a potential therapeutic direction aimed at modestly improving clearance efficiency. We summarize current findings from pharmacological approaches targeting aquaporin-4 or vascular endothelial growth factor C signaling, non-invasive methods such as photobiomodulation and focused ultrasound, and emerging surgical or lifestyle interventions designed to enhance drainage. Early clinical attempts, including deep cervical lymphovenous anastomosis (dCLVA), provide preliminary proof of concept but require careful validation. Progress in this field also depends on developing sensitive, non-invasive imaging markers and defining appropriate intervention windows. By situating lymphatic modulation within the broader AD drug-development landscape, we highlight its possible role within multimodal therapeutic strategies.},
}

*Alzheimer Disease/therapy/metabolism
Humans
*Brain/metabolism
*Lymphatic Vessels
Glymphatic System
Animals

@article {pmid42151697,
year = {2026},
author = {Visentini, AE and Reichert, KP and Schetinger, MRC and Bottari, NB and Miron, VV and Castro, MFV and da Silveira, MV and Assmann, CE and Schirmann, AA and Morsch, VMM},
title = {Resveratrol as a potential natural compound to ameliorate cognitive impairment in aluminum-exposed mice: impacts on behavior, purinergic system, and brain inflammation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42151697},
issn = {1573-7365},
}

@article {pmid42151713,
year = {2026},
author = {Stijven, F and Mallinckrodt, C and Molenberghs, G and Alonso, A and Dickson, SP and Hendrix, SB},
title = {Time-Scale Target Parameters and Two-Step Estimation in Longitudinal Trials for Progressive Diseases.},
journal = {Statistics in medicine},
volume = {45},
number = {10-12},
pages = {e70591},
doi = {10.1002/sim.70591},
pmid = {42151713},
issn = {1097-0258},
support = {//Agentschap Innoveren en Ondernemen/ ; HBC.2022.0145//Johnson & Johnson Innovative Medicine/ ; },
mesh = {Humans ; *Disease Progression ; Longitudinal Studies ; Alzheimer Disease/drug therapy/therapy ; *Randomized Controlled Trials as Topic/statistics & numerical data/methods ; Computer Simulation ; Models, Statistical ; Time Factors ; Treatment Outcome ; Data Interpretation, Statistical ; },
abstract = {In progressive diseases such as Alzheimer's, treatments that slow progression should start early to preserve higher levels of functioning for a longer period. In corresponding clinical trials, treatment effects are usually expressed as mean differences on a clinical scale at fixed time points. Early in the disease course, however, these mean differences may appear small but may nonetheless correspond to an important slowing of disease progression. This complicates the appreciation of the relevance of observed treatment effects. We introduce a class of target parameters that quantify treatment effects on the time scale in longitudinal studies; for instance, in terms of time saved or percentage slowing of progression. We focus on data from randomized trials where the target parameters are identified under regularity assumptions. These target parameters remain well defined if treatment was not randomized, but additional untestable assumptions are required for identification. We propose general two-step estimators. In the first step, the data can be analyzed with standard methods for longitudinal data and standard software can thus be used. In the second step, summary statistics from the first step are used for inferences about the target parameters. The second step has been implemented in the TCT R package. We study the asymptotic properties and efficiency of these two-step estimators, and evaluate them in an extensive simulation study. These estimators are used in a phase 2/3 clinical trial for Alzheimer's disease, leading to important additional insights into the treatment effect.},
}

Humans
*Disease Progression
Longitudinal Studies
Alzheimer Disease/drug therapy/therapy
*Randomized Controlled Trials as Topic/statistics & numerical data/methods
Computer Simulation
Models, Statistical
Time Factors
Treatment Outcome
Data Interpretation, Statistical

@article {pmid42151724,
year = {2026},
author = {Chong Chie, JAK and Persohn, SA and Simcox, OR and Collins, A and Salama, P and Territo, PR and , },
title = {Neurovascular-metabolic dysregulation, metabolic connectomics, and metabolic functional changes in Alzheimer's disease: A preclinical and clinical comparison.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71496},
doi = {10.1002/alz.71496},
pmid = {42151724},
issn = {1552-5279},
support = {T32AG071444//Stark Neuroscience Research Institute/ ; U54AG054345//Stark Neuroscience Research Institute/ ; },
mesh = {*Alzheimer Disease/metabolism/diagnostic imaging ; Animals ; Humans ; Mice ; *Brain/metabolism/diagnostic imaging/blood supply ; Disease Models, Animal ; Male ; Female ; *Connectome ; Aged ; Cerebrovascular Circulation/physiology ; Positron-Emission Tomography ; },
abstract = {Historically, imaging diagnostics in Alzheimer's disease (AD) have focused primarily on amyloid and tau accumulation; however, recent work suggests that neurometabolic and vascular dysregulation (MVD) may precede protein deposition and persist throughout the disease spectrum, preclinically and clinically. Translating these findings between human patients and preclinical mouse models remains challenging due to cross-species differences. To address this, regional MVD phenotypes were identified using cerebral metabolism and blood flow, and region-set enrichment analysis (RSEA) was conducted to assess brain functional category (BFC) changes based on metabolic variations, facilitating systematic cross-species comparisons. Clinically, MVD showed progressive alterations across the AD spectrum, while mouse models demonstrated similar genotype- and age-dependent changes. Although direct one-to-one regional correspondence is limited, RSEA revealed changes in comparable BFCs. Our findings suggest that imaging-based MVD mapping and RSEAs can bridge species differences, offering a translational framework to support early diagnostics of AD, enhance disease stratification, and enable therapeutic testing.},
}

*Alzheimer Disease/metabolism/diagnostic imaging
Animals
Humans
Mice
*Brain/metabolism/diagnostic imaging/blood supply
Disease Models, Animal
Male
Female
*Connectome
Aged
Cerebrovascular Circulation/physiology
Positron-Emission Tomography

@article {pmid42151730,
year = {2026},
author = {Sutherland, GT and Chen, A and Nguyen-Hao, HT and Mundell, H and Aladyeva, E and Hofer, MJ and Harari, O and Twigg, SM},
title = {How does type 2 diabetes modify the risk of Alzheimer's disease?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71471},
doi = {10.1002/alz.71471},
pmid = {42151730},
issn = {1552-5279},
support = {//Lucas Papaw Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/epidemiology ; *Diabetes Mellitus, Type 2/metabolism/complications ; Brain/metabolism/pathology ; Microglia/metabolism ; Risk Factors ; Blood-Brain Barrier/metabolism ; Inflammation ; Insulin Resistance ; Apolipoproteins E/metabolism ; },
abstract = {Type 2 diabetes (T2D) and Alzheimer's disease (AD) are both increasing exponentially worldwide. T2D has also been identified as one of 14 modifiable risk factors for dementia, but the mechanism is unknown. T2D could promote dementia via vascular or AD neuropathological changes, and mechanistic hypotheses include central insulin resistance and T2D's peripheral inflammation promoting central inflammation. Here we examine these different hypotheses by reviewing the recent literature in combination with re-analysis of post mortem brain tissue molecular data. Collectively, recent studies and single-cell transcriptomic data suggest that peripheral lipid anomalies and inflammation seen in T2D act together to reduce brain-blood barrier integrity, facilitating aberrant immune signaling between the periphery and the brain. The subsequent promotion of AD-specific microglial subtypes is the most likely mechanism linking T2D and AD. These AD-specific microglial subtypes may be reduced by therapeutic targeting of triggering receptor expressed on myeloid cells 2-apolipoprotein E signaling pathway.},
}

Humans
*Alzheimer Disease/metabolism/pathology/epidemiology
*Diabetes Mellitus, Type 2/metabolism/complications
Brain/metabolism/pathology
Microglia/metabolism
Risk Factors
Blood-Brain Barrier/metabolism
Inflammation
Insulin Resistance
Apolipoproteins E/metabolism

@article {pmid42151732,
year = {2026},
author = {Hammers, DB and Foster, E and Eloyan, A and Thangarajah, M and Taurone, A and Touroutoglou, A and La Joie, R and Beckett, L and Gao, S and Vemuri, P and Nudelman, KN and Kirby, K and Dage, JL and Aisen, P and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Parand, L and Womack, K and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Dickerson, BC and Rabinovici, GD and Carrillo, MC and Apostolova, LG and , },
title = {Cognitive dispersion profiles and prediction of cognitive change in early-onset dementias: Results from LEADS.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71492},
doi = {10.1002/alz.71492},
pmid = {42151732},
issn = {1552-5279},
support = {AARG-22-926940/ALZ/Alzheimer's Association/United States ; LDRFP-21-818464/ALZ/Alzheimer's Association/United States ; K23 AG080071/ALZ/Alzheimer's Association/United States ; R56 AG057195/ALZ/Alzheimer's Association/United States ; U01AG6057195/ALZ/Alzheimer's Association/United States ; U24AG021886/ALZ/Alzheimer's Association/United States ; U01 AG016976/ALZ/Alzheimer's Association/United States ; P30 AG010133/ALZ/Alzheimer's Association/United States ; P50 AG008702/ALZ/Alzheimer's Association/United States ; P50 AG025688/ALZ/Alzheimer's Association/United States ; P50 AG005146/ALZ/Alzheimer's Association/United States ; P30 AG062421/ALZ/Alzheimer's Association/United States ; P30 AG062422/ALZ/Alzheimer's Association/United States ; P50 AG023501/ALZ/Alzheimer's Association/United States ; P30 AG010124/ALZ/Alzheimer's Association/United States ; P30AG066506/ALZ/Alzheimer's Association/United States ; P30 AG013854/ALZ/Alzheimer's Association/United States ; P50 AG005681/ALZ/Alzheimer's Association/United States ; P50AG047366/ALZ/Alzheimer's Association/United States ; U24AG021886/ALZ/Alzheimer's Association/United States ; R56AG057195/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; Neuropsychological Tests/statistics & numerical data ; *Dementia/psychology ; *Cognition/physiology ; Biomarkers ; Middle Aged ; *Alzheimer Disease/psychology ; Age of Onset ; },
abstract = {INTRODUCTION: Research into cognitive dispersion - a cognitive process score measuring the intra-individual variability (IIV) across a single testing session - suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early-onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition.

METHODS: A total of 309 participants (188 amyloid-positive EOAD, 43 amyloid-negative early-onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion-related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain-specific cognitive trajectories, and its convergence with imaging biomarkers.

RESULTS: EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD-specific biomarkers. Additionally, cognitive dispersion was associated with 12-month reliable change across several cognitive domains.

DISCUSSION: These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.},
}

Humans
Female
Male
Neuropsychological Tests/statistics & numerical data
*Dementia/psychology
*Cognition/physiology
Biomarkers
Middle Aged
*Alzheimer Disease/psychology
Age of Onset

@article {pmid42151735,
year = {2026},
author = {Landau, SM and Liu, P and Harrison, TM and Taggett, J and Ward, TJ and Murphy, A and Lockhart, SN and Lovato, LC and Koeppe, R and Farias, ST and Papp, KV and Snyder, HM and Harvey, DJ and Espeland, M and Maillard, P and DeCarli, C and Vemuri, P and Weiner, M and Baker, LD and Jagust, WJ and , },
title = {Elevated AD biomarkers do not explain cognitive performance in a community-recruited clinical trial cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71472},
doi = {10.1002/alz.71472},
pmid = {42151735},
issn = {1552-5279},
support = {U.S. POINTER-19-611541/ALZ/Alzheimer's Association/United States ; //Alzheimer's Disease Neuroimaging Initiative/ ; R01AG062689/NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //Intramural Research Program of the National Institute on Aging/ ; //Center for Alzheimer's and Related Dementias/ ; //Intramural Research Program/ ; AG000546/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; *Biomarkers/cerebrospinal fluid/metabolism ; *Alzheimer Disease/metabolism ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism/cerebrospinal fluid ; Aged ; Cohort Studies ; *Cognition/physiology ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {INTRODUCTION: To examine the generalizability of Alzheimer's disease (AD) biomarker models in real-world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics.

METHODS: We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community-recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics.

RESULTS: Elevated β-amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk.

DISCUSSION: The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.},
}

Humans
Female
Male
*Biomarkers/cerebrospinal fluid/metabolism
*Alzheimer Disease/metabolism
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism/cerebrospinal fluid
Aged
Cohort Studies
*Cognition/physiology
Neuropsychological Tests
Aged, 80 and over

@article {pmid42151912,
year = {2026},
author = {Stuardo, N and Cáceres-Quezada, Á and Guzmán, D and Lamaizon, CM and Leal R, N and Koleske, AJ and Álvarez R, A},
title = {Abl kinase activation promotes axon initial segment disassembly and protein sorting defects in Alzheimer's disease.},
journal = {BMC biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12915-026-02624-5},
pmid = {42151912},
issn = {1741-7007},
abstract = {BACKGROUND: Axon initial segment (AIS) dysfunction disrupts neuronal compartmentalization, which leads to pathological processes like Tau missorting in Alzheimer's disease (AD). However, the molecular mechanisms that destabilize the AIS scaffold are incompletely understood. Our group has previously shown that the Abl1 non-receptor tyrosine kinase is aberrantly activated in AD mouse models and promotes dendritic spine collapse, Tau hyperphosphorylation, and neuronal apoptosis. Given the important role of Abl1 in AD and its emerging significance in Tau pathology, we examined how it contributes to AIS collapse.

RESULTS: We find that activation of Abl1 by amyloid-β fibrils promotes AIS disruption, as determined by the loss of clustered AnkG in the proximal axon, and that this can be prevented by pharmacological inhibition of Abl kinases. Cytosolic extraction experiments show that active Abl1 associates to the AIS scaffold, and this association increases in response to amyloid-β fibril treatment. Furthermore, using expansion microscopy, we show that Abl1 localizes to the AIS in dissociated hippocampal cultures and in mouse brain slices. We find a decrease in AIS actin patches, key for maintenance of neuronal compartmentalization, following Abl kinase activation. Finally, we show that Abl1 activation promotes missorting of somatodendritic Rab11 into the axon and the axonal protein Tau into the somatodendritic compartment, indicating a bidirectional failure in AIS barrier function.

CONCLUSIONS: Taken together, our results show that Abl1 plays an important role in AIS destabilization and that its activation compromises protein compartmentalization in a primary neuron culture model of AD.},
}

@article {pmid42151941,
year = {2026},
author = {Luo, M and Zhao, FK and Wang, YM and Bian, J and Luo, Y},
title = {Bibliometric analysis of nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders (1997-2025): trends and future directions.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04529-5},
pmid = {42151941},
issn = {1477-3155},
support = {Zunyi Science and Technology Talent Team Project [2024] No. 6//Zunyi Science and Technology Bureau/ ; No. 39 (2023)//Zunshi Science and Technology Cooperation Letter/ ; (QZYY-2024-094)//Science and technology research topic of traditional Chinese medicine and ethnic medicine of Guizhou Provincial Administration of Traditional Chinese Medicine/ ; No: 24QNMP019//Health Commission of Sichuan Province Medical Science and Technology Program/ ; 25MSZX259//Scientific Research Projects of the Sichuan Provincial Administration of Traditional Chinese Medicine/ ; 2026NSFSC1634//Sichuan Province Natural Science Foundation/ ; },
abstract = {Nanomaterials have demonstrated substantial promise in the diagnosis and treatment of neurological and psychiatric disorders, offering novel strategies to overcome the limitations of traditional therapies. This review utilizes bibliometric analysis to evaluate global trends in nanomaterial research for neurological and psychiatric diseases, based on a corpus of 3,987 publications retrieved from the Web of Science Core Collection spanning from 1997 to August 2025. The analysis reveals a consistent upward trajectory in annual publications, reflecting substantial and growing international interest across diverse regions. Following an overview of global research dynamics, this review explores the pathogenesis of neurological and psychiatric disorders, such as Alzheimer's disease, Parkinson's disease, depression, and schizophrenia. The mechanisms underlying these conditions, including neuroinflammation, oxidative stress, protein aggregation, and neurotransmitter imbalances, are systematically discussed. Subsequently, the review focuses on how nanomaterials, including nanoparticles, nanocomposites, and nanocarriers, target these pathogenic mechanisms. The therapeutic applications of nanomaterials are evaluated with respect to their ability to modulate neuroinflammation, reduce oxidative stress, improve drug delivery to the brain, and facilitate the repair of neuronal damage. Despite the promising potential of nanomaterials, several challenges remain, including biocompatibility, targeted delivery, and scalability of treatment options. The review concludes by highlighting future directions for research, emphasizing the need for continued innovation in nanomaterial design and application to address these challenges and advance clinical treatments for neurological and psychiatric disorders.},
}

@article {pmid42152074,
year = {2026},
author = {Erisir, A and Maher, EE and Anderson, Z and Chawla, S and Hanley, L and Zhao, A and Birisik, K and Toklucu, ES and Keskinoz, EN},
title = {Dysregulated oligodendrocyte and myelin dynamics as an early pathological feature of neuropil degeneration in Alzheimer's disease: an ultrastructural study.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02320-z},
pmid = {42152074},
issn = {2051-5960},
support = {ARDRAF-16-2//Alzheimer's and Related Diseases Research Award Fund/ ; 3501- 219S307//Scientific and Technological Research Council of Turkey (TÜBİTAK), Career Development Program/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by the accumulation of amyloid‑β plaques and neurofibrillary tangles. Increasing evidence suggests that white‑matter degeneration and myelin disruption occur early in disease progression and may contribute to neuropathological vulnerability. Here, we performed ultrastructural analyses in the 3xTg and 5xFAD mouse models of AD across developmental stages (3-12 months of age), including ages preceding overt amyloid plaque formation or neuronal loss. We identify a spectrum of oligodendrocyte‑ and myelin‑associated abnormalities, including single‑membrane herniations, myelin outfolds, and ectopic myelination of neuronal processes, which are evident as early as 3 months of age and are frequently associated with altered neuropil architecture and incipient dystrophic neurite morphology. These malformations were confirmed to be oligodendrocyte‑derived through O4 immunolabeling. Collectively, our findings reveal early, widespread myelin‑associated ultrastructural alterations that form a consistent structural component of neuritic pathology in AD models. We propose that dysregulated oligodendrocyte membrane remodeling represents an early pathological feature of AD, providing a framework for future studies examining how glial pathology intersects with neuronal degeneration and plaque‑associated neuritic remodeling.},
}

@article {pmid42152119,
year = {2026},
author = {Skácelíková, E and Vyhnálek, M and Děchtěrenko, F and Nikolai, T and Veverová, K},
title = {Willingness and barriers to blood-based biomarker testing of Alzheimer's disease in the general population in the Czech Republic.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02070-z},
pmid = {42152119},
issn = {1758-9193},
support = {PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; CZ.02.01.01/00/22_008/0004595//European Regional Development Fund, under the project "Beyond Security: Role of Conflict in Resilience-Building"/ ; },
abstract = {BACKGROUND: Blood-based biomarkers (BBBM) for Alzheimer's disease (AD) are entering clinical practice with new clinical practice guidelines and the first FDA-approved blood test. Their implementation will depend not only on assay performance but also on public willingness, trust, and understanding of probabilistic results. We examined attitudes towards BBBM in the general population and psychosocial factors that may facilitate or hinder uptake.

METHODS: We conducted an online cross-sectional survey among adults aged ≥ 35 years (M = 51.08, SD = 9.79) in the Czech Republic (N = 666). The survey assessed willingness to undergo BBBM testing, sociodemographic characteristics, experience with AD, depressive symptoms (Patient Health Questionnaire, PHQ-9), concerns about developing AD, and medical distrust (Medical Distrust Index, MDI). Logistic regression models (unweighted and weighted for gender and region) were estimated to examine the association with willingness. Open-ended responses were analyzed thematically to identify motivators and barriers.

RESULTS: Overall, 92.8% of participants reported that they would undergo BBBM testing. Greater concern about developing AD was the strongest facilitator (OR = 1.59-2.34). Having AD in a close family member was associated with lower willingness (OR = 0.31-0.43), as was higher medical distrust (MDI OR = 0.79 in the fully weighted model). Education, age, gender, depressive symptoms, and AD knowledge were not significantly associated with willingness. Qualitative analyses showed that participants viewed BBBM as a way to "take action in time", "know one's health status" and "prepare for the future", whereas fear of AD, preference "not to know", perceived lack of treatment, test uncertainty/"only probability", and privacy concerns were common barriers.

CONCLUSIONS: Public willingness to undergo BBBM testing is high, but psychosocial barriers, particularly familial experience of AD and medical distrust, may limit real-world uptake. Addressing these barriers through targeted education, probabilistic risk communication, and trusted primary-care pathways will be essential for the responsible implementation of BBBM in clinical practice.},
}

@article {pmid42152268,
year = {2026},
author = {Huang, QQ and Zhang, XL and He, SJ and Zhou, YH and Wang, T and Zhang, CX},
title = {Exploring the Mechanism of Saponins from Panax japonicus in Improving Alzheimer's Disease Based on Network Pharmacology and Molecular Docking.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050471394260327075445},
pmid = {42152268},
issn = {1875-5828},
abstract = {INTRODUCTION: To study the mechanism of saponins from Panax japonicus (SPJ) in improving Alzheimer's disease based on network pharmacology and molecular docking technology.

METHODS: The active components in the SPJ were obtained from the databases of CNKI, PubMed, and PubChem. The active component targets were retrieved from the databases of Swiss Target Prediction and Super-PRED. The disease targets were retrieved from the databases GeneCards, OMIM, and PharmGKB. Drug-disease intersection targets were obtained via Venny 2.1.0. The String database was utilized to establish the protein network. The drug- active ingredient- target network was constructed by Cytoscape 3.10.1 software. The Metascape database was employed to conduct the gene ontology function enrichment analysis and KEGG pathway enrichment analysis. AutoDock Tools 1.5.7 was used to perform the molecular docking analysis.

RESULTS: A total of 57 active components were obtained from the SPJ, and 438 drug targets and 2294 disease targets were identified, including 169 identical targets. The key targets were SRC, STAT3, PIK3R1, AKT1, ESR1, EGFR, and JUN. Pseudoginsenoside F11, Vina-ginsenoside R2, and Chikusetsusaponin III might be the key active components of SPJ in improving Alzheimer's disease. The key active components showed good binding energy and better binding affinity within the active targets.

DISCUSSION: Network pharmacology has screened out 57 potential active components of SPJ, including pseudo ginsenoside F11, ginsenoside R2, and III, which may exert therapeutic effects by acting on key targets such as SRC, STAT3, PIK3R1, AKT1, ESR1, EGFR, and JUN. These targets are closely related to core pathological processes of AD, such as Aβ production, Tau protein phosphorylation, neuroinflammation, neuronal survival, and synaptic plasticity. Functional analysis indicates that SPJ may act on multiple cellular sites, such as receptor complexes and synaptic membranes, by influencing biological processes such as cell migration, inflammatory response, and membrane potential regulation. Pathway enrichment suggests that its mechanism of action may be related to Alzheimer's disease pathways, the NF-κB signaling pathway, and the calcium signaling pathway. The continuous activation of NF-κB can exacerbate neuroinflammation and oxidative damage, while the disorder of the calcium signaling pathway will lead to intracellular calcium overload, mitochondrial dysfunction, and synaptic damage, all of which play key roles in the progression of AD.

CONCLUSION: SPJ exerts a therapeutic effect and provides the basis for Alzheimer's disease through multiple components, targets, and pathways.},
}

@article {pmid42152315,
year = {2026},
author = {Gao, X and Wang, L},
title = {Associations of gut bacterial classes Clostridia and Deltaproteobacteria with type 2 diabetes and Alzheimer's disease: A two-sample Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {20},
pages = {e48685},
doi = {10.1097/MD.0000000000048685},
pmid = {42152315},
issn = {1536-5964},
support = {2021C018//Development and Reform Commission of Jilin Province/ ; JJKH20210062KJ//Jilin Provincial Department of Education/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/microbiology/genetics/epidemiology ; *Alzheimer Disease/microbiology/genetics/epidemiology ; Mendelian Randomization Analysis ; *Gastrointestinal Microbiome/genetics ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; },
abstract = {Using a 2-sample Mendelian randomization (MR) approach, we evaluated MR evidence for genetically proxied effects of 10 pre-specified gut bacterial classes on type 2 diabetes mellitus (T2DM) and Alzheimer disease (AD), and assessed MR evidence for a direct genetically proxied effect of T2DM on AD. Mediation by T2DM was explored where feasible. We performed 2-sample MR using MiBioGen gut microbiota GWAS summary statistics as exposure, and DIAMANTE (T2DM) and European AD GWAS data as outcomes. Inverse-variance weighted (IVW) MR was the primary analysis, with MR-Egger, weighted median, and weighted mode as sensitivity analyses. Heterogeneity and directional pleiotropy were assessed, and IVW results were false discovery rate (FDR) corrected using Benjamini-Hochberg. MR analysis using 184 independent SNPs provided no robust evidence for a direct genetically proxied effect of T2DM on AD risk (IVW odds ratio [OR] = 0.98, 95% confidence interval [CI]: 0.94-1.02, P = .28). After FDR correction, higher genetically predicted Clostridia abundance was associated with lower AD risk (IVW OR = 0.86, 95% CI: 0.77-0.96, FDR < 0.05), and higher genetically predicted Deltaproteobacteria abundance was associated with higher T2DM risk (IVW OR = 1.11, 95% CI: 1.04-1.20, FDR < 0.05). Other classes were not significant after FDR correction. Reverse MR and multivariable MR were not testable due to insufficient SNP overlap after harmonization (effective SNPs < 3). These findings provide MR evidence consistent with genetically proxied effects of Clostridia on AD and Deltaproteobacteria on T2DM and do not support robust MR evidence for a direct genetically proxied effect of T2DM on AD. Results are hypothesis-generating and require replication in diverse ancestries and follow-up mechanistic/experimental studies, given that included GWAS sources are predominantly of European ancestry.},
}

Humans
*Diabetes Mellitus, Type 2/microbiology/genetics/epidemiology
*Alzheimer Disease/microbiology/genetics/epidemiology
Mendelian Randomization Analysis
*Gastrointestinal Microbiome/genetics
Polymorphism, Single Nucleotide
Genome-Wide Association Study

@article {pmid42152579,
year = {2026},
author = {Shi, W and Zhu, Z and Wu, M and Cheng, W and Xu, H},
title = {Hip Bone Marrow Adiposity as a Risk Factor for Alzheimer's Disease: Insights From Mendelian Randomization Analysis.},
journal = {Annals of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1111/ahg.70041},
pmid = {42152579},
issn = {1469-1809},
support = {//Key Clinical Research Project of the Morning Light Program under the Exploration Program of Wuhan Natural Science Foundation/ ; //Youth Project of the Natural Science Foundation of Hubei Province/ ; },
abstract = {BACKGROUND: The bone-brain axis has emerged as a critical framework linking skeletal metabolism to neurodegeneration. Within this axis, bone marrow adipose tissue (BMAT) represents a unique fat depot with distinct endocrine and hematopoietic functions, yet its contribution to Alzheimer's disease (AD) remains unclear.

METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics to assess the causal effects of six fat depots-abdominal subcutaneous, visceral, spinal, femoral head, total hip, and femoral diaphysis fat-on AD risk. Mediation analysis was further performed to evaluate whether femoral neck bone mineral density (BMD) mediates these associations.

RESULTS: Among the six depots, only total hip BMAT showed a significant causal association with AD risk (OR = 1.28, 95% CI: 1.09-1.51, p = 0.003). Total hip BMAT was inversely related to femoral neck BMD (β = -0.43, 95% CI: -0.61 to -0.24, p < 0.001), whereas no causal relationship was detected between BMD and AD (OR = 1.01, 95% CI: 0.89-1.15, p = 0.849), excluding bone loss as a mediator.

CONCLUSIONS: This study provides the first genetic evidence that excessive hip BMAT increases the risk of AD, supporting the bone-brain axis hypothesis. These findings highlight BMAT as a novel target for understanding and potentially preventing AD.},
}

@article {pmid42152586,
year = {2026},
author = {Yuan, L and Asghar, MA and Zhang, Y and Yang, Y and Zhang, X and Zhao, Q},
title = {Effective Amelioration of Alzheimer's Disease in Preclinical Models With Electrophilic Compounds via Nrf2 Pathway Activation.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {6},
pages = {e70909},
doi = {10.1002/jbt.70909},
pmid = {42152586},
issn = {1099-0461},
mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; *NF-E2-Related Factor 2/metabolism ; Humans ; Animals ; *Oxidative Stress/drug effects ; *Antioxidants/therapeutic use/pharmacology ; *Signal Transduction/drug effects ; Disease Models, Animal ; *Phytochemicals/therapeutic use/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes, with no effective treatments currently available. Oxidative stress has been shown to be associated with AD, but the causal relationship of AD by oxidative stress remains unestablished. Activation of the Nrf2 pathway is a powerful way to counteract oxidative stress. There are lines of evidence that the pathological features, including Aβ deposition, Tau phosphorylation, neuroinflammation, and mitochondrial dysfunction, could be ameliorated by different antioxidant measures. A group of Nrf2 pathway activators, functioning as Michael acceptors, can covalently modify the Keap1 protein. Such a reaction triggers a conformational change of Keap1, facilitating the release of functional Nrf2 and its subsequent translocation into the nucleus. As a result, a cascade of antioxidant related proteins is expressed. Many plant-derived compounds with Nrf2 pathway activation properties were shown to improve the AD symptom in animal models. This review summarizes the phytochemicals and FDA-approved drugs with diverse structure, including isothiocyanates, polyphenols, phenylpropanoids, flavonoids, terpenes, and alkaloids, but all with Nrf2 pathway activation function and effects on the ameliorating effects on AD symptoms. Three of FDA-approved drugs, being Nrf2 activators, are for the disorders in nervous system. Therefore, Nrf2 could be a promising target for future drug development based on rational design or on the screening from the phytochemicals.},
}

*Alzheimer Disease/metabolism/drug therapy/pathology
*NF-E2-Related Factor 2/metabolism
Humans
Animals
*Oxidative Stress/drug effects
*Antioxidants/therapeutic use/pharmacology
*Signal Transduction/drug effects
Disease Models, Animal
*Phytochemicals/therapeutic use/pharmacology

@article {pmid42152587,
year = {2026},
author = {Atasoy, T and Sajedi, H and Khodadadi, D and Tozoğlu, B and Güler, MŞ and Aka, ST and Babaei, M},
title = {Intermittent Fasting Potentiates Aerobic Exercise to Reduce Hippocampal Amyloid Burden and Oxidative Stress via Suppression of NF-κB/NLRP3 Signaling in an Aβ-Injected Rat Model.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {e9921337},
doi = {10.1155/omcl/9921337},
pmid = {42152587},
issn = {1942-0994},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Hippocampus/metabolism/pathology ; Male ; *Oxidative Stress ; Rats ; *Amyloid beta-Peptides/toxicity/metabolism ; *Fasting ; Rats, Wistar ; *Physical Conditioning, Animal ; *NF-kappa B/metabolism ; Signal Transduction ; Disease Models, Animal ; *Alzheimer Disease/metabolism/pathology ; Intermittent Fasting ; },
abstract = {NOD-like receptor protein 3 (NLRP3) inflammasome-driven neuroinflammation contributes to Alzheimer's disease (AD) progression, yet effective strategies to target this pathway are limited. We investigated whether aerobic exercise performed in a fasted state, rather than the fed state, would potentiate β-hydroxybutyrate (BHB)-dependent inhibition of NLRP3 inflammasome signaling. Twenty-month-old male Wistar rats were randomly assigned to five groups: AD, AD + intermittent fasting (ADIF), AD + aerobic exercise (ADAE), ADIF + aerobic exercise (ADIFAE), and sham-injected control (SC). AD-like pathology was induced by bilateral intrahippocampal injection of amyloid-β (Aβ)1-42. The IF regimen consisted of a daily 14-h fast (06:00-20:00). Exercise consisted of moderate-intensity treadmill running (5 days/week for 4 weeks), either in the fed state or after ∼12.5 h of fasting. Aβ injection impaired spatial learning and memory, elevated soluble Aβ1-42 (sAβ), malondialdehyde (MDA), NF-κB, NLRP3, caspase-1, interleukin-1β (IL-1β), and IL-18, and reduced superoxide dismutase (SOD) activity and brain-derived neurotrophic factor (BDNF) expression in the hippocampus (p < 0.05). Both IF and exercise partially reversed cognitive impairments by reducing sAβ and oxidative stress, increasing BHB, suppressing NF-κB/NLRP3 signaling, and restoring BDNF (p < 0.05), while fasted-state exercise produced significantly larger effects than either intervention alone (p < 0.05). Our findings suggest that performing exercise in a fasted state provides complementary metabolic, anti-inflammatory, and cognitive benefits that exceed those of either intervention alone. This combined regimen may represent a promising nonpharmacological strategy for targeting metabolic-immune and neurotrophic pathways relevant to AD progression.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Hippocampus/metabolism/pathology
Male
*Oxidative Stress
Rats
*Amyloid beta-Peptides/toxicity/metabolism
*Fasting
Rats, Wistar
*Physical Conditioning, Animal
*NF-kappa B/metabolism
Signal Transduction
Disease Models, Animal
*Alzheimer Disease/metabolism/pathology
Intermittent Fasting

@article {pmid42152599,
year = {2026},
author = {Casey, N and Faraco, G},
title = {Mechanisms of neurovascular regulation in health and disease: Insights from experimental animal models.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261448670},
doi = {10.1177/0271678X261448670},
pmid = {42152599},
issn = {1559-7016},
abstract = {The brain is an energetically demanding organ that relies on a continuous and precisely regulated blood supply to sustain neuronal function. This regulation is achieved through an intricate vascular network and sophisticated control mechanisms that dynamically match cerebral blood flow (CBF) to local metabolic demands. Central to this process is the neurovascular unit (NVU), a multicellular ensemble composed of endothelial cells, mural cells, astrocytes, neurons, microglia, and extracellular matrix components. Through coordinated interactions, the NVU governs vascular tone, blood-brain barrier integrity, and metabolic exchange. In this Review, we first describe the structural organization of the cerebrovascular tree and the specialized features of its cellular constituents. We then examine the principal mechanisms controlling CBF, including neurovascular coupling, cerebrovascular autoregulation, and endothelial regulation of vascular tone, highlighting the underlying molecular and cellular pathways. Emphasis is placed on mechanistic insights derived from experimental animal models, which have been fundamental for dissecting the basic biology of neurovascular regulation. Finally, we discuss how disruption of these regulatory systems contributes to cerebrovascular and neurodegenerative diseases, including hypertension and Alzheimer's disease (AD), primarily drawing on preclinical evidence.},
}

@article {pmid42152645,
year = {2026},
author = {Kishor, K and Arora, A and Yashika, and Yadav, S and Singh, A},
title = {Extracellular Vesicles in Alzheimer's Disease: Mechanisms, Immunotherapy Links, and Clinical Translation.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128464813260512100753},
pmid = {42152645},
issn = {1873-4286},
abstract = {Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction, neuroinflammation, and cognitive impairment. Although amyloid-β and tau continue to serve as core biomarkers and therapeutic targets, the clinical efficacy of recent biologic agents targeting amyloid has led to a new paradigm in AD treatment. Nevertheless, emerging data show that lipid metabolism is an important and well-established aspect of AD pathophysiology rather than a new theory. Lipid processing in microglia, astrocytes, and neurons is disrupted, leading to chronic inflammation, impaired amyloid clearance, mitochondrial dysfunction, and synaptic dysfunction. This review critically analyzes how lipid accumulation and lipid droplet biology contribute to Alzheimer's disease using cellular, animal, and human studies. Special focus is placed on enzymatic regulators such as DGAT2, cholesterol transport, and neuron-glia metabolic linkages. This review synthesizes existing mechanistic and translational data to emphasize lipid dysregulation as a complementary therapeutic target and potential biomarker axis that may improve current amyloid- and taudirected therapeutic strategies.},
}

@article {pmid42152660,
year = {2026},
author = {Younas, S and Badshah, I and Akbar, K and Al-Otaibi, JS and Khan, H},
title = {3-(2,4-Dimethylbenzylidene)-6-chloroindolin-2-one Alleviates Memory Impairment in D-Galactose-induced Alzheimer Like Pathology in a Mouse Model.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X434400260421062719},
pmid = {42152660},
issn = {1875-6190},
abstract = {INTRODUCTION: Oxidative stress and neuroinflammation are the main contributors to Alzheimer's disease (AD). The current study evaluated the neuroprotective efficacy of 3-(2,4- dimethylbenzylidene)-6-chloroindolin-2-one (DMO) against D-Galactose (GAL)-induced neuroinflammation, oxidative stress, and memory impairment in mice.

METHODS: Swiss Male albino mice weighing (25-30 g) were assigned to five experimental groups (n=6) (i) Normal group (received normal saline 0.9%) (ii) Control group (received GAL 100 mg/kg i.p) (iii) Standard group (received Donepezil 5 mg/kg + GAL 100 mg/kg i.p) (iv) Treatment group 1 (received DMO 5 mg/kg + GAL 100 mg/kg i.p) and Treatment group 2 (received DMO 10 mg/kg + GAL 100 mg/kg i.p) once daily for 8 weeks. After treatment, the mice were subjected to behavioral analysis, followed by sacrifice for further analysis.

RESULTS: DMO alleviated GAL-induced cognitive impairment as shown by the Morris water maze test (MWM), Y-maze, elevated plus maze (EPM), and open field (OF) test. Brain tissue histology showed reversal of distorted neuronal structures and decreased pyknosis upon DMO treatment. DMO also decreased the levels of Glutathione-S-Transferase (GST), reduced Glutathione (GSH), and catalase (CAT), concomitant with increased lipid peroxidase (LPO). Furthermore, levels of TNF-α and NF- ҡB, were significantly reduced in the DMO treatment groups as quantified by ELISA. In addition, Reverse transcription polymerase chain reaction (RT-PCR) showed a substantial decrease in the expression of β-amyloid and Tau protein.

DISCUSSION: The results showed that DMO inhibits D-gal induced oxidative stress, neuroinflammation and consequently alleviates memory impairment.

CONCLUSION: Our novel findings suggest that DMO could be a promising therapeutic modality for the treatment of brain aging-associated disorders.},
}

@article {pmid42152663,
year = {2026},
author = {Xu, G and Li, R and Hong, Z and Gan, D and Wu, Y and Yang, X and Wang, C},
title = {CREB-Mediated Regulation of Microglial Polarization in Central Nervous System Diseases.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X446686260228190032},
pmid = {42152663},
issn = {1875-6190},
abstract = {The cAMP response element-binding protein (CREB) is a crucial transcription factor that regulates cell survival, synaptic plasticity, and immune responses in the central nervous system (CNS). Recent studies have highlighted its key role in modulating microglial polarization, a pivotal process in neuroinflammation. CREB activation promotes the anti-inflammatory M2 phenotype by upregulating IL-10 and Arg-1, while repressing M1-associated pro-inflammatory genes such as TNF-α and COX-2. Beyond these direct transcriptional effects, CREB functions as a signalintegration hub that interfaces with cAMP/PKA, NF-κB, PI3K/Akt and MAPK cascades, and cooperates with metabolic regulators, including PGC-1α, Nrf2 and PPARγ, to coordinate mitochondrial function and redox balance. CREB also influences neurotrophic factor expression (e.g., BDNF and NGF), inflammasome activity, and phagocytic responses, thereby coupling microglial states to neuronal survival. This review summarizes current advances in the molecular mechanisms of CREBregulated microglial polarization and discusses how these pathways contribute to CNS disorders such as Alzheimer's and Parkinson's disease, cerebral ischemia, multiple sclerosis, affective disorders, and pain-related disorders. Finally, we outline emerging CREB-targeted pharmacological and biological strategies, and highlight key knowledge gaps and safety considerations that must be addressed before CREB-based modulation of microglia can be translated into effective neuroimmune therapies.},
}

@article {pmid42152670,
year = {2026},
author = {Bjørklund, G and Izmailovich, M and Glushkova, N and Semenova, Y},
title = {Vitamin E in Alzheimer's Disease: A Perspective on Antioxidant Therapy.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673386940251024110821},
pmid = {42152670},
issn = {1875-533X},
abstract = {This study explores the relationship between vitamin E and Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline, memory loss, and language impairment. Vitamin E is a fat-soluble antioxidant crucial in protecting cells from oxidative damage. The biochemistry and bioavailability of vitamin E are discussed, including its absorption, transport, and storage in the body. The section on interactions between vitamin E and other nutrients and herbals highlights how combining vitamin E supplements with other supplements or medications can affect its absorption, metabolism, and effectiveness. This study also discusses the potential therapeutic effects of vitamin E on AD, including its ability to reduce oxidative stress and inflammation, which are thought to play a role in the pathophysiology of AD. It explores the synergistic effects of vitamin E with pharmaceuticals and potential side effects, and covers the use of vitamin E in combination with other drugs for AD treatment, such as cholinesterase inhibitors and memantine, as well as the possible adverse effects of vitamin E supplementation. Overall, this study highlights the importance of vitamin E in preventing and managing AD and underscores the need for further research in this area.},
}

@article {pmid42152699,
year = {2026},
author = {Oba, GMJ and Sahu, R and Shah, K and Singh, AP},
title = {Interesting Potential Derivatives Based on the Coumarin Scaffold for the Treatment of Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575449515260428094401},
pmid = {42152699},
issn = {1875-5607},
abstract = {As the most common and deadly age-related neurodegenerative disease, Alzheimer's Disease (AD) affects the vast majority of elderly individuals. As such, new drugs are being produced, and their safety is still being assessed. Coumarin-based medications are among the most important pharmacophores in both natural and synthetic medicinal compounds. Targeting several essential receptors or enzymes, this six-membered aromatic heterocycle, linked by two oxygen atoms, has numerous therapeutic applications in research and offers many opportunities for future improvements in anti-Alzheimer's drugs. Several coumarin compounds have been shown to inhibit not just enzymes and receptors but also a wide range of additional targets involved in the battle against AD. The expansion of new derivatives based on coumarins in conjunction with other moieties for the treatment of AD is the current focus of research. In order to help scientists design effective drugs with the right pharmacological activity, this study sheds light on the current therapeutic expansion of coumarin-based derivatives as well as their synthesis methods.},
}

@article {pmid42152706,
year = {2026},
author = {Karayat, M and Kaushik, N and Paliwal, D},
title = {Scopoletin as a Potential Therapeutic Agent for Neurodegenerative Disorders: Mechanisms and Perspectives.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266399675251201111538},
pmid = {42152706},
issn = {1873-4294},
abstract = {Neurodegenerative diseases, such as Alzheimer's and Parkinson's, continue to pose significant challenges due to their complex aetiology and limited treatment options. Scopoletin, a naturally occurring coumarin found in a variety of medicinal plants, is being explored as a potential therapeutic agent because of its broad pharmacological profile. This review investigates scopoletin's neuroprotective potential, with particular emphasis on its antioxidant, anti-apoptotic, and cholinergic-regulating properties. It also highlights its ability to reduce oxidative stress, modulate neurotransmitter balance, and prevent protein aggregation, which are key pathological features of neurodegeneration. Despite promising preclinical findings, further research is required to establish its efficacy, optimise its bioavailability, and evaluate its safety in clinical settings. Overall, scopoletin demonstrates considerable potential as a neuroprotective compound, offering new avenues for the development of innovative therapeutics for neurodegenerative disorders. This comprehensive review aims to provide a foundation for future research and the advancement of scopoletin as a promising agent against neurodegeneration.},
}

@article {pmid42152708,
year = {2026},
author = {Singh, K and Sethi, P and Jain, D and Gupta, JK and Waqar, Z and Singh, B and Syed, R and Tabish, M and Sharma, MC},
title = {Molecular Mechanisms of Neurodegeneration: A Focus on Cholinergic Dysfunction and the Therapeutic Potential of Rivastigmine Derivatives.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266380856251204044937},
pmid = {42152708},
issn = {1873-4294},
abstract = {Neurodegenerative diseases progressively impair neuronal structure and function, leading to cognitive decline, motor dysfunction, and paralysis. Among the underlying mechanisms, cholinergic dysfunction-characterized by degeneration of cholinergic neurons and reduced acetylcholine (ACh) levels-plays a central role in disease progression, particularly in Alzheimer's disease (AD) and Parkinson's disease (PD). According to the cholinergic hypothesis, memory loss and cognitive impairment are directly linked to disrupted ACh-mediated neurotransmission. Rivastigmine, a dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor, enhances synaptic ACh levels but is limited by a short half-life, modest efficacy, and gastrointestinal side effects. This review highlights the molecular mechanisms underlying cholinergic dysfunction, including oxidative stress, mitochondrial impairment, protein aggregation, neuroinflammation, and synaptic dysregulation, while emphasizing rivastigmine and its derivatives as emerging therapeutic candidates. Structural modifications of rivastigmine have yielded multifunctional derivatives with improved selectivity, blood-brain barrier penetration, and neuroprotective properties, including antioxidant, anti-amyloid, and anti-inflammatory activities. These advances suggest that rivastigmine derivatives could serve as promising multi-targeted agents for neurodegenerative disorders. Future directions include integrating these compounds with nanotechnology-based delivery systems and precision medicine approaches to overcome pharmacokinetic limitations and optimize patient outcomes.},
}

@article {pmid42152767,
year = {2026},
author = {Han, S and Naderi, E and Wang, K and Ma, Y and Biessels, GJ and Ahmadizar, F},
title = {Prediabetes as a critical stage for risk of dementia and stroke: evidence from the UK Biobank and Mendelian Randomization.},
journal = {European journal of preventive cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurjpc/zwag278},
pmid = {42152767},
issn = {2047-4881},
abstract = {BACKGROUND AND AIMS: Type 2 diabetes (T2D) is a recognized risk factor for dementia and stroke, but whether risks begin during prediabetes remains unclear. We aimed to determine the risks of these neurological conditions among individuals with prediabetes and the glycemic thresholds at which risks emerge.

METHODS: We studied 432,887 adults (mean age, 57 years; 55% women) from the UK Biobank who were free of dementia or stroke at baseline, categorized by glycemic status (normoglycemia, prediabetes, and T2D). Incident dementia, stroke, and Magnetic Resonance Imaging (MRI)-derived brain markers, including brain volumes and white matter hyperintensity volumes, were assessed for these conditions. HbA1c was modeled continuously using natural cubic splines to assess linear and non-linear effects. Outcomes were estimated using Cox proportional hazards and linear regression models, adjusted for demographic, lifestyle, and clinical factors. Two-sample Mendelian randomization (MR) was used to test causality.

RESULTS: During a median 13.7 years of follow-up, prediabetes (n=52,693) was associated with higher risks of vascular dementia (hazard ratio (HR):1.36; 95% confidence interval (CI): 1.14-1.61), stroke (HR:1.09; 95% CI: 1.01-1.16), ischemic stroke (HR:1.10; 95% CI: 1.02-1.19), and intracerebral hemorrhage (HR:1.19; 95% CI: 1.01-1.39) compared with normoglycemia, after adjustment for major confounding factors and across extensive sensitivity analyses. In the brain MRI cohort (N=39,996), gray matter volumes (β = -0.04, 95% CI -0.07 to -0.01) and hippocampal volumes (β = -0.03, 95% CI -0.06 to 0.00) were smaller, and log-transformed white matter hyperintensity volume (β = 0.04, 95% CI 0.01 to 0.07) was larger in prediabetes. Spline models indicated that adverse outcomes were associated with higher HbA1c levels, even before the diagnostic threshold for T2D was reached. Risks were further elevated in T2D. MR analyses supported causal effects of glycemia on dementia, stroke and hippocampal atrophy.

CONCLUSION: Prediabetes is not a benign state: even modest HbA1c elevations are linked to vascular dementia, stroke, and brain structural decline. These risks emerge below current diagnostic glycemic thresholds, underscoring prediabetes as a critical stage for early intervention to preserve brain health.},
}

@article {pmid42153007,
year = {2026},
author = {Keyvanfard, F and Nasiraei-Moghaddam, A},
title = {Blind Identification of Altered Functional Subnetworks in Alzheimer's Disease Using Resting-State fMRI.},
journal = {Biomedical engineering and computational biology},
volume = {17},
number = {},
pages = {11795972251404254},
pmid = {42153007},
issn = {1179-5972},
abstract = {INTRODUCTION: Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to examine functional connectivity (FC) alterations in neurological disorders such as Alzheimer's disease (AD). Traditional studies either employ whole-brain analyses or focus on specific regions, yet the vast number of FCs and their interrelations complicate interpretation. This study adopts a data-driven, hypothesis-free approach to detect altered functional subnetworks in AD.

METHODS: Independent component analysis (ICA) was applied to FC matrices from 34 AD patients and 49 healthy controls (HCs) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). After pruning, significant subnetworks distinguishing AD from HC were identified. Graph theoretical parameters were computed for each subnetwork, and their associations with Mini-Mental State Examination (MMSE) scores were assessed.

RESULTS: Three subnetworks effectively differentiated AD patients from HCs. One subnetwork showed significant group differences in network strength, clustering coefficient, and local efficiency, despite no whole-brain differences. Abnormal functional lateralization also emerged within subnetworks. Moreover, FC weights in the identified subnetworks positively correlated with MMSE scores, linking cognitive performance to subnetwork connectivity.

CONCLUSION: These results demonstrate the utility of a data-driven approach in detecting AD-specific altered subnetworks. By providing a modular perspective, this method facilitates targeted examination of connectivity changes, improves interpretability, and deepens understanding of functional disruptions in AD.},
}

@article {pmid42153198,
year = {2026},
author = {Khosh Ravesh, R and Khodashenas, V and Goudarzi, M and Mohammadi, L and Baluchnejadmojarad, T and Roghani, M},
title = {Promising Therapeutic Potential of miR-220-3p Mimic Against Murine Trimethyltin Hippocampal Injury.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {25},
number = {1},
pages = {e165755},
pmid = {42153198},
issn = {1726-6890},
abstract = {BACKGROUND: Trimethyltin (TMT) is an organotin compound known to induce neurotoxicity within the limbic system of the brain, particularly in the hippocampal region, with neurodegenerative changes resembling those of Alzheimer's disease (AD).

OBJECTIVES: This investigation examined the impact of miRNA-220-3p (miR-220-3p) on TMT-induced neurotoxicity and associated behavioral abnormalities, such as spatial learning and memory impairments, and identified the potential molecular mechanisms.

METHODS: To induce neurotoxicity, TMT was injected (8 mg/kg, i.p. once), and after 1 hour, miR-220-3p was microinjected intraventricularly (ICV route, once) for the possible mitigation of TMT-induced neurotoxicity. Different behavioral assessments were employed to determine spatial learning and memory function. Moreover, hippocampal measurements of brain-derived neurotrophic factor (BDNF) and Sirtuin-1, oxidative stress-, apoptosis-, and neuroinflammation-related factors, and histochemical changes were performed.

RESULTS: The TMT injection led to behavioral abnormalities in the novel object discrimination and Barnes maze tests, heightened oxidative stress [elevating reactive oxygen species (ROS) levels, nitrite, and lipid peroxidation and decreasing the activities of antioxidant enzymes, including catalase (CAT) and superoxide dismutase (SOD)], reduced BDNF and Sirtuin-1 levels, increased neuroinflammation [escalating the secretion of pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)], raised activities of acetylcholinesterase (AChE), myeloperoxidase (MPO), beta-secretase 1 (BACE-1), caspase-1, and caspase-3, accompanied by a reduced number of CA1 pyramidal neurons and higher glial fibrillary acidic protein (GFAP) immunoreactivity. In contrast, microinjection of miR-220-3p reversed most of these alterations.

CONCLUSIONS: The findings of this investigation imply that miR-220-3p may mitigate TMT-induced neurotoxicity, which is attributed to the suppression of hippocampal oxidative stress, neuroinflammation, and caspase-dependent apoptosis and pyroptosis, and part of its beneficial effect is associated with the upregulation of BDNF and Sirtuin-1.},
}

@article {pmid42153219,
year = {2026},
author = {Urso, D and Volpe, G and Valguarnera, A and Vilella, D and Vitulli, A and Gnoni, V and Giugno, A and Rollo, E and Griffiths, MD and Logroscino, G},
title = {Problematic Internet Use in Frontotemporal Dementia: A Case Series.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70417},
pmid = {42153219},
issn = {2328-9503},
support = {D.G.R. n. 2117 of 21.11.2018 (CUPB84I18000540002)//Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione./ ; },
abstract = {The present study investigated problematic internet use (PIU) among 61 patients with frontotemporal dementia (FTD) compared to a cohort of 354 patients with mild cognitive impairment (MCI) and Alzheimer's dementia. PIU was identified in 22.9% of FTD patients compared to only 0.8% of AD patients (p < 0.001). Behaviors included compulsive social media use, gaming, and online shopping. These findings suggest that PIU may represent an emerging behavioral feature associated with FTD, significantly more prevalent than in MCI and Alzheimer's dementia. Recognizing these digital behaviors could provide valuable clinical insights for diagnosis and management in the digital age.},
}

@article {pmid42153492,
year = {2026},
author = {Palmqvist, S and Tengzelius, R and Schöll, M and Nägga, K and Mattsson-Carlgren, N and Zetterberg, H},
title = {[New blood-based biomarkers for Alzheimer's disease].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42153492},
issn = {1652-7518},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/cerebrospinal fluid ; *Biomarkers/blood/cerebrospinal fluid ; *tau Proteins/blood ; Amyloid beta-Peptides/blood ; },
abstract = {Blood-based biomarkers, particularly plasma p-tau217, have rapidly improved the detection of Alzheimer's disease pathology and can in some settings replace cerebrospinal fluid analysis or amyloid PET in clinical diagnostics. Clinically available assays now achieve high accuracy, especially when using a two-cutoff approach that classifies results as negative, intermediate, or positive, thereby supporting their use for confirming or ruling out disease. Implementation is likely to be straightforward in specialized clinics but more challenging in settings without prior biomarker experience or access to confirmatory testing for intermediate results, such as primary care.},
}

Humans
*Alzheimer Disease/blood/diagnosis/cerebrospinal fluid
*Biomarkers/blood/cerebrospinal fluid
*tau Proteins/blood
Amyloid beta-Peptides/blood

@article {pmid42153497,
year = {2026},
author = {Borgh Skillbäck, T and Palmqvist, S and Eriksdotter, M and Skoog, I and Kern, S},
title = {[Alzheimer's disease and other neurocognitive disorders - epidemiology and new diagnostic criteria].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42153497},
issn = {1652-7518},
mesh = {Humans ; *Alzheimer Disease/diagnosis/epidemiology ; Sweden/epidemiology ; Biomarkers/blood ; *Neurocognitive Disorders/diagnosis/epidemiology ; },
abstract = {Neurocognitive disorders are progressive conditions leading to brain atrophy and functional decline, representing the third leading cause of death in Sweden after cardiovascular disease and cancer. Approximately 150 000 individuals live with a dementia diagnosis, with Alzheimer's disease (AD) comprising two-thirds of cases, followed by vascular cognitive impairment. Diagnosis is usually initiated in primary care through patient history, cognitive testing, laboratory analyses, and brain imaging, while more advanced assessments in specialist clinics may include cerebrospinal fluid or blood biomarkers. Traditionally, diagnoses in Sweden have relied on ICD-10, emphasizing cognitive decline affecting daily life. Recently, biomarker-based frameworks such as NIA-AA and IWG have redefined AD either as a purely biological entity (NIA-AA) or as a clinico-biological construct (IWG). While these are primarily used in research, they highlight the importance of integrating biological markers with clinical evaluation. Preventive strategies remain crucial, as pathological processes can precede symptoms by decades.},
}

Humans
*Alzheimer Disease/diagnosis/epidemiology
Sweden/epidemiology
Biomarkers/blood
*Neurocognitive Disorders/diagnosis/epidemiology

@article {pmid42154093,
year = {2026},
author = {Mohan, AA and Talwar, P},
title = {Gene Expression Analysis of Mitochondria-Associated Membrane (MAM)-Related Genes in ER Stress and Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01726-6},
pmid = {42154093},
issn = {1573-6830},
abstract = {Alzheimer's Disease (AD) is a devastating neurodegenerative disease, strongly linked to cellular stress originating from the accumulation of the Amyloid-beta (Aβ) peptide and phosphorylated tau protein. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) are reported as early events in the AD pathology. Mitochondria-Associated Membrane (MAM) is a proteinaceous tethering between the ER and mitochondria that plays a role in regulating ER stress and related responses. A high level of ER-mitochondria tethering, thereby mitochondrial Calcium (Ca[2+]) overload and cell death, has been reported in AD brain cells. Despite the independent recognition of these pathways, a precise mechanism that integrates MAM activity, ER stress response, and AD pathogenesis remains elusive. We used three transcriptomic datasets collected from the NCBI-Gene Expression Omnibus (GEO) database, which deal with AD, ER stress, and MAM, and processed them with a multi-layered bioinformatics approach combining differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), protein interaction network construction, and identification of hub genes using different cytoHubba topological algorithms. Four hub genes, namely Calreticulin (CALR), Calnexin (CANX), Heat Shock Protein 90 Beta Family Member 1 (HSP90B1), and Valosin-Containing Protein (VCP), were identified. CALR, CANX, and HSP90B1 are known chaperones that regulate proteostasis. VCP is an ER ATPase that induces autophagy. These genes are not only associated with MAM regulation and ER stress but also with AD pathology. The results suggest hub genes as a new set of biomarkers and the likely existence of a 'three-component system' among MAM, ER stress, and Neurodegeneration. The study highlights the potential of MAM-related genes as therapeutic targets of AD.},
}

@article {pmid42154301,
year = {2026},
author = {Zhong, G and Shi, J and Jiang, Y and Li, S and Wang, X and Zhang, T and Chen, Z and Wang, Q and Liu, S},
title = {Mechanistic study on the alleviating effects of cinnamaldehyde on aluminum chloride-induced cognitive impairment in zebrafish through modulating the TLR4/NF-κB signaling pathway.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42154301},
issn = {1573-7365},
support = {82274616//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Acrolein/analogs & derivatives/pharmacology/therapeutic use ; Zebrafish ; *Toll-Like Receptor 4/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; Aluminum Chloride/toxicity ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Molecular Docking Simulation ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative condition distinguished by intricate pathological mechanisms. Cinnamaldehyde, a natural active chemical sourced from the bark of Cinnamomum species, exhibits remarkable neuroprotective properties that have been validated in various neurological disorders. In this study, network pharmacology alongside zebrafish experiments was employed to investigate the molecular mechanisms and signaling pathways through which cinnamaldehyde ameliorates AD. Potential targets of cinnamaldehyde were found using the SuperPred, TargetNet, SwissTargetPrediction, and SEA databases, whilst AD-related targets were obtained from TTD, OMIM, GeneCards, and DrugBank databases. Subsequently, protein-protein interaction analysis was performed using the STRING database, followed by GO and KEGG enrichment studies via the DAVID platform. Finally, molecular docking validation was conducted using CB-Dock2. The network pharmacology results indicated that cinnamaldehyde might impact its beneficial effects on AD via regulating the toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-κB) signaling pathway. To further validate this mechanism, an AD model was established in zebrafish induced by aluminum chloride (AlCl3). Behavioral assays demonstrated that cinnamaldehyde significantly improved AlCl3-induced cognitive impairment. Hematoxylin-eosin and Nissl staining revealed that cinnamaldehyde attenuated neuropathological damage. Biochemical analyses indicated that cinnamaldehyde alleviated oxidative stress and restored cholinergic dysfunction. Furthermore, RT-qPCR findings indicated that cinnamaldehyde reduced inflammatory mediator expression and diminished TLR4 and NF-κB p65 mRNA levels, while western blotting confirmed reduced TLR4 and phosphorylated NF-κB p65 protein expression. In summary, cinnamaldehyde may mitigate neuroinflammation through suppressing the TLR4/NF-κB signaling pathway, thereby ameliorating AlCl3-induced cognitive impairment, neuropathological injury, oxidative stress imbalance, and cholinergic system dysfunction in zebrafish.},
}

Animals
*Acrolein/analogs & derivatives/pharmacology/therapeutic use
Zebrafish
*Toll-Like Receptor 4/metabolism
*NF-kappa B/metabolism
*Signal Transduction/drug effects
Aluminum Chloride/toxicity
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
Molecular Docking Simulation

@article {pmid42154338,
year = {2026},
author = {Attia, MSM and Ahmad, SF and Nadeem, A and Ansari, MA and Al-Hamamah, MA and Harisa, GI and Bakheet, SA and Emran, TB and Singh, T and Attia, SM},
title = {Tirzepatide attenuates neurotoxicity by suppressing inflammation, apoptosis and restoring neurotrophin expression in an Alzheimer's disease-like rat model.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42154338},
issn = {1573-7365},
support = {ORF-2026-748//King Saud University/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced/pathology ; *Apoptosis/drug effects ; Rats ; Male ; Disease Models, Animal ; *Inflammation/metabolism/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Nerve Growth Factors/metabolism/biosynthesis ; Rats, Sprague-Dawley ; Galactose/toxicity ; Amyloid beta-Peptides/metabolism ; Tirzepatide ; },
abstract = {BACKGROUND: Despite numerous milestones in Alzheimer's disease (AD) research, the disease remains incurable, with a high prevalence and significant financial burdens. As a result, researchers are keen to look for new medications that can help manage or prevent the disease.

MATERIALS AND METHODS: The effects of long-term exposures to tirzepatide, a novel dual GIP/GLP-1 receptor agonist, on neurotoxicity and behavioral changes in the D-galactose/aluminium chloride (D-gal/AlCl3)-induced rats' AD-like pathological model were evaluated. Additionally, we investigated the underlying mechanism for tirzepatide's protective effects against neurotoxicity caused by D-gal/AlCl3.

RESULTS AND CONCLUSION: The present findings show that long-term administration of tirzepatide effectively reduced D-gal/AlCl3-induced AD-like neuronal and behavioral deficits and improved rats' learning, spatial memory, and locomotor activity. Tirzepatide restored the aberrant levels of acetylcholine, Aβ1-42, and pTau proteins, major AD hallmarks. Tirzepatide can alleviate behavioral impairments in D-gal/AlCl3-exposed rats by lowering acetylcholinesterase activation and inflammatory markers COX-2, IL-6, and TNF-α levels. This suggests that tirzepatide may alleviate inflammation, leading to restoring the level of acetylcholine and increasing the expression of the neurotrophin BDNF to reduce Aβ-induced neurodegeneration and apoptosis in rats exposed to D-gal/AlCl3. The neuroprotective effect of tirzepatide was also confirmed by lowering the histopathological alterations generated by D-gal/AlCl3 administration, highlighting the possibility of using tirzepatide as a therapeutic candidate to treat AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/chemically induced/pathology
*Apoptosis/drug effects
Rats
Male
Disease Models, Animal
*Inflammation/metabolism/drug therapy
*Neuroprotective Agents/pharmacology/therapeutic use
*Nerve Growth Factors/metabolism/biosynthesis
Rats, Sprague-Dawley
Galactose/toxicity
Amyloid beta-Peptides/metabolism
Tirzepatide

@article {pmid42154340,
year = {2026},
author = {Bagwe Parab, S and Tripathi, P and Barve, K and Kaur, G},
title = {Neuroprotective effects of trans-anethole on AlCl3-induced memory impairment: targeting AChE, oxidative stress, and NLRP3 inflammasome: a promising approach for neurodegeneration prevention.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42154340},
issn = {1573-7365},
mesh = {Animals ; *Oxidative Stress/drug effects ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Memory Disorders/chemically induced/metabolism/prevention & control/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Aluminum Chloride/toxicity ; Male ; *Acetylcholinesterase/metabolism ; *Inflammasomes/metabolism/drug effects ; *Allylbenzene Derivatives/pharmacology/therapeutic use ; *Anisoles/pharmacology/therapeutic use ; Rats, Wistar ; *Neurodegenerative Diseases/prevention & control/chemically induced/metabolism ; Maze Learning/drug effects ; },
abstract = {Aluminum, a widely occurring environmental metal, has been implicated as a neurotoxic agent and is associated with the development of several neurodegenerative conditions, including Alzheimer's disease (AD). Its neurotoxicity is largerly attributed to the induction of oxidative stress , which exacerbates neuroinflammation, leading to cognitive deficits and progressive neuronal dysfunction. Trans-anethole (TA) possesses diverse pharmacological activities, including anti-inflammatory, antioxidant, antifungal, and anticancer effects. However, its neuroprotective potential against AlCl3-induced neurodegeneration, particularly in the context of memory impairment mediated by inflammation and oxidative stress, remains unknown. Therefore, this study was conducted to evaluate the potential role of TA in mitigating neurodegeneration. To establish an aluminum-induced neuroinflammation-associated neurodegenerative model, rats received oral administration of 150 mg/kg AlCl3 for 90 days. TA was administered at three different dosages between days 31 and 90: 40, 80, and 160 mg/kg between days 31 and 90. Cognitive performance was assessed using the Morris water maze (MWM) and passive avoidance test (PAT). Neuroprotective effects were evaluated by analyzing acetylcholinesterase (AChE) activity, oxidative stress markers (catalase, glutathione, and malondialdehyde levels), and neuroinflammatory mediators (NLRP3 inflammasome, Interleukin-1β, and TNF-α) in AlCl3-exposed rats. TA significantly mitigated aluminum-induced neuronal damage by restoring antioxidant defence, inhibiting AChE activity, and downregulating inflammatory proteins, including NLRP3, TNF-α, and IL-1β. Histopathological analysis further confirmed its neuroprotective role. The findings of this study suggests that TA holds therapeutic potential for neurodegenerative disorders by mitigating memory deficits, neuroinflammation, and oxidative stress.},
}

Animals
*Oxidative Stress/drug effects
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Memory Disorders/chemically induced/metabolism/prevention & control/drug therapy
*Neuroprotective Agents/pharmacology/therapeutic use
Rats
Aluminum Chloride/toxicity
Male
*Acetylcholinesterase/metabolism
*Inflammasomes/metabolism/drug effects
*Allylbenzene Derivatives/pharmacology/therapeutic use
*Anisoles/pharmacology/therapeutic use
Rats, Wistar
*Neurodegenerative Diseases/prevention & control/chemically induced/metabolism
Maze Learning/drug effects

@article {pmid42155171,
year = {2026},
author = {Czuba, M and Szafrańska, K and Kolaczkowski, M and Marcinkowska, M},
title = {Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond.},
journal = {European journal of medicinal chemistry},
volume = {315},
number = {},
pages = {118951},
doi = {10.1016/j.ejmech.2026.118951},
pmid = {42155171},
issn = {1768-3254},
abstract = {TRPML1, a lysosomal Ca[2+] channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This evidence has prompted TRPML1 drug discovery efforts across academia and industry, with several small-molecule agonists advancing toward clinical development. In this review, we provide a comprehensive overview of the therapeutic potential of TRPML1 as a molecular target from a medicinal chemistry perspective. We summarize the structural basis of channel activation and inhibition, highlighting insights from recent cryo-EM studies that define the principal ligand-binding sites and mechanisms of allosteric modulation. We systematically survey the chemical space of TRPML1 ligands reported to date, including diverse agonist and antagonist chemotypes, and extend this analysis to encompass undisclosed or recently disclosed compounds emerging from industry pipelines. Furthermore, we discuss key determinants of ligand design and developability, including the challenges associated with targeting a deeply embedded, lipophilic binding pocket within the membrane. Overall, the available evidence positions TRPML1 as a promising target for small-molecule drug discovery and provides a framework for the rational design of next-generation lysosome-directed therapeutics.},
}

@article {pmid42155345,
year = {2026},
author = {Peng, G and Yang, Y and Wang, Y and Chandekar, SA and Yu, J},
title = {Biomarkers in preclinical and early Alzheimer's disease in China: a scoping review.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100599},
doi = {10.1016/j.tjpad.2026.100599},
pmid = {42155345},
issn = {2426-0266},
abstract = {This scoping review synthesizes evidence on fluid and neuroimaging biomarkers for preclinical and early Alzheimer's disease (AD)-including mild cognitive impairment (MCI) and mild AD dementia-in Chinese populations, where a comprehensive overview has been lacking despite AD's increasing biomarker-based definition. We systematically searched four English databases (PubMed, EMBASE, Cochrane, and Web of Science) and three Chinese databases (CNKI, Wanfang, and CQVIP) for studies (2013-2023) reporting diagnostic accuracy of these biomarkers in Chinese preclinical and early AD (eAD) cohorts for clinical use. Due to rapid advancements in biomarker research in China, a supplementary search was conducted in the four English databases for studies published between 2024 and April 30, 2025. Of the 366 included studies investigating fluid or neuroimaging biomarkers in AD, 48 specifically evaluated biomarker performance in biomarker‑confirmed AD populations. Plasma p-tau217 showed strong performance for diagnosing MCI due to AD, and plasma p-tau217, p-tau181/Aβ42, and p-tau217/Aβ42 effectively classified amyloid-β (Aβ) pathology. Multimodal combinations and MRI-based biomarkers also performed well, though evidence is limited. In China, biomarker diagnosis of MCI due to AD is advancing rapidly, while approaches for preclinical AD, machine learning, and multi-protein panels remain in early development.},
}

@article {pmid42155557,
year = {2026},
author = {Gonzalez, AI and Martinez, JE and Giudicessi, A and Rowe, M and Ku, V and Tristão-Pereira, C and He, B and Malotaux, V and Quiroz, YT},
title = {Clinical and biological relevance of objectively-defined subtle cognitive decline in Alzheimer's disease: a narrative review of neuroimaging, biomarker, and clinical progression studies.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100604},
doi = {10.1016/j.tjpad.2026.100604},
pmid = {42155557},
issn = {2426-0266},
abstract = {Preclinical Alzheimer's Disease stages represent possible targets for disease-modifying intervention as well as opportunity for early identification of risk for future decline. Recent research has explored the use of objectively-defined subtle cognitive decline (Obj-SCD), an emerging classification that may identify individuals at risk for neurodegeneration before the onset of mild cognitive impairment (MCI). The Edmonds/Thomas actuarial Obj-SCD criteria (> 1 SD below expectations, single cognitive test impaired per domain) aims to capture those who exhibit minimal cognitive difficulties that do not meet a MCI or dementia diagnosis. Given the novelty of the Obj-SCD classification, this narrative review provides an overview of neuroimaging, biomarker, and clinical progression studies to evaluate its biological and clinical significance. Using fluid-based biomarkers, neuroimaging, and longitudinal designs, studies have indicated that the Obj-SCD classification has the potential to capture AD-related pathological changes detectable before the clinical onset of MCI. In particular, recent studies indicate a unique pathological profile of Obj-SCD, differentiating it from the cognitively unimpaired and MCI stages. Studies comparing Obj-SCD and subjective cognitive complaints show that the Obj-SCD criteria may be more closely associated to early AD pathology. While the existing literature is limited, findings uphold Obj-SCD as a sensitive classification able to identify individuals at risk for future cognitive impairment. Studies on Obj-SCD indicate utility in research settings, although it faces challenges regarding its clinical implementation and effectiveness.},
}

@article {pmid42155784,
year = {2026},
author = {Brechtel, J and Lietz, C and Adscheid, SA and Friedland, K},
title = {Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108227},
doi = {10.1016/j.phrs.2026.108227},
pmid = {42155784},
issn = {1096-1186},
abstract = {Mitochondrial dysfunction is considered one of the key drivers of neurodegeneration and pathological aging, characterized by impaired energy production, oxidative stress, disrupted mitophagy, and biogenesis. Because mitochondria regulate bioenergetics, redox balance, and neuronal survival, therapeutic strategies that restore mitochondrial integrity are of growing interest. This review outlines mechanisms of mitochondrial function and failure, links them to Alzheimer's and Parkinson's disease, and summarizes evidence on phytochemicals and mitochondria-targeted small molecules, which enhance biogenesis, mitophagy, respiratory efficiency, and antioxidant defence in preclinical models together with life-style interventions. Although many compounds demonstrate preventive rather than restorative benefit and clinical evidence remains limited, next-generation approaches, including nanoparticles for mitochondrial delivery, mtDNA editing, and mitochondrial transfer, suggest increasing therapeutic potential. We underline that future success will rely on improved delivery, synergistic combinations, and rigorous clinical trials. Mitochondria-directed therapies may ultimately provide disease-modifying or preventive strategies for neurodegenerative disorders.},
}

@article {pmid42155790,
year = {2026},
author = {Liu, X and Du, T and Gu, Q and Zhang, Z and Hui, L and Tao, L and Shan, H and Chen, X and Zhang, M},
title = {Hydrogen selenide and selenium donors: From Gasotransmitter biology to precision Neurotherapeutics.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112609},
doi = {10.1016/j.cellsig.2026.112609},
pmid = {42155790},
issn = {1873-3913},
abstract = {Hydrogen selenide (H2Se), selenium's central metabolic intermediate, is emerging as the candidate fourth gasotransmitter. This membrane permeable gas mediates rapid redox signaling and serves as the obligate precursor for selenoprotein biosynthesis, essential for neuronal redox homeostasis and survival. Engineered selenium donors, designed for controlled H2Se release or targeted selenoprotein support, exert neuroprotection by attenuating oxidative stress, reducing neuroinflammation, inhibiting ferroptosis, and preserving synaptic integrity across Alzheimer's disease, Parkinson's disease, epilepsy, traumatic brain injury, and stroke. Advances in stimuli-responsive donor chemistry and nanocarrier platforms enable spatiotemporally precise delivery, mitigating selenium's narrow therapeutic window. However, H2Se is cytoprotective at physiological concentrations but toxic at supraphysiological levels and its clinical translation demands rigorous pharmacokinetic optimization, context-aware targeting, and dynamic biomarkers. This review bridges gasotransmitter biology with translational pharmacology, delineating H2Se metabolism, donor design principles, and disease-specific applications. By integrating mechanistic insights with precision delivery strategies, we provide a roadmap for harnessing H2Se and selenium donors as next-generation, clinically viable neurotherapeutics.},
}

@article {pmid42155951,
year = {2026},
author = {Zhang, X and Han, W and Li, Y and Yang, P and Jia, Y and Sun, L and Wang, R and Shi, M and Zheng, X and Zhang, Y and Zhu, Z},
title = {Association of sarcopenia, sarcopenic obesity with incident dementia, cognitive functions, and brain structure: findings from the UK Biobank Study.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {7},
pages = {100879},
doi = {10.1016/j.jnha.2026.100879},
pmid = {42155951},
issn = {1760-4788},
abstract = {BACKGROUND: Several small-sample studies have suggested that sarcopenia and sarcopenic obesity are implicated in cognitive decline. We aimed to prospectively investigate the associations of possible sarcopenia, sarcopenia and sarcopenic obesity with incident dementia, cognitive functions, and brain structure based on the UK Biobank.

METHODS: A total of 420,916 participants without dementia and cardiovascular diseases at baseline were analyzed. Sarcopenia status was defined according to the European Working Group on Sarcopenia in Older People 2. Obesity was defined according to body mass index. Cox models were applied to evaluate the longitudinal associations.

RESULTS: During a median follow-up of 13.69 years, 4,019 incident all-cause dementia events (including 2,650 Alzheimer's disease and 527 vascular dementia) were recorded. Comparted with individuals without sarcopenia, the multivariable-adjusted hazard ratios (95% confidence interval) of all-cause dementia were 1.44 (1.32-1.58), 1.37 (1.03-1.82) and 3.06 (1.89-4.93) for those with possible sarcopenia, sarcopenia and severe sarcopenia, respectively. Individuals with sarcopenic obesity (hazard ratios = 1.69, 1.41-2.03) had the highest risk of all-cause dementia than those with obesity only, sarcopenia only or neither. The significant associations remained in all dementia types (Alzheimer's disease or vascular dementia). In addition, those with sarcopenic obesity was associated with unfavorable cognitive functions, and worse brain structure.

CONCLUSIONS: Our findings suggested that possible sarcopenia, sarcopenia and sarcopenic obesity were associated with a higher risk of all-cause dementia and its subtypes.},
}

@article {pmid42142451,
year = {2026},
author = {Razavi, A and Hou, J and Lin, SJ and Zhang, C and Kremen, WS and Fennema-Notestine, C and Elman, J and Holmans, P and Faraone, SV and Gaiteri, C and Hess, JL and Glatt, SJ},
title = {Predicted brain-regional gene expression patterns in individuals living with Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {29-40},
doi = {10.1016/j.neurobiolaging.2026.04.006},
pmid = {42142451},
issn = {1558-1497},
abstract = {Studying brain gene expression in Alzheimer's Disease (AD) remains difficult as postmortem brain is difficult to access, cannot be used to guide donor treatment, may be confounded by environmental factors before and after death, and is difficult to link to early AD states or disease progression. To circumvent these limitations, several studies have tested blood transcriptome biomarkers for AD. However, gene-expression levels in the blood have limited correlation with those in the brain. To evaluate the potential of monitoring Alzheimer's progression with peripheral data, we used transcriptome-imputation to identify brain-region-specific AD-associated gene-expression differences in cohorts with blood-based transcriptome data. This approach provides a high-resolution image of AD-associated molecular differences in the brains of individuals actively living with disease. We analyzed eight AD studies (777 AD cases, 779 cognitively unimpaired controls), imputing transcriptomes in 10 brain regions via the Brain Gene Expression and Network Imputation Engine (BrainGENIE). Hundreds of differentially expressed genes (DEGs) associated with AD were identified in nine brain regions, with anterior cingulate cortex and amygdala showing the most differential expression. AD-associated genes were enriched in pathways such as proteostasis, mitochondrial dysfunction, and immune activation. We observed significant yet moderate concordance between imputed AD-associated changes and those directly measured in the dorsolateral prefrontal cortex and cerebellum. These transcriptomic changes can guide future in vitro studies focused on pathogenesis or be targets of novel therapeutic development. In conclusion, we demonstrated the scope and utility of brain expression imputation from the peripheral transcriptome, laying the groundwork for biomarker discovery and prospective AD studies.},
}

@article {pmid42142504,
year = {2026},
author = {Abd-Eldayem, AM and Mohammed, RA},
title = {Riluzole in neuroinflammation and neurodegeneration: Mechanistic insights and experimental validation.},
journal = {Current opinion in pharmacology},
volume = {88},
number = {},
pages = {102632},
doi = {10.1016/j.coph.2026.102632},
pmid = {42142504},
issn = {1471-4973},
abstract = {Neuroinflammation and neurodegeneration are tightly interconnected processes that drive the progression of multiple central nervous system (CNS) disorders. Riluzole, a benzothiazole derivative approved for amyotrophic lateral sclerosis (ALS), has been widely investigated for its broader neuroprotective potential. Its actions include modulation of glutamatergic transmission through presynaptic inhibition and upregulation of excitatory amino acid transporters. Additionally, Riluzole inhibits voltage-gated sodium channels, thereby reducing neuronal hyperexcitability and excitotoxicity. Its anti-inflammatory properties are mediated through the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and the attenuation of microglial activation, while its antioxidant effects involve the activation of the nuclear factor erythroid 2-related factor 2/heme Oxygenase-1 (Nrf2/HO-1) pathway and the preservation of mitochondrial function. These mechanisms have been supported by preclinical evidence across models of ALS, Alzheimer's disease (AD), Huntington's disease (HD), and spinal cord injury (SCI), with emerging clinical data supporting its broader therapeutic relevance. Although clinical findings remain limited and disease-specific, the mechanistic breadth of Riluzole continues to motivate interest in its potential utility across neuroinflammatory and neurodegenerative conditions. This review synthesizes recent advances in Riluzole pharmacology and outlines key considerations for future mechanistic and translational research.},
}

@article {pmid42142537,
year = {2026},
author = {Saido, TC},
title = {Animal models of Alzheimer's disease and related disorders.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {105069},
doi = {10.1016/j.neures.2026.105069},
pmid = {42142537},
issn = {1872-8111},
}

@article {pmid42142562,
year = {2026},
author = {Keramat, SA and Dao-Tran, TH and Nguyen, KH and Welch, A and Comans, T},
title = {Assessing the agreement between self- and proxy-reported responses for measuring health-related quality of life in people with dementia using the Alzheimer's Disease Five Dimensions instrument.},
journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jval.2026.04.011},
pmid = {42142562},
issn = {1524-4733},
abstract = {BACKGROUND: The level of agreement between utility values derived from self- and proxy-reports, assessed using the preference-based health-related quality of life (HRQoL) instrument, the Alzheimer's Disease Five Dimensions (AD-5D), remains unclear. We aimed to investigate the agreement between self- and proxy-reported HRQoL, measured using the AD-5D, a dementia-specific, preference-based HRQoL instrument.

METHODS: The data comprise 77 Australian dyads of people with dementia and their caregivers. The agreement between AD-5D utility values derived from self- and proxy-reports was analysed using a Bland-Altman plot. The ordinary least squares regression technique was employed to identify factors associated with the AD-5D utility value sets and to assess agreement between the resulting AD-5D utility values derived from self- and proxy-reports.

RESULTS: The mean AD-5D utility value derived from self-reports (0.667) was higher than the value derived from proxy-reports (0.523). The Bland-Altman plot shows that 7.79% of the differences in AD-5D utility values fell outside the limits of agreement. The regression results indicated that the AD-5D utility value derived from self-reports for people with dementia aged 80 years or older was, on average, 0.20 points lower (β = 0.20, SE = 0.10) than that for people with dementia aged less than 70 years.

CONCLUSION: Utility values derived from self-reports were higher than those derived from caregiver proxy-reports. While proxy reporting is a necessary alternative when self-reporting is not feasible, these perspectives are not interchangeable. Future economic evaluations should incorporate sensitivity analyses to account for this systematic 'proxy-gap'.},
}

@article {pmid42142620,
year = {2026},
author = {Shang, X and Chen, SY and Zhang, XY and Regina, I and Zhang, T and Luo, J and Yan, YZ and Qiao-yuanYao, and Tong, F and Pan, LH},
title = {Insulin in brain: The physiological functions and therapeutic insights for neurodegenerative diseases.},
journal = {Life sciences},
volume = {398},
number = {},
pages = {124468},
doi = {10.1016/j.lfs.2026.124468},
pmid = {42142620},
issn = {1879-0631},
abstract = {This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail. We emphasize the essential roles of insulin in the maintenance of cerebral glucose homeostasis, modulation of cognitive performance, regulation of appetite, promotion of cerebrovascular angiogenesis, and exertion of neuroprotective effects. We demonstrate how insulin resistance exacerbates characteristic neuropathological features in Alzheimer's disease (AD) and Parkinson's disease (PD), while insulin-based interventions ameliorate these pathologies through multiple mechanisms including increasing the activity of insulin-degrading enzyme, suppressing Aβ neurotoxicity, and reducing α-synuclein deposition. The review also systematically examines the neuroprotective effects of insulin sensitizers and their potential to reduce the risk of AD, while noting the complexity of their bidirectional regulatory role in PD, which warrants further investigation. Notably, intranasal insulin administration emerges as a promising non-invasive therapeutic approach that bypasses the blood-brain barrier via olfactory and trigeminal pathways, suggesting significant potential for cognitive enhancement and neuropathological mitigation. Nonetheless, it must be noted that the optimal dosage, long-term safety, and sustained efficacy of insulin therapy remain unclear, and the current evidence is derived primarily from preclinical studies or small-scale clinical trials. In summary, this review paper underscores the critical physiological roles of insulin in the brain and outlines novel therapeutic strategies for using insulin in the treatment of AD and PD.},
}

@article {pmid42142765,
year = {2026},
author = {Feng, Y and Zhang, C and Wei, Y and Liu, E and Sun, H and Flatt, P and Gault, V and Irwin, N and Hölscher, C and Hao, L and Zhang, Z},
title = {A novel bifunctional peptide predicted to target neuropeptide Y4 and GLP-1 receptors alleviates cognitive deficits in 5 × FAD mice by modulating cGAS-STING-mediated neuroinflammation.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118074},
doi = {10.1016/j.bcp.2026.118074},
pmid = {42142765},
issn = {1873-2968},
abstract = {Effective disease-modifying therapies for Alzheimer's disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo, NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden (P < 0.05), alleviated neuronal injury (P < 0.01), improved synaptic integrity (P < 0.01), and attenuated mitochondrial abnormalities (P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) (P < 0.05), cGAS (P < 0.05), STING (P < 0.05), and phosphorylated IRF3 (P < 0.01), together with decreased IL-1β (P < 0.05) and increased IL-10 (P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling (P < 0.05) and inflammatory responses (P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.},
}

@article {pmid42143322,
year = {2026},
author = {Gröbner, LS and Pietrzik, CU},
title = {Transport pathways across the blood-brain barrier for waste clearance and drug delivery.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00812-7},
pmid = {42143322},
issn = {2045-8118},
abstract = {The blood-brain barrier (BBB) displays a highly organized and complex structure, which is important for maintaining brain homeostasis and protecting the brain from foreign molecules or pathogens. Receptor-mediated transcytosis (RMT) is one of the main delivery pathways across the BBB for molecules that cannot pass the barrier via, e.g. paracellular diffusion. For understanding the treatment options in neurodegenerative diseases such as Alzheimer´s disease (AD), it is important to investigate transport pathways and mechanisms at the BBB for a potential delivery of drugs, antibodies or other compounds across the BBB. This review provides an overview of the different transport variants across the BBB and how they can be targeted in order to promote internalization or secretion into or out of the brain. Therefore, we want to focus on two characterized proteins: the low-density lipoprotein receptor-related protein 1 (LRP1), which is a key mediator of amyloid β (Aβ) clearance from the brain during AD, and transferrin receptor 1 (TfR1), which is already used as a target for antibody-delivery into the brain. Additionally, this review discusses two other important proteins, which have been less frequently addressed in research regarding transport mechanisms: P-glycoprotein (P-gp) as another transporter at the BBB and proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol homeostasis which promotes the degradation of the low-density lipoprotein receptor (LDLR) and LRP1. For these four main proteins, we aim to highlight existing approaches for targeting or inhibiting the aforementioned receptors or proteins. The approaches enable a higher penetration of the BBB, a better distribution in the brain, and ultimately fewer side effects of antibodies or nanoparticles. Here, we include lecanemab, trontinemab, dual TfR/CD98hc shuttles, evolocumab and alirocumab, immunoliposomes and other nanoparticles targeting TfR1 or LRP1. We will further highlight approaches which differ from these common ideas and demonstrate the current state of the art regarding drug delivery and waste clearance across the BBB.},
}

@article {pmid42143738,
year = {2026},
author = {Budrovic, K and Gunstad, J and Hamrick, P},
title = {Formulaic and novel language dissociate in Alzheimer's clinical syndrome: evidence for the Dual-Process Model.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13803395.2026.2674224},
pmid = {42143738},
issn = {1744-411X},
abstract = {INTRODUCTION: Spontaneous speech is commonly disrupted in persons with Alzheimer's disease (AD) and/or Alzheimer's clinical syndrome (ACS). Importantly, different aspects of speech (e.g. formulaic versus more novel or flexible speech) place different demands on distinct cognitive systems. Formulaic language may rely on automatized procedural processes, while more novel or diverse speech requires more flexible lexical-semantic processes associated with the subsystems of declarative memory. Given that AD/ACS are associated with impaired declarative processes and relatively spared procedural processes, we predicted that individuals with ACS may show increased reliance on formulaic language along with reduced diversity in speech.

METHOD: We analyzed the spontaneous speech of 81 individuals with ACS (aged 56-88) and 61 healthy controls (aged 47-80) who completed a picture description task using computational tools for the analysis of formulaic language (operationalized as proportion of frequent trigrams produced and mutual information score of trigrams) and novel language (operationalized as root type-token ratio, measure of textual lexical diversity, and semantic diversity).

RESULTS: Across all measures, individuals with ACS produced significantly more formulaic language than control participants and significantly less novel language than control participants, with small-to-medium overall model effect sizes. Machine learning classifiers trained on these patterns of formulaic and novel language distinguished between controls and individuals with ACS with reasonable accuracy, sensitivity, and specificity.

CONCLUSION: The spontaneous speech of individuals with ACS contains more formulaic language and less novel language than that of healthy controls, consistent with the Dual-Process Model. These differences may have clinical relevance and warrant further investigation. Keywords: Alzheimer's Disease, Alzheimer's clinical syndrome, formulaic language, lexical diversity, spontaneous speech.},
}

@article {pmid42144109,
year = {2026},
author = {Loukil, I and Vachon, A and Çaku, A and Plourde, M},
title = {Krill oil increase plasma omega-3 fatty acids more than fish oil in healthy adults: a double blind randomized controlled trial.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101346},
doi = {10.1016/j.ajcnut.2026.101346},
pmid = {42144109},
issn = {1938-3207},
abstract = {BACKGROUND: Omega-3 fatty acids (ω-3 FAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are recognized for their health benefits. However, their circulating levels after supplementation may be modulated by several factors, including sex, carriage of the apolipoprotein E4 allele (APOE4), and the chemical form of the supplement. Krill-oil delivers ω-3 FAs primarily as phospholipids (PL), whereas fish oil provides them as triglycerides (TG).

OBJECTIVE: To compare EPA and DHA concentrations after a supplementation with krill oil and fish oil and assess whether sex and APOE4 genotype modifies responses to supplementation.

METHODS: This double-blind, randomized clinical trial included 72 healthy adults (53 females, 19 males) matched for age and body mass index (BMI). Participants received 1.1 g/day ω-3 FAs through either krill oil (n=36) or fish oil (n=36) for 12 weeks. Plasma fatty acids were measured at baseline and at weeks 1, 2, 4, and 12 by gas chromatography-flame ionization detection. Differences in plasma ω-3 FAs concentrations by treatment, sex and APOE4 status, were analyzed.

RESULTS: Time-by-treatment interactions were significant for plasma delta over baseline concentrations of EPA (p = 0.0001) and DHA (p = 0.005), with krill oil resulting in ∼ 1.5-fold higher ΔEPA and ΔDHA compared to fish oil. The time-by-sex interaction was significant only for EPA (p = 0.026), with females having 1.5-fold greater increase than males at 12 weeks. Following supplementation with either krill oil or fish oil, APOE4 carriers had 3-fold and 1.6-fold higher EPA and DHA respectively, compared to baseline; however, these increases were not significantly different from those found in non-carriers.

CONCLUSIONS: Krill oil increased plasma ω-3 FAs more than fish oil, regardless of APOE4 genotype. Individuals with higher ω-3 FA requirements may achieve adequate enrichment with lower doses of krill oil compared to fish oil supplementation.

REGISTRATION NUMBER: NCT04279743. In https://clinicaltrials.gov.},
}