@article {pmid42990710,
year = {2026},
author = {Zhang, N and Liu, M and Gu, J},
title = {Paths of Aging Minds: Health Journeys of Older Adults with Mild Cognitive Impairment.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42990710},
issn = {2693-5015},
support = {R01 AG083179/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is often conceptualized as an intermediate stage between normal cognition and dementia. However, emerging evidence suggests that cognitive status may change bidirectionally, with individuals experiencing reversion to normal cognition, persistent impairment, or progression to dementia. Previous studies have focused on single transitions or clinical samples frequently. This study aimed to characterize dynamic transitions among normal cognition, MCI, and dementia following incident MCI using longitudinal population-based data.

METHODS: We conducted a retrospective cohort study using data from the Health and Retirement Study (HRS) from 1992 to 2022. Cognitive status was classified at each biennial assessment using the Langa-Weir cognitive classification based on the modified TICS and proxy assessments. Incident MCI was defined as a transition from previously observed normal cognition to MCI. Participants were followed for up to five subsequent HRS waves (approximately 10 years). Descriptive statistics were used to describe changes of cognitive status between waves. A continuous-time multistate Markov model wase used to estimate transition intensities and transition probabilities among normal cognition, MCI, and dementia, including both progression and reversion.

RESULTS: Among 10,489 participants with incident MCI, the mean age at the incident MCI wave was 70.6 years (SD = 11.53), and 56.6% were female. Two years after incident MCI, 62.3% of observed participants were classified as having normal cognition, 31.2% remained in MCI, and 6.5% were classified as having dementia. At 4, 6, 8, and 10 years after incident MCI, the proportion classified as normal cognition declined while the proportion of participants with dementia increased. The multistate model demonstrated substantial bidirectional movement among cognitive states. The estimated transition intensity from MCI to normal cognition was 0.453 (95% CI 0.443-0.463), compared with 0.126 (95% CI 0.121-0.131) for MCI to dementia. Transitions also occurred from normal cognition to MCI (0.265; 95% CI 0.257-0.273) and dementia (0.037; 95% CI 0.035-0.041), as well as from dementia to MCI (0.226; 95% CI 0.209-0.245) and normal cognition (0.064; 95% CI 0.055-0.074).

CONCLUSIONS: Cognitive trajectories following incident MCI were heterogeneous and dynamic, involving reversion, persistence, progression, and recurrent transitions among cognitive states. These findings support a multistate conceptualization of cognitive aging rather than a predominantly unidirectional model of progression toward dementia. Although reversion in cognitive classification should not be interpreted as definitive biological recovery, its frequent occurrence highlights the importance of repeated longitudinal assessment and further investigation of factors associated with cognitive resilience and dementia risk.},
}

@article {pmid43025711,
year = {2026},
author = {Ardjmand, A and Khoshnam, SE and Zarjani, AK and Arjmand, A and Forutan, G and Vastegani, SM},
title = {Recent advances on the role of microRNAs in Alzheimer's Disease: Unraveling Mechanisms and Therapeutic Potential.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112209},
doi = {10.1016/j.brainresbull.2026.112209},
pmid = {43025711},
issn = {1873-2747},
abstract = {MicroRNAs (miRNAs) are now recognized as key regulators of the pathogenesis of Alzheimer's disease (AD) and offer promising opportunities for early detection and treatment. Some miRNAs are responsible for controlling and modulating neuroinflammatory responses, while others directly affect the process of amyloid beta (Aβ) production. Their relative stability in biological fluids supports their potential use in diagnostic panels; however, their diagnostic performance requires further validation before clinical application. From a therapeutic perspective, miRNA antagonists and mimetics have been shown in preclinical studies to reduce amyloid pathology, ameliorate cognitive impairment, and stimulate neurogenesis in animal models of AD. In this review article, we summarize the evidence on the diverse and multifaceted functions of miRNAs in key aspects of AD pathology, including Aβ synthesis via BACE1 and APP regulation, tau aggregation and phosphorylation, APOE4 signaling cascades, oxidative stress, neuroinflammation, and synaptic plasticity. By linking mechanistic understanding of miRNAs with potential translational applications, miRNA-based strategies may offer promising opportunities for improving the early diagnosis and treatment of AD. However, further preclinical validation and rigorous clinical studies are needed to establish their safety, efficacy, and clinical utility.},
}

@article {pmid43025890,
year = {2026},
author = {Dumurgier, J},
title = {Metformin and the ageing brain: what biomarkers can and cannot tell us.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2026-340228},
pmid = {43025890},
issn = {1468-330X},
}

@article {pmid43025892,
year = {2026},
author = {Abanto, J and Dwivedi, AK and Imbimbo, C and Del Prato, S and Imbimbo, BP and Espay, AJ and , },
title = {Metformin use is associated with lower plasma NfL, higher CSF Aβ42 and better cognitive performance.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2026-339219},
pmid = {43025892},
issn = {1468-330X},
}

@article {pmid43026126,
year = {2026},
author = {Kaplan, C and Perepezko, K and Pontone, GM and Bakker, A},
title = {Transdiagnostic Mechanisms Underlying Nonaffective Psychosis: A Role for Hippocampal Networks?.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
pmid = {43026126},
issn = {1545-7214},
support = {R01 MH123552/MH/NIMH NIH HHS/United States ; R01 MH139576/MH/NIMH NIH HHS/United States ; },
abstract = {Psychosis is a functionally disruptive syndrome that results in an impaired sense of reality. People with psychosis have higher rates of mortality and institutionalization compared to the general population, necessitating evaluation and treatment in both neurologic and psychiatric practice. Effective treatments for psychosis require an understanding of the underlying neurobiological mechanisms that may be driving specific psychosis symptoms; however, previous efforts to assess these mechanisms have been challenging due to the heterogenous course and presentation. This review aims to provide a synthesis of what is currently known about psychosis and psychotic symptoms in primary and secondary nonaffective disorders, focusing on the most prevalent conditions in which these symptoms occur: schizophrenia, Parkinson's disease, and Alzheimer's disease. We review the phenomenology, prevalence, and natural history of psychosis in these disorders and highlight features and mechanisms thought to underlie specific psychosis symptoms across these disorders. The reviewed evidence reveals that psychosis is diagnosed differently depending on the disease context; however, the onset of well-formed psychotic symptoms is consistently preceded by a prodromal period in which attenuated symptoms present and insight is retained. In addition, symptoms are strongly linked to cognitive impairment, particularly short-term memory impairment, further supporting the notion of transdiagnostic mechanisms underlying psychosis. While this review provides an overview of key similarities and differences in psychosis symptoms across schizophrenia, Parkinson's disease, and Alzheimer's disease, more research is needed to explore several gaps identified in this review.},
}

@article {pmid43026196,
year = {2026},
author = {Ghisays, V and Denkinger, MN and Singh, A and Marques, TM and Malek-Ahmadi, M and Jensen, KV and Protas, HD and Sohankar, J and Goradia, DD and Devadas, V and Chen, Y and Li, S and Langbaum, JB and Weiner, MW and Reiman, EM and Su, Y and Ashton, NJ and , },
title = {Prognostic value of plasma brain-derived phosphorylated Tau.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
doi = {10.1002/alz.71983},
pmid = {43026196},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; /NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood/metabolism ; Positron-Emission Tomography ; Disease Progression ; *Alzheimer Disease/blood/diagnostic imaging ; Phosphorylation ; Female ; Prognosis ; Biomarkers/blood ; *Brain/metabolism/diagnostic imaging ; Aged ; Male ; Cognitive Dysfunction/diagnostic imaging/blood ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Plasma brain-derived phosphorylated Tau217 (BD-pTau217) may provide a more Alzheimer's disease (AD) -specific plasma tau measure than total pTau217, but its prognostic value is unclear.

METHODS: We compared baseline plasma NULISAseq biomarkers for amyloid positron emission tomography (PET) progression (positivity: Centiloid ≥ 24.1; n = 175) and clinical progression to mild cognitive impairment or AD dementia (n = 508) in cognitively unimpaired Alzheimer's Disease Neuroimaging Initiative (ADNI) participants using Cox models and time-dependent areas under the curve (tdAUCs).

RESULTS: Over a median clinical follow-up of 6 years (interquartile range [IQR], 3.0-7.3), BD-pTau217 and total pTau217 had similar discrimination (full-follow-up AUC = 0.66 each; high-versus-low hazard ratios [HRs]; 95% confidence interval [CIs]: 2.8 [1.89-4.06] and 2.9 [1.96-4.35], respectively). Among initially amyloid-negative participants, BD-pTau217 better predicted progression to amyloid PET positivity at 2.5 years (tdAUC 0.82 vs. 0.69; HR = 10.54 [95% CI 2.3-48.1], p = 0.00015) and 4 years (tdAUC 0.77 vs. 0.64; HR = 7.03 [95% CI 1.9-25.6], p = 0.00055) compared to total pTau217.

CONCLUSION: BD-pTau217 better predicted near-term progression to amyloid PET positivity than total pTau217, but showed no advantage for clinical progression, supporting its potential value as an early marker of AD pathological change.},
}

Humans
*tau Proteins/blood/metabolism
Positron-Emission Tomography
Disease Progression
*Alzheimer Disease/blood/diagnostic imaging
Phosphorylation
Female
Prognosis
Biomarkers/blood
*Brain/metabolism/diagnostic imaging
Aged
Male
Cognitive Dysfunction/diagnostic imaging/blood
Aged, 80 and over

@article {pmid43026203,
year = {2026},
author = {Oveisgharan, S and Yu, L and Taylor, ZW and Gritsenko, MA and Hutchinson Bunch, CM and Mast, DH and Fillmore, TL and Moore, RJ and Libby, JB and De Jager, PL and Hohman, TJ and Schneider, JA and Petyuk, VA and Bennett, DA},
title = {Tau ubiquitination and phosphorylation in relation to Alzheimer's disease in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
doi = {10.1002/alz.71985},
pmid = {43026203},
issn = {1552-5279},
support = {R01AG17917/NH/NIH HHS/United States ; U01AG072572/NH/NIH HHS/United States ; U01AG046152/NH/NIH HHS/United States ; R01AG088643/NH/NIH HHS/United States ; R01AG061518/NH/NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/metabolism ; Phosphorylation ; *Alzheimer Disease/metabolism/pathology ; *Ubiquitination ; Female ; Aged ; Male ; Neurofibrillary Tangles/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Neuropsychological Tests ; Brain/pathology/metabolism ; },
abstract = {INTRODUCTION: It is unknown how soluble tau protein turns into insoluble tau tangle. We tested whether tau ubiquitination and phosphorylation were associated with tau tangles.

METHODS: Data were from participants in the Rush Memory and Aging Project. Proteomic analysis quantified tau protein and its ubiquitination and phosphorylation levels. Pathological examination collected Alzheimer's disease (AD) pathological indices (amyloid-β [Aβ] load and tau tangles), and neuropsychological tests' scores were used for estimating cognitive decline.

RESULTS: Tau ubiquitination positions were correlated and related to more tau tangles while tau phosphorylation at only some positions was related to tau tangles. Tau ubiquitination statistically mediated the association of tau phosphorylation with tau tangles, and tau phosphorylation and ubiquitination statistically mediated 56.5% of Aβ-tau tangle association, suggesting phosphorylation and ubiquitination of tau contributing to tau tangle formation.

CONCLUSION: Targeting pathways underlying tau ubiquitination may partially slow down the accumulation of Aβ-induced tau tangle accumulation.},
}

Humans
*tau Proteins/metabolism
Phosphorylation
*Alzheimer Disease/metabolism/pathology
*Ubiquitination
Female
Aged
Male
Neurofibrillary Tangles/pathology/metabolism
Amyloid beta-Peptides/metabolism
Aged, 80 and over
Neuropsychological Tests
Brain/pathology/metabolism

@article {pmid43026259,
year = {2026},
author = {Leenings, R and Winter, NR and Ernsting, J and Konowski, M and Holstein, V and Meinert, S and Spanagel, J and Barkhau, C and Fisch, L and Goltermann, J and Gerdes, MF and Grotegerd, D and Leehr, EJ and Peters, A and Krist, L and Willich, SN and Pischon, T and Völzke, H and Haubold, J and Kauczor, HU and Niendorf, T and Richter, M and Dannlowski, U and Berger, K and Jiang, X and Cole, J and Opel, N and Hahn, T and , },
title = {Contextualizing biological heterogeneity in brain structural normativity assessments across the aging continuum with the nearest neighbor normativity framework.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {43026259},
issn = {2730-664X},
support = {DA1151/11-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; CRC 1450-431460824//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; HA7070/3//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
abstract = {BACKGROUND: Despite established consensus about the individuality of brain physiology and structural changes, current neuroimaging biomarker paradigms heavily rely on population averages. Here, we define normativity not as a single reference point but as a landscape of permissible configurations arising from diverse physiological manifestations.

METHODS: We introduce the Nearest Neighbor Normativity (N[3]) framework, designed to parse the natural heterogeneity in brain structural measurements into a diversity-aware biomarker of brain structural decline. Through repeated comparisons within different demographic subgroups, N[3] contextualizes an individual's measurements from several viewpoints along the aging continuum. Relying on local density estimation, it accommodates multiple, shared normative configurations within and across age groups. We use T1-weighted MRI data from 29,883 individuals for training and 7,013 individuals for validation, and benchmark our framework against Brain Age models and Normative Modeling. We evaluate each biomarker's ability to detect neurodegenerative diseases, using them as representative models of atypical brain structural decline.

RESULTS: In group-level analyses, the N[3] biomarker shows the largest effect sizes in the detection of Mild Cognitive Impairment, Alzheimer's Disease, and Frontotemporal Dementia. Similarly, the N[3] biomarker achieves the highest predictive performance in the classification of neurodegenerative diseases on a single subject level. Notably, the N[3] estimates remain stable across age and robust to compositional changes in the reference sample. Finally, correlation analyses indicate that it captures distinct and complementary aspects of brain structural variation compared to existing approaches.

CONCLUSIONS: Our findings underscore that rethinking normativity assessments to explicitly accommodate natural inter-individual variability can advance our collective efforts toward truly personalized patient care.},
}

@article {pmid43026288,
year = {2026},
author = {Jester, HM and Wang, X and Li, T and Suhocki, A and Zhou, X and Proud, CG and Rosenblum, K and Ma, T},
title = {Suppression of neuronal eEF2K alleviates cognitive deficits and apathy-like behavior in APP/PS1 AD model mice.},
journal = {Translational psychiatry},
volume = {16},
number = {1},
pages = {},
pmid = {43026288},
issn = {2158-3188},
support = {R01 AG073823 and RF1 AG082388//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {Animals ; *Elongation Factor 2 Kinase/metabolism/antagonists & inhibitors/genetics ; *Alzheimer Disease/genetics/metabolism ; Disease Models, Animal ; Mice ; Phosphorylation ; *Cognitive Dysfunction/genetics/metabolism ; *Neurons/metabolism ; Mice, Transgenic ; Neuronal Plasticity ; Behavior, Animal ; Male ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by synaptic failure, cognitive impairment and neuropsychiatric symptoms (NPS). Apathy is the most common NPS seen in AD patients, and its underlying mechanisms remain unknown. Here, we investigated the roles of neuronal eukaryotic elongation factor 2 (eEF2) phosphorylation (by its kinase eEF2K) in AD-associated cognitive deficits and NPS. We performed a series of experiments using a multidisciplinary approach including genetics, behavioral assays, synaptic electrophysiology, and unbiased proteomics. The results demonstrated that neuron-specific inhibition of eEF2K and eEF2 phosphorylation can alleviate cognitive deficits, synaptic plasticity impairments, and apathy-like behavior in aged APP/PS1 AD model mice. Our findings indicate the therapeutic potential of targeting the eEF2K signaling in the treatment of dementia and NPS in AD and related dementias (ADRDs).},
}

Animals
*Elongation Factor 2 Kinase/metabolism/antagonists & inhibitors/genetics
*Alzheimer Disease/genetics/metabolism
Disease Models, Animal
Mice
Phosphorylation
*Cognitive Dysfunction/genetics/metabolism
*Neurons/metabolism
Mice, Transgenic
Neuronal Plasticity
Behavior, Animal
Male
Amyloid beta-Protein Precursor/genetics

@article {pmid43026462,
year = {2026},
author = {Kennedy, WM and Troyano-Rodriguez, E and Higgs, MH and Yates, NE and Carter, KA and Liter, LR and Blankenship, HE and Korukonda, A and Weinshenker, D and Sharpe, AL and Rice, HC and Beckstead, MJ},
title = {Tau conveys intrinsic hyperactivity of VTA dopamine neurons but an inability to sustain burst firing.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
doi = {10.1002/alz.71981},
pmid = {43026462},
issn = {1552-5279},
support = {R35 GM142726/GM/NIGMS NIH HHS/United States ; I01 BX005396//U.S. Department of Veterans Affairs/ ; I01RD001498//U.S. Department of Veterans Affairs/ ; R01 NS135830/NS/NINDS NIH HHS/United States ; R21 AG093578/AG/NIA NIH HHS/United States ; F32AG097386/AG/NIA NIH HHS/United States ; T32AG052363/AG/NIA NIH HHS/United States ; RF1AG079199/AG/NIA NIH HHS/United States ; F31AG079620/AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; },
mesh = {Animals ; *Ventral Tegmental Area/physiopathology/metabolism ; *tau Proteins/metabolism/genetics ; *Dopaminergic Neurons/physiology/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Alzheimer Disease/physiopathology/metabolism ; Humans ; *Action Potentials/physiology ; Mice ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {INTRODUCTION: Ventral tegmental area (VTA) dopamine is implicated in neuropsychiatric symptoms in Alzheimer's disease (AD). Mouse AD models show dopamine neuron hyperexcitability, but also decreased dopamine release and disrupted reward learning. Specific roles for amyloid and tau have not been determined.

METHODS: We investigated the triggers of disrupted dopamine neuron firing in mouse AD models: 3xTg-AD (amyloid+tau), APP[NL] [-G-F] (amyloid only), and a viral model expressing pathogenic human tau (p-tau).

RESULTS: 3xTg-AD dopamine neurons showed less bursting in vivo, yet faster non-burst spiking. In ex vivo slices, these neurons showed impaired ability to sustain firing during depolarization, which we mimicked with depolarizing current in wild-type neurons. Inducing p-tau expression similarly caused firing aberrations, effects not recapitulated in APP[NL-G-F] neurons.

DISCUSSION: P-tau induces hyperexcitability within individual dopamine neurons, but this likely reduces transmission in vivo through impaired bursting. Further studies investigating dopamine release in vivo may elucidate timepoints for early AD intervention.},
}

Animals
*Ventral Tegmental Area/physiopathology/metabolism
*tau Proteins/metabolism/genetics
*Dopaminergic Neurons/physiology/metabolism
Mice, Transgenic
Disease Models, Animal
*Alzheimer Disease/physiopathology/metabolism
Humans
*Action Potentials/physiology
Mice
Amyloid beta-Protein Precursor/genetics

@article {pmid43026550,
year = {2026},
author = {Lund, AN and Thompson, RC and Wang, YC and Shah, H and Roussos, P and Sebra, R and Nadkarni, GN and Nestler, EJ and Charney, AW and Beckmann, ND},
title = {Updates to the reference genome alter the detection and direction of genes differentially expressed in Alzheimer's disease.},
journal = {Genome biology},
volume = {27},
number = {1},
pages = {},
pmid = {43026550},
issn = {1474-760X},
mesh = {*Alzheimer Disease/genetics ; Humans ; *Genome, Human ; Gene Expression Profiling ; *Transcriptome ; },
abstract = {BACKGROUND: Alzheimer's Disease gene expression studies often rely on the reproducibility of known disease associations to build confidence in novel discoveries. This approach assumes that true biological variation associated with Alzheimer's Disease is robust to a range of technical and biological confounders that likely differ across experiments. Here, we systematically assess the impact of an important yet frequently overlooked technical confounder in Alzheimer's Disease differential expression analysis: changes in gene quantification resulting from ongoing updates to the human genome reference and transcriptome annotations.

RESULTS: To investigate this, gene expression in a large brain transcriptomic dataset from Alzheimer's Disease patients and controls (ROSMAP) was quantified using five transcriptome annotations mapped across a broad range of human genome references, from NCBI36 to CHM13v2.0. Although nearly all genes exhibit significant differences in expression between reference pairs (i.e., were differentially quantified), genome-wide Alzheimer's Disease differential expression signatures remain highly concordant across references. Notably, while a core set of significantly differentially expressed Alzheimer's Disease genes is largely conserved across references, reference-specific Alzheimer's Disease-associated genes are enriched for pathways known to be involved in the disease. Genes whose direction of association with Alzheimer's Disease significantly differs across references are also identified, highlighting the potential influence of reference choice on Alzheimer's Disease-relevant genes and pathways. All results were replicated in an independent transcriptomics dataset (MSBB) derived from the same brain region.

CONCLUSIONS: These findings demonstrate that reference genome choice impacts the identification and interpretation of specific Alzheimer's Disease-associated genes, despite overall reproducibility of genome-wide differential expression signatures, underscoring the critical importance of reference selection in Alzheimer's Disease transcriptomic studies.},
}

*Alzheimer Disease/genetics
Humans
*Genome, Human
Gene Expression Profiling
*Transcriptome

@article {pmid43026650,
year = {2026},
author = {Guterman, EL and Dulaney, SA and Sawyer, RJ and Hanson, LR and Olney, N and Hess, M and Lum, HD and Brickell, E and Rosenbloom, M and Ward, KT and Wood, AJ and Allen, IE and Scheffler, AW and Barclay, M and Chow, C and Holguin, I and Svitak, AL and Osorio, CP and Tatro, A and Lesko, A and Kuebrich, ME and Ochoa, AID and France, CE and Lopez, X and Sideman, A and Possin, KL},
title = {Caregiver well-being after multisite implementation of the Care Ecosystem.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {11},
pages = {},
doi = {10.1002/alz.72005},
pmid = {43026650},
issn = {1552-5279},
support = {/ALZ/Alzheimer's Association/United States ; NIA R01 AG074710/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Caregivers/psychology ; Female ; Male ; *Dementia/nursing/psychology/therapy ; Aged ; Depression/psychology ; Middle Aged ; Anxiety/psychology ; Self Efficacy ; Psychological Well-Being ; },
abstract = {INTRODUCTION: Collaborative dementia care models improve outcomes in prior randomized trials, but whether these benefits are maintained when implemented at scale remains uncertain. We evaluated the association of community-based implementation of the Care Ecosystem with caregiver well-being.

METHODS: We conducted a pragmatic multisite study of 1186 persons living with dementia (PLWD) and caregiver dyads enrolled across six US health systems between January 17, 2023 and July 12, 2024. Participants received the Care Ecosystem, a navigator-led dementia care program delivered remotely through multidisciplinary teams. The primary outcome was caregiver depression (9-item Patient Health Questionnaire [PHQ-9]). Secondary outcomes included anxiety, caregiver distress related to neuropsychiatric symptoms of the PLWD, caregiver strain, and self-efficacy. Outcomes were assessed at baseline, 6 months, and 12 months using linear mixed-effects models.

RESULTS: Among 1186 dyads, caregivers had a median age of 65.4 years (interquartile range: 54.8-74.9) and 71.9% were women. Caregiver depression scores were lower at 12 months (mean change in PHQ-9 score, -0.48; 95% confidence interval [CI], -0.71 to -0.25). Improvements were also observed in anxiety (-0.23; 95% CI, -0.33 to -0.13), distress related to neuropsychiatric symptoms (-0.82; 95% CI, -1.32 to -0.32), caregiver strain (-0.45; 95% CI, -0.80 to -0.11), and self-efficacy (2.01; 95% CI, 1.82 to 2.20). Larger improvements were observed among caregivers of persons with moderate-to-severe dementia and in several caregiver groups, including adult children and those who identified as Black and Hispanic.

DISCUSSION: These findings suggest that implementation of collaborative dementia care in routine practice may be associated with improvements in caregiver well-being.},
}

Humans
*Caregivers/psychology
Female
Male
*Dementia/nursing/psychology/therapy
Aged
Depression/psychology
Middle Aged
Anxiety/psychology
Self Efficacy
Psychological Well-Being

@article {pmid43026662,
year = {2026},
author = {Horie, K and Koppisetti, RK and VandeVrede, L and Asken, BM and Li, Y and Yen, D and Ghoshal, N and Paterson, RW and Lario Lago, A and Seeley, WW and Grinberg, LT and Bateman, RJ and Boxer, AL and Spina, S and Sato, C},
title = {Fluid eMTBR-tau243 as a Biomarker of Mixed 3-Repeat and 4-Repeat Tau Pathology.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.24689},
pmid = {43026662},
issn = {1538-3598},
abstract = {IMPORTANCE: Neurodegenerative diseases with abnormal tau protein aggregation in the brain (ie, tauopathies) can be classified by the tau isoform that accumulates: 3-repeat (3R), 4-repeat (4R), or mixed 3R/4R tauopathies, which include chronic traumatic encephalopathy (CTE), some forms of frontotemporal lobar degeneration, and Alzheimer disease (AD). The endogenously cleaved form of tau microtubule binding region containing the residue 243 (eMTBR-tau243) can be detected in cerebrospinal fluid (CSF) and blood and has been associated with AD tau pathology, but its specificity and biological interpretation in non-AD tauopathies remains unclear.

OBJECTIVE: To evaluate biofluid eMTBR-tau243 in a range of tauopathies.

This case-control study included 4 biorepositories based in the US that contributed CSF and plasma samples from participants with and without tauopathies, many of whom had antemortem biofluid samples paired with autopsy or genetically defined neuropathology. Samples were analyzed between August 2023 and December 2025. Data analysis occurred from August 2024 to July 2026.

EXPOSURE: CSF and plasma eMTBR-tau243 concentrations measured using a mass spectrometry-based assay.

MAIN OUTCOMES AND MEASURES: Outcomes included mixed 3R/4R tauopathy (eg, AD and CTE) based on autopsy, frontotemporal lobar degeneration with MAPT variants (FTLD-MAPT), and CTE stage. Differences in biomarker levels between groups were evaluated using analysis of variance or analysis of covariance, and area under the receiver operating characteristic curve (AUC) was calculated to evaluate the discriminative performance of fluid eMTBR-tau243.

RESULTS: Among the 229 participants (196 with CSF samples and 55 with plasma samples [22 with both]), mean (SD) age at fluid sample collection was 63 (13) years and 108 (47%) were female. Median (IQR) CSF eMTBR-tau243 was increased in 10 patients with AD (0.459 [0.246-0.801] fmol/mL) compared with 29 cognitively unimpaired controls (0.002 [0.001-0.005] fmol/mL) (adjusted P < .001), but other autopsy-confirmed non-AD tauopathies (which included 52 individuals with conditions including progressive supranuclear palsy and corticobasal degeneration) did not demonstrate an increase (0.015 [0.008, 0.039] fmol/mL). Six symptomatic FTLD-MAPT variant carriers with mixed 3R/4R tauopathy (R406W, V337M, and G389R) had increased median (IQR) CSF eMTBR-tau243 (0.140 [0.055-0.174] fmol/mL) compared with 15 4R tauopathy variant carriers including N279K and P301L (0.004 [0.001-0.044] fmol/mL) (P = .001). Median (IQR) plasma eMTBR-tau243 was increased in 11 patients with CTE (1.93 [0.42-3.68] fmol/L) compared with 20 cognitively unimpaired controls (0.29 [0.05-0.62] fmol/L) (adjusted P = .007), but did not increase as high as among 14 patients with AD (11.25 [2.29-19.38] fmol/L). Plasma eMTBR-tau243 distinguished CTE stage III and IV from controls (AUC, 0.97; 95% CI, 0.92-1.00), but not CTE stage I from controls (AUC, 0.64; 95% CI, 0.32-0.97).

CONCLUSIONS AND RELEVANCE: This study found that plasma and CSF eMTBR-tau243 were increased in mixed 3R/4R tauopathies including AD, high-stage CTE, and a subset of genetic FTLD-MAPT, compared with cognitively unimpaired controls. Further validation in larger cohorts is needed to determine the clinical utility of eMTBR-tau243 as a potential diagnostic biomarker for CTE and other tauopathies beyond AD.},
}

@article {pmid43026723,
year = {2026},
author = {Cheng, F and Fransson, LÅ and Mani, K},
title = {Apolipoprotein E4 (ApoE4) causes disruption of glypican-1 recycling and processing in ApoE4/4 fibroblasts and induced neurons.},
journal = {Glycobiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/glycob/cwag109},
pmid = {43026723},
issn = {1460-2423},
abstract = {The apolipoprotein E4 (ApoE4) isoform confers increased risk of developing Alzheimer's disease. ApoE2 and ApoE3 can be S-nitrosylated (Cys-SNO), but not ApoE4. The recycling heparan sulfate (HS) proteoglycan glypican-1 (GPC1) can also carry SNO and release HS by a Cu/NO dependent cleavage. ApoE3/3 and ApoE4/4 fibroblasts and the respective induced neurons (-iN) were exposed to inhibitors of NO-synthases (NOS), to NO donor or ascorbate and examined by immunofluorescence microscopy. Exposure to NO donor increased co-localization between ApoE3-SNO and GPC1 in ApoE3/3 fibroblasts. Co-localization between ApoE3 and GPC1 diminished when cNOS/NOS3 was inhibited in ApoE3/3 fibroblasts. Exposure to NO donor or ascorbate indicated almost fully utilized capacity to release HS from GPC1. When nNOS/NOS1 and iNOS/NOS2 were inhibited in ApoE3/3-iN, release of HS decreased, and exposure to ascorbate again showed that the capacity to release HS was almost fully utilized. In ApoE4/4 fibroblasts endosome transport was retarded and HS and GPC1-SNO accumulated in late endosomes. Inhibition of cNOS/NOS3 in ApoE4/4 fibroblasts had no effect on HS release but inhibition of iNOS/NOS2 had a substantial effect. Exposure to NO donor or ascorbate revealed unutilized capacity to release HS from GPC1. In ApoE4/4-iN, nNOS/NOS1 and iNOS/NOS2 were major producers of NO. Inhibition of nNOS/NOS1 and iNOS/NOS2 in ApoE4/4-iN again showed unutilized capacity to release HS. We propose that expression of ApoE4, which retards endosome trafficking, but also activates iNOS/NOS2, results in accumulation of GPC1-SNO and slow exit of HS from endosomes which can be restored by ascorbate.},
}

@article {pmid43026981,
year = {2026},
author = {Lu, Y and Vyavahare, S and Gulhane, M and Dong, X and Jarrahi, A and Singh, HD and Braun, M and Brann, DW and Dhandapani, KM},
title = {Early Hypothalamic Aromatase Loss Is Associated with Neuronal Insulin-Resistance Signaling During Progression of Experimental Alzheimer's Disease.},
journal = {Biology},
volume = {15},
number = {21},
pages = {},
pmid = {43026981},
issn = {2079-7737},
support = {5R01AG083947-02A01/NH/NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a neurodegenerative disorder characterized by central insulin resistance and cerebral hypometabolism. The steroid hormone, 17β-estradiol (E2), interacts closely with insulin signaling pathways and is locally synthesized in the brain by the enzyme aromatase. However, the spatial and temporal dynamics of brain aromatase during AD progression and its relationship to central insulin resistance remain poorly understood. Using the 5xFAD mouse model, we examined whole-brain, regional, and neuron/astrocyte-specific alterations in aromatase expression along disease progression. Whole-brain aromatase expression remained unchanged at 2 months of age but progressively declined at 5 and 9 months, inversely correlating with amyloid-β plaque burden. Regional analysis of the cortex, hippocampal CA1, and hypothalamus revealed progressive aromatase loss in all regions; notably, the hypothalamus exhibited a significant decline at the earliest disease stage examined, preceding comparable changes in the cortex and hippocampus, while an age-related decline cannot be fully excluded, as only a single-aged wild-type (WT) control was used. Cell-level analysis revealed a progressive reduction in neuronal aromatase expression, whereas astrocytic aromatase displayed a biphasic response, increasing during early disease stages before declining at later stages. In parallel, neuronal insulin-resistance signaling increased progressively with disease advancement and was negatively correlated with neuronal aromatase expression across all regions examined (r = -0.82 to -0.87). Collectively, these findings demonstrate progressive regional and neuron/astrocyte-specific alterations in brain aromatase during the progression of amyloid pathology, identifying early hypothalamic vulnerability as a feature of AD-associated altered insulin signaling.},
}

@article {pmid43027275,
year = {2026},
author = {Lipski, A and Koszela, K and Pingot, J and Słupiński, M and Irzmański, R and Woldańska-Okońska, M},
title = {The Impact of Selected Physical Factors on Neurogenesis-What Do We Know?.},
journal = {Cells},
volume = {15},
number = {21},
pages = {},
pmid = {43027275},
issn = {2073-4409},
mesh = {Humans ; *Neurogenesis/physiology ; Animals ; Brain/physiology ; },
abstract = {New discoveries are constantly being made regarding cognitive processes, pain perception, the development of degenerative diseases, brain aging, and many other functions of the nervous system. Neurogenesis plays a significant role in all of these processes. As a manifestation of brain plasticity, neurogenesis continues throughout life, and its intensity can vary depending on internal and external factors. The process by which neurons are generated can be disrupted. This depends, among other things, on age and represents one of the potential targets for interventions aimed at improving cognitive function. Inhibition of neurogenesis increases the risk of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and other conditions that lead to dependence on others in their advanced stages. The status of the neurogenesis process can be monitored by measuring the levels of mediators in the blood. The state of the brain can be influenced by providing stimuli that increase the concentration of mediators stimulating neurogenesis. People are exposed to physical factors that can inhibit the neurogenesis process, but there are also phenomena that stimulate it. Magnetic stimulation, ultrasound, electrostimulation, light therapy, normobaric and hyperbaric oxygen therapy, whole-body cryotherapy, as well as touch and vibrations, can have a significant impact on neurogenesis and accelerate this process. The aim of this study is to present the impact of physical factors on the process of neurogenesis in humans and animals, which can significantly influence the course of this process. The review uses the wording originally used in the source articles.},
}

Humans
*Neurogenesis/physiology
Animals
Brain/physiology

@article {pmid43027279,
year = {2026},
author = {Canal, C and Aguilar, K and Comes, G and Molinero, A and Giralt, M and Sanchis, P and Hidalgo, J},
title = {Effects of Interleukin-6 Dysregulation in a Mouse Model of Alzheimer's Disease: Unraveling Complexity Beyond Amyloidosis.},
journal = {Cells},
volume = {15},
number = {21},
pages = {},
pmid = {43027279},
issn = {2073-4409},
support = {SAF2014-56546-R//Ministerio de Economía y Competitividad/ ; SAF2014-56546-R//Fondo Europeo de Desarrollo Regional/ ; RTI2018-101105-B-I00//Ministerio de Ciencia, Innovación y Universidades/ ; RTI2018-101105-B-I00//Fondo Europeo de Desarrollo Regional/ ; PID2021-126602OB-I00//Ministerio de Ciencia e Innovación/ ; PID2021-126602OB-I00//Fondo Europeo de Desarrollo Regional/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Interleukin-6/metabolism/deficiency ; Disease Models, Animal ; *Amyloidosis/metabolism/pathology ; Female ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Male ; Plaque, Amyloid/pathology/metabolism ; Brain/metabolism/pathology ; },
abstract = {Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in neuroinflammation and Alzheimer's disease (AD) pathophysiology, but its contribution to the phenotype associated with amyloid precursor protein (APP) overexpression remains unclear. Here, we investigated the effects of systemic IL-6 deficiency in Tg2576 mice by assessing survival, physiological parameters, behavior, learning and memory, APP/amyloid-β (Aβ)-related pathology, and gliosis in young and aged male and female mice. In this specific cohort of animals, Tg2576 mice exhibited reduced survival and body weight, together with age- and sex-dependent alterations in behavioral and cognitive parameters. Notably, despite increased circulating Aβ40 and Aβ42, Aβ40 and Aβ42 were undetectable in the brain, and amyloid plaques were absent in Tg2576 mice compared with plaque-positive control mice. IL-6 deficiency partially rescued several of these phenotypes, particularly in females. Thus, the APP overexpression-associated phenotype observed here occurred in the absence of detectable cerebral amyloidosis, highlighting that APP overexpression-associated alterations can manifest independently of amyloid plaque deposition. Together, our findings underscore the complexity of AD pathogenesis and emphasize the multifaceted nature of IL-6 in both physiological and neurodegenerative processes, particularly in the context of AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Interleukin-6/metabolism/deficiency
Disease Models, Animal
*Amyloidosis/metabolism/pathology
Female
Mice
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Amyloid beta-Protein Precursor/metabolism
Male
Plaque, Amyloid/pathology/metabolism
Brain/metabolism/pathology

@article {pmid43027299,
year = {2026},
author = {Sabbir, MG and Hsiao, K},
title = {MT-CO2 Dysregulation in Alzheimer's Disease and Its Modulation by Photobiomodulation: Implications for Mitochondrial Function.},
journal = {Cells},
volume = {15},
number = {21},
pages = {},
pmid = {43027299},
issn = {2073-4409},
support = {//Capillus/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Mitochondria/metabolism/radiation effects ; *Electron Transport Complex IV/metabolism ; Male ; Female ; Cell Line, Tumor ; Aged ; },
abstract = {Mitochondrial dysfunction contributes to Alzheimer's disease (AD), but the roles of individual respiratory-chain proteins remain incompletely understood. We examined mitochondrially encoded cytochrome c oxidase subunit II (MT-CO2) and nuclear encoded succinate dehydrogenase complex iron-sulfur subunit B (SDHB) in postmortem temporal cortex from cognitively normal (CN) individuals and patients with AD, Lewy body dementia/Parkinson's disease (LBD/PD), or progressive supranuclear palsy (PSP). MT-CO2 abundance was lower in AD than in CN and LBD/PD, whereas SDHB was lower in AD than in CN, LBD/PD, and PSP. A significant protein × diagnosis interaction indicated distinct diagnostic-group patterns for MT-CO2 and SDHB. In BE(2)-C neuroblastoma cells, repeated 650 nm red-light and 808 nm near-infrared (NIR) photobiomodulation increased MT-CO2 abundance, with the largest responses following 10- and 15-min exposures. shRNA-mediated MT-CO2 reduction impaired Complex IV-dependent respiration and attenuated the bioenergetic response to 808 nm treatment. Photobiomodulation did not significantly alter mitochondrially encoded MT-CO1 or MT-CO3 abundance. These findings identify alterations in MT-CO2 and SDHB in AD temporal cortex and demonstrate that MT-CO2 contributes to Complex IV-dependent respiration and photobiomodulation-associated bioenergetic enhancement. Because mitochondrial content was not independently measured, the tissue findings cannot distinguish broader mitochondrial loss from protein-specific dysregulation.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Mitochondria/metabolism/radiation effects
*Electron Transport Complex IV/metabolism
Male
Female
Cell Line, Tumor
Aged

@article {pmid43027308,
year = {2026},
author = {Taguchi, T and Maher, P},
title = {Methylglyoxal Impairs Mitochondrial Bioenergetics and Microglial Functions.},
journal = {Cells},
volume = {15},
number = {21},
pages = {},
pmid = {43027308},
issn = {2073-4409},
support = {1RF1AG054714-05A1/NH/NIH HHS/United States ; 5R01AG069206-04A1/NH/NIH HHS/United States ; },
mesh = {*Microglia/drug effects/metabolism ; *Pyruvaldehyde/pharmacology ; *Mitochondria/metabolism/drug effects ; Animals ; *Energy Metabolism/drug effects ; Mice ; Membrane Potential, Mitochondrial/drug effects ; Cell Line ; Reactive Oxygen Species/metabolism ; Phagocytosis/drug effects ; Lipopolysaccharides/pharmacology ; Cell Proliferation/drug effects ; Cytokines/metabolism ; },
abstract = {Aging is accompanied by a progressive disruption of brain homeostasis, yet the molecular mechanisms underlying this age-associated deterioration remain poorly understood. Microglia play a critical role in maintaining brain homeostasis by clearing cellular debris and neurotoxic protein aggregates. Here, we investigated the effects of methylglyoxal (MG), a highly reactive endogenous metabolite that accumulates with aging, on microglial functions using the murine microglial cell line BV2. We assessed the effects of MG exposure on multiple aspects of microglial biology in both control and bacterial lipopolysaccharide (LPS)-treated cells, including phagocytic activity, cellular proliferation, cytokine secretion, mitochondrial bioenergetics, mitochondrial membrane potential, and intracellular and mitochondrial reactive oxygen species. We found that MG significantly impaired mitochondrial bioenergetics, leading to reduced cellular energy production, and markedly suppressed multiple essential microglial functions, including phagocytosis. Given the high reactivity of MG with arginine, we also investigated whether arginine depletion contributes to these functional impairments. Arginine depletion recapitulated the impairment of mitochondrial bioenergetics and microglial function induced by MG, demonstrating that arginine availability is a critical determinant of microglial metabolic fitness and immune function. These findings suggest that the age-associated accumulation of MG impairs mitochondrial bioenergetics and microglial functions, thereby potentially accelerating neurodegenerative processes.},
}

*Microglia/drug effects/metabolism
*Pyruvaldehyde/pharmacology
*Mitochondria/metabolism/drug effects
Animals
*Energy Metabolism/drug effects
Mice
Membrane Potential, Mitochondrial/drug effects
Cell Line
Reactive Oxygen Species/metabolism
Phagocytosis/drug effects
Lipopolysaccharides/pharmacology
Cell Proliferation/drug effects
Cytokines/metabolism

@article {pmid43027309,
year = {2026},
author = {Wei, L and Jiang, MQ and Zhao, Y and Takashima, D and Li, Y and Hekmatyar, K and Wu, L and Sastry, A and Yang, JJ and Yu, SP},
title = {Functional Deficits and Diffusion Tensor Magnetic Resonance Imaging of the Olfactory and Vision Systems in the Alzheimer's Disease Model of Aging GluN3A Knockout Mice.},
journal = {Cells},
volume = {15},
number = {21},
pages = {},
pmid = {43027309},
issn = {2073-4409},
support = {AG067473-A2/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Receptors, N-Methyl-D-Aspartate/deficiency/metabolism/genetics ; *Alzheimer Disease/physiopathology/diagnostic imaging/pathology/genetics ; Mice, Knockout ; *Diffusion Tensor Imaging ; *Aging/pathology ; Mice ; Male ; Disease Models, Animal ; *Vision, Ocular ; Mice, Inbred C57BL ; },
abstract = {Sensory dysfunction, such as olfactory and visual deficits, is a notorious symptom during the progression of Alzheimer's disease (AD) and related dementia (ADRD). The causal factor/s and structural disruptions underlying the sensory dysfunction in the AD/ADRD brain are not well understood. The NMDA receptor subunit GluN3A (NR3A) negatively regulates the receptor activity to uphold cellular Ca[2+] homeostasis. In GluN3A knockout (KO) mice, animals spontaneously develop chronic neurodegenerative excitotoxicity, cognitive decline, and AD-like pathology. Using diffusion tensor imaging (DTI), we examined neuronal network destruction together with sensory dysfunction in the GluN3A KO mouse. Specific attention was given to the selective vulnerability of the olfactory and visual nuclei, white matter injury in regional connections between subcortical centers and the cortex and hippocampus. Compared to age-matched wild-type (WT) controls (male), consistent with our early reports in younger ages, 18-month-old aging/aged GluN3A KO mice (male) suffered significant olfactory, visual and social deficits, accompanied by marked Aβ42 deposition in the brain. Ex vivo MR images of the GluN3A KO and control brains were acquired on the 7T MRI system, using a four-channel mouse array RF coil. High-resolution 3D T2-weighted RARE anatomical and DTI scans were performed. The DTI analysis revealed that GluN3A KO mice developed brain atrophy, involving significant damage in the white and gray matter of the olfactory and visual systems and impaired pathways among the superior colliculus, lateral geniculate nucleus, and the hippocampus and/or the cortex. This investigation disclosed a receptor-mediated neurodegeneration that explains sensory syndromes featured in a sporadic AD mouse model.},
}

Animals
*Receptors, N-Methyl-D-Aspartate/deficiency/metabolism/genetics
*Alzheimer Disease/physiopathology/diagnostic imaging/pathology/genetics
Mice, Knockout
*Diffusion Tensor Imaging
*Aging/pathology
Mice
Male
Disease Models, Animal
*Vision, Ocular
Mice, Inbred C57BL

@article {pmid43027364,
year = {2026},
author = {Choo, CT and Ngian, ZK and Ong, CT},
title = {Cross-Species and Cell-Type-Specific H3K27ac Dynamics Link Brain Aging to Alzheimer's Disease Genes.},
journal = {Cells},
volume = {15},
number = {21},
pages = {},
pmid = {43027364},
issn = {2073-4409},
support = {3160//Temasek Life Sciences Laboratory/ ; },
mesh = {Animals ; Humans ; *Aging/genetics ; *Alzheimer Disease/genetics/pathology/metabolism ; *Brain/metabolism/pathology ; *Histones/metabolism ; Mice ; Species Specificity ; Neurons/metabolism ; Gene Expression Regulation ; Super Enhancers ; Drosophila melanogaster ; },
abstract = {Active H3K27ac marks are dynamically remodelled during brain aging, but their cell-type-specific regulatory roles remain unclear. We integrated genome-wide H3K27ac profiles and transcriptomes from aging Drosophila heads, mouse NeuN+ forebrain neurons, and human NeuN+/NeuN- frontal cortex cells. In Drosophila, age-gained differential (Δ) H3K4me1 and H3K27ac peaks were associated with RNA processing and immune response genes, respectively, suggesting distinct regulatory programs. Despite limited biological replicates, mouse analyses revealed a strong association between promoter-associated ΔH3K27ac and synaptic gene expression in young neurons. Age-related gene-body H3K27ac loss coincided with increased expression of genes involved in GTPase signalling and vesicular transport. In humans (n = 29), NeuN- cells exhibited more age-associated ΔH3K27ac alterations than NeuN+ cells. Genes associated with age-gained peaks were enriched for gliogenesis and amyloid precursor protein metabolic processes, while age-related transcriptional changes associated positively with super-enhancer activity. Comparison with pan-tissue aging signatures revealed shared and cell-type-specific age-related ΔH3K27ac patterns in NeuN+ and NeuN- cells. Integrative analyses showed that age-gained ΔH3K27ac peaks in NeuN- cells overlapped with AD-associated ΔH3K27ac peaks, differentially expressed AD genes, and AD GWAS-linked variants, including those mapped to BIN1 and CR1. These findings highlight extensive H3K27ac remodelling in aging NeuN- cells and its convergence with AD-associated molecular alterations.},
}

Animals
Humans
*Aging/genetics
*Alzheimer Disease/genetics/pathology/metabolism
*Brain/metabolism/pathology
*Histones/metabolism
Mice
Species Specificity
Neurons/metabolism
Gene Expression Regulation
Super Enhancers
Drosophila melanogaster

@article {pmid43027393,
year = {2026},
author = {Li, Y and Ji, Y and Uzun, C and Islam, ST and Hu, M and Zhao, D and Li, Y and Lee, H and Wang, Z and Li, H and Jones, JW and Liu, S and Wu, J},
title = {Isoflurane and Surgery Aggravate APOE4-Dependent Lipid Dysregulation, Neural Dysfunction, and Neurological Impairment in Male Mice.},
journal = {Cells},
volume = {15},
number = {21},
pages = {},
pmid = {43027393},
issn = {2073-4409},
support = {R01 AG077541/AG/NIA NIH HHS/United States ; R01 NS094527/NS/NINDS NIH HHS/United States ; R01 NS145443/NS/NINDS NIH HHS/United States ; R01 AG074216/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Male ; *Apolipoprotein E4/metabolism/genetics ; *Isoflurane/adverse effects/pharmacology ; Mice ; Olfactory Bulb/metabolism/drug effects ; *Lipid Metabolism/drug effects ; Hippocampus/metabolism/drug effects ; Neurons/metabolism/drug effects ; Humans ; *Nervous System Diseases/metabolism ; Mice, Transgenic ; Microglia/metabolism/drug effects ; Mice, Inbred C57BL ; },
abstract = {Perioperative exposure to the volatile anesthetic isoflurane (ISO) during surgery (OP) has been associated with cognitive and olfactory deficits and may increase the risk of Alzheimer's disease (AD). Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, contributes to disease pathogenesis through disrupted lipid homeostasis. However, whether ISO/OP interacts with APOE genotype to influence neurological vulnerability remains unclear. Young adult, presymptomatic humanized APOE4 and APOE3 knock-in mice underwent laparotomy under 2 h of ISO anesthesia. Microglia and astrocytes were isolated from the olfactory bulb (OB) and hippocampus (HI) for lipidomic profiling. Awake in vivo OB recordings assessed neuronal excitability and network activity, while ex vivo patch-clamp recordings assessed synaptic transmission in the OB and HI. On day 7, APOE4/ISO/OP glia showed greater lipid perturbations than APOE3/ISO/OP glia. In vivo recordings revealed genotype-dependent alterations in OB excitability and network operation, while patch-clamp recordings identified altered excitatory and inhibitory synaptic transmission in the OB and HI. APOE4/ISO/OP mice exhibited persistent odor memory deficits, transient olfactory sensitivity loss, early motor impairment, and delayed cognitive dysfunction. OB RNA sequencing identified alterations in calcium transport and metabolic pathways in APOE4 male mice at 90 days following exposure. Together, these findings demonstrate APOE4-dependent vulnerability to ISO/OP, characterized by glial lipid dysregulation, neural circuit dysfunction, and neurological impairment, and support a potential mechanistic contribution of altered lipid homeostasis.},
}

Animals
Male
*Apolipoprotein E4/metabolism/genetics
*Isoflurane/adverse effects/pharmacology
Mice
Olfactory Bulb/metabolism/drug effects
*Lipid Metabolism/drug effects
Hippocampus/metabolism/drug effects
Neurons/metabolism/drug effects
Humans
*Nervous System Diseases/metabolism
Mice, Transgenic
Microglia/metabolism/drug effects
Mice, Inbred C57BL

@article {pmid43027738,
year = {2026},
author = {Cipriano, GL and Agostinelli, E and Floramo, A and Argento, V and Spinelli, S and Calabrò, M and Anchesi, I},
title = {Tuning the Brain: How Acoustic Energies Modulate Neural and Glial Phenotypes.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43027738},
issn = {1422-0067},
support = {RRC-2026-23688274//Ministero della Salute/ ; },
mesh = {Humans ; Animals ; *Neuroglia/metabolism/physiology ; *Neurons/metabolism/physiology ; *Brain/physiology/metabolism ; *Mechanotransduction, Cellular ; *Acoustic Stimulation ; Phenotype ; },
abstract = {The traditional view of neuronal communication is shifting toward a mechanobiological paradigm. This review examines how mechanical energy from diverse acoustic stimuli-audible sound and whole-body or vibrotactile vibration, low-intensity pulsed ultrasound (LIPUS), low-intensity focused ultrasound (LIFU), high-intensity focused ultrasound (HIFU), and extracorporeal shockwave therapy (ESWT)-translates into biochemical signals. Evidence is stratified throughout by model system (in vitro, animal in vivo, human) and by reported exposure dose, and sensory-pathway or network-level effects of audible sound are kept distinct from direct cellular mechanotransduction. Acoustic forces are directly detected by primary mechanosensitive ion channels, such as Piezo1 and TRPV4, and experimental evidence links this mechanotransduction to neurotrophic signaling (mechanistic target of rapamycin (mTOR); p38 mitogen-activated protein kinase (MAPK); brain-derived neurotrophic factor (BDNF)) that supports neurite outgrowth and structural repair, whereas a continuous signaling axis running from the cytoskeleton through the linker of nucleoskeleton and cytoskeleton (LINC) complex to epigenetic regulation remains a mechanistic hypothesis that has not been demonstrated in any acoustically stimulated neural cell. Furthermore, glial cells act as active mechanosensors, and emerging evidence suggests that acoustic stimulation can promote microglial polarization toward neuroprotective M2 phenotypes and may support Schwann cell-mediated peripheral nerve regeneration. We discuss the emerging concept of "acoustic pharmacology," in which specific waveforms and frequencies dictate distinct therapeutic outcomes. From targeted amyloid clearance in Alzheimer's disease to the non-invasive neural circuit control offered by sonogenetics, acoustic stimulation is a tunable but still predominantly preclinical frontier in regenerative medicine and neuromodulation: of the 144 sources cited here, seven report human studies, and the only randomized, sham-controlled evidence with a clinical endpoint concerns ablative high-intensity focused ultrasound; for the non-ablative neuromodulatory, neuroprotective, and regenerative regimes that are the subject of this review, no such trial is present in this evidence base.},
}

Humans
Animals
*Neuroglia/metabolism/physiology
*Neurons/metabolism/physiology
*Brain/physiology/metabolism
*Mechanotransduction, Cellular
*Acoustic Stimulation
Phenotype

@article {pmid43027755,
year = {2026},
author = {Fukuhara, K and Mori, K and Okiyama, Y and Takaki, T and Misawa, T and Tsuchiya, K and Demizu, Y and Shibanuma, M and Ohno, A},
title = {DOPA-Substituted KLVFFA Peptides Potently Inhibit Amyloid-β Aggregation and Mitigate Neurotoxicity.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43027755},
issn = {1422-0067},
support = {22K06508//Ministry of Education, Culture, Sports, Science and Technology/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Humans ; *Peptide Fragments/chemistry/metabolism ; *Dihydroxyphenylalanine/chemistry ; *Protein Aggregates/drug effects ; Alzheimer Disease/metabolism/drug therapy ; Cell Line, Tumor ; *Protein Aggregation, Pathological/drug therapy/metabolism ; },
abstract = {Alzheimer's disease (AD) is driven primarily by the self-assembly of amyloid-β (Aβ) peptides, a process stabilized by intermolecular π-π stacking interactions involving Phe19 and Phe20 residues of adjacent Aβ molecules. To competitively disrupt these interactions, we designed novel peptide inhibitors derived from the Aβ recognition motif KLVFFA (Aβ16-21), in which phenylalanine residues were replaced with L-3,4-dihydroxyphenylalanine (DOPA), featuring a catechol moiety capable of enhanced aromatic stacking and hydrogen bonding. The DOPA-substituted peptides effectively inhibited Aβ1-42 (Aβ42) aggregation, as demonstrated via Thioflavin T fluorescence assays, circular dichroism spectroscopy, and transmission electron microscopy. These complementary analyses collectively revealed substantial suppression of β-sheet formation and fibril elongation. Notably, the anti-aggregation potency was dependent on the substitution position, with the Phe19-substituted analog (KDF) exhibiting stronger inhibitory activity than the Phe20-substituted analog (KFD). The dual-substituted analog (KDD) displayed the greatest overall anti-aggregation activity. Molecular simulations further supported the superior activity of KDF over KFD, revealing a more favorable binding free energy for KDF compared to the parent peptide. Furthermore, the DOPA peptides potently mitigated Aβ42-induced neurotoxicity in SH-SY5Y cells, with the dual-substituted analog (KDD) providing the highest level of cytoprotection. Collectively, these findings validate that targeted modulation of aromatic interactions through DOPA substitution represents a powerful molecular strategy for controlling Aβ42 self-assembly, positioning these peptides as promising therapeutic tools for the treatment of AD.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Humans
*Peptide Fragments/chemistry/metabolism
*Dihydroxyphenylalanine/chemistry
*Protein Aggregates/drug effects
Alzheimer Disease/metabolism/drug therapy
Cell Line, Tumor
*Protein Aggregation, Pathological/drug therapy/metabolism

@article {pmid43027761,
year = {2026},
author = {Benchohra, A and Juárez-Alía, C and Serrano, G and Segura, T and Peinado, JR and Rabanal-Ruiz, Y},
title = {Blood-CSF MiRNA Signatures in Alzheimer's Disease Reveal Novel Biomarker Candidates: A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43027761},
issn = {1422-0067},
support = {//EuroCajaRural/ ; },
mesh = {*Alzheimer Disease/blood/cerebrospinal fluid/genetics ; Humans ; *MicroRNAs/blood/cerebrospinal fluid/genetics ; *Biomarkers/cerebrospinal fluid/blood ; Gene Expression Profiling ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. MicroRNAs (miRNAs) have emerged as promising regulators of AD-related pathways and potential minimally invasive biomarkers. However, existing meta-analyses have yielded inconsistent results, and whether miRNA signatures are conserved across biological fluids remains unclear. The present work aimed to systematically review studies performing miRNA discovery or multi-candidate profiling in blood and CSF during the last 15 years, in order to identify miRNAs showing significant and consistent differential expression across independent studies. By systematically comparing the direction and consistency of miRNA dysregulation across independent studies and biological sources, we identified 80 miRNAs consistently dysregulated in both blood and CSF, revealing a reproducible cross-fluid signature of AD-associated molecular alterations. Notably, miR-451a and miR-16-5p emerged among the most consistently dysregulated miRNAs across fluids. In contrast, several miRNAs displayed divergent or compartment-specific patterns, highlighting that blood and CSF may capture distinct aspects of AD-related molecular changes. Among these, miR-484, miR-3200-3p and miR-598 were identified as novel CSF candidates, while miR-20a-5p, miR-363-3p and miR-5006-3p represented novel blood-specific candidates. Furthermore, a substantial proportion of detected miRNAs was associated with extracellular vesicle/exosomal fractions, supporting their potential stability and biological relevance. Overall, our findings demonstrate that AD-associated miRNA dysregulation comprises both conserved and biofluid-specific signatures. From a clinical perspective, the current evidence primarily supports further evaluation of miRNAs as diagnostic/discriminative biomarkers rather than validated tools for early detection, disease monitoring, or prognosis. Their clinical translation remains limited by biofluid and methodological heterogeneity and requires harmonized cross-cohort and longitudinal validation.},
}

*Alzheimer Disease/blood/cerebrospinal fluid/genetics
Humans
*MicroRNAs/blood/cerebrospinal fluid/genetics
*Biomarkers/cerebrospinal fluid/blood
Gene Expression Profiling

@article {pmid43027795,
year = {2026},
author = {Issilbayeva, A and Kozhakhmetov, S and Kushugulova, A and Askarova, S and Kaiyrlykyzy, A and Tuigunov, D and Dolmatova, O and Zholdassova, Z and Omarov, Y and Nurgozhin, T},
title = {Gut Microbiome Alterations in Alzheimer's Disease: A Shotgun Metagenomic Case-Control Study.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43027795},
issn = {1422-0067},
support = {AP23489983//Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; },
mesh = {Humans ; *Alzheimer Disease/microbiology ; Case-Control Studies ; Female ; *Gastrointestinal Microbiome/genetics ; *Metagenomics/methods ; Male ; Aged ; Metagenome ; Shotgun Sequencing ; Cross-Sectional Studies ; Bacteria/classification/genetics ; Kazakhstan ; },
abstract = {The gut microbiome has been proposed as a contributor to Alzheimer's disease (AD) pathogenesis via the microbiota-gut-brain axis, but findings across cohorts are inconsistent and scarce data exist from Central Asian populations. We used shotgun metagenomic sequencing to compare the gut microbiome of AD patients and cognitively healthy controls from Kazakhstan. In a cross-sectional case-control study (35 AD, 39 Control), we profiled taxonomic and functional (HUMAnN pathway) composition, and compared alpha/beta diversity, individual taxa and pathways, and their association with clinical and demographic variables (Mann-Whitney U test, PERMANOVA/PERMDISP, OLS regression, all BH-FDR corrected, sensitivity analysis using ANCOM-BC2), with sensitivity analyses adjusting for age and BMI and applying Bonferroni correction. Within the AD group, circulating adiponectin-measured only in this group-was examined for associations with microbiome features in an exploratory analysis. Alpha diversity was lower in AD (q < 0.05). Community composition also separated by group on PERMANOVA (R[2] = 8.6%, p = 0.001), and this separation held after adjusting for age and BMI. A total of 178 taxa differed significantly between groups (BH-FDR; 37 were also Bonferroni-significant), most prominently depletion of Faecalibacterium and enrichment of Eisenbergiella and Desulfovibrio in AD; 100 pathways differed significantly (20 Bonferroni-significant). Three clinical/demographic variables (total bilirubin, atherogenic index, BMI) were associated with specific taxa or pathways. Within the AD group, adiponectin correlated negatively with the pathway assimilatory sulfate reduction IV (rho = -0.60, q = 0.015). AD in this Central Asian cohort was associated with a less diverse, compositionally distinct gut microbiome, with depletion of butyrate-producing Firmicutes and enrichment of sulfate-reducing taxa, alongside other taxa whose direction of association differed from prior reports.},
}

Humans
*Alzheimer Disease/microbiology
Case-Control Studies
Female
*Gastrointestinal Microbiome/genetics
*Metagenomics/methods
Male
Aged
Metagenome
Shotgun Sequencing
Cross-Sectional Studies
Bacteria/classification/genetics
Kazakhstan

@article {pmid43027915,
year = {2026},
author = {Curecheriu, LM and Iliescu, BF and Stanciu, GD and Mazarianu, I and Szilagyi, A and Gogu, MR and Ciorpac, M and Balmus, IM and Tutu, P and Horodincu, L and Daraban Bocaneti, F and Hritcu, OM and Pasca, AS and Tamba, BI and Turliuc, MD},
title = {A Comparative Analysis of Microglial and Astrocyte Transplantation in an Amyloid-Induced Rat for Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43027915},
issn = {1422-0067},
support = {The Health Programme (PS) 2021 - 2027, Policy Objective 4, Priority 3, Project title 'Support for Enhancing Performance and In-novation in Excellent Medical Doctoral Research', acronym INNODOC-MED, SMIS code 351058//Grigore T. Popa University of Medicine and Pharmacy/ ; },
mesh = {Animals ; *Astrocytes/transplantation/metabolism ; *Microglia/transplantation/metabolism ; *Alzheimer Disease/therapy/chemically induced/pathology/metabolism ; Male ; *Amyloid beta-Peptides/toxicity ; Rats ; Glial Fibrillary Acidic Protein/metabolism ; Rats, Sprague-Dawley ; Disease Models, Animal ; Hippocampus/metabolism/pathology ; Female ; Receptors, Immunologic/metabolism ; Peptide Fragments ; Membrane Glycoproteins/metabolism ; Tumor Necrosis Factor-alpha/blood ; Maze Learning ; },
abstract = {Alzheimer's disease (AD) is recognized as a neuroglial disorder in which dysregulated glial responses contribute to cognitive decline. We investigated whether intrahippocampal transplantation of primary glial cells modifies cognitive trajectories in an amyloid-induced rat model of AD. Sprague-Dawley rats received bilateral hippocampal injections of pre-aggregated Aβ1-42, followed by transplantation of primary astrocytes (AA) or microglia (AM). Memory was assessed using the Y-maze and novel object recognition (NOR) tests. Body weight and serum IL-6 and TNF-α were monitored for adverse effects, and GFAP, S100, Iba1 and TREM2 immunolabeling was quantified with QuPath. Mixed-effects models showed significant session and group x session effects on Y-maze spatial novelty recognition. Both treated groups improved compared with AD animals, with a stronger late effect in the AM group and a significant group × session × sex interaction. In the NOR test, both treated groups outperformed AD animals at the final session, without differences between them. GFAP (glial fibrillary acidic protein) immunoreactivity was reduced in the AM group but remained elevated in the AA group, while TREM2 increased after microglial and decreased after astrocyte transplantation. No adverse effects were detected in the monitored parameters. Intrahippocampal glial transplantation, particularly with microglia, may influence cognitive trajectories in established amyloid pathology.},
}

Animals
*Astrocytes/transplantation/metabolism
*Microglia/transplantation/metabolism
*Alzheimer Disease/therapy/chemically induced/pathology/metabolism
Male
*Amyloid beta-Peptides/toxicity
Rats
Glial Fibrillary Acidic Protein/metabolism
Rats, Sprague-Dawley
Disease Models, Animal
Hippocampus/metabolism/pathology
Female
Receptors, Immunologic/metabolism
Peptide Fragments
Membrane Glycoproteins/metabolism
Tumor Necrosis Factor-alpha/blood
Maze Learning

@article {pmid43027945,
year = {2026},
author = {Sun, Y and Xia, J},
title = {Research Progress of Insulin-like Growth Factor-1 in Major Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43027945},
issn = {1422-0067},
mesh = {Humans ; *Insulin-Like Growth Factor I/metabolism/therapeutic use/genetics ; *Neurodegenerative Diseases/metabolism/drug therapy ; Animals ; Signal Transduction ; Neuroprotective Agents/therapeutic use ; },
abstract = {Major neurodegenerative diseases (NDDs) represent a large category of disorders characterized by the progressive loss of structure, function, or eventual death of neuronal cells in the brain and spinal cord. Current conventional therapeutic strategies for NDDs primarily focus on symptomatic relief. In contrast, IGF-1 is a pleiotropic protein with neurotrophic, synaptogenic, and anti-apoptotic properties, and its neuroprotective potential has been demonstrated in various preclinical models of Alzheimer's disease, Parkinson's disease, and other NDDs. However, the clinical efficacy of IGF-1-based interventions-whether for symptomatic relief or disease modification-has not been established in humans. Research on IGF-1 as a therapeutic target for NDDs remains predominantly preclinical, and its translation into effective clinical treatments requires further validation. This narrative review summarizes the mechanisms of action and therapeutic advances of IGF-1 in the progression of NDDs, encompassing the following four aspects: (1) Strategies based on signaling pathway regulation that target key pathways such as IGF-1/PI3K/Akt to reduce neuronal loss, promote synaptogenesis and structural remodeling, correct anomalous tau hyperphosphorylation, and improve amyloid-β (Aβ) clearance impairment. (2) Strategies based on restoring central sensitivity that focus on ameliorating cerebral insulin/IGF-1 resistance and utilizing agents to indirectly restore the neuroprotective function of IGF-1, thereby delaying cognitive decline. (3) Strategies based on delivery systems: in animal models, these employ viral vectors or nanomaterials to achieve targeted brain delivery of IGF-1, effectively promoting the survival of dopaminergic and motor neurons. (4) Future research directions that further elucidate the dynamic evolution of IGF-1 signaling across different disease stages and the development of stage-specific regulatory strategies. This review discusses approaches to restoring central IGF-1 signaling, ameliorating cerebral insulin resistance, and improving brain-targeted delivery, while emphasizing that their therapeutic relevance remains predominantly preclinical and requires validation in human studies.},
}

Humans
*Insulin-Like Growth Factor I/metabolism/therapeutic use/genetics
*Neurodegenerative Diseases/metabolism/drug therapy
Animals
Signal Transduction
Neuroprotective Agents/therapeutic use

@article {pmid43027988,
year = {2026},
author = {Huang, X and Shihab, MHI and Bhagchandani, RL and Dong, Y and Wang, Y},
title = {An Explainable MRI-Conditioned Generative Framework for Gene-Feature Representations in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43027988},
issn = {1422-0067},
mesh = {*Alzheimer Disease/genetics/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; Autoencoder ; Generative Artificial Intelligence ; Neuroimaging/methods ; Female ; },
abstract = {Magnetic resonance imaging (MRI) and peripheral-blood transcriptomics capture complementary aspects of Alzheimer's disease (AD), but whether MRI can condition a meaningful molecular representation remains unclear. We developed and independently evaluated an explainable imaging-genetics conditional variational autoencoder (IG-CVAE) in Alzheimer's Disease Neuroimaging Initiative (ADNI) and AddNeuroMed (ANM) cohorts using fixed 80% train-validation and 20% independent test sets with five-fold cross-validation. IG-CVAE comprises a genetic branch encoding expression into 128-dimensional gene-feature vectors (GFV128), an imaging branch encoding MRI into 128-dimensional MRI-feature vectors (MFV128), and a conditional variational autoencoder that generates GFV128 from MFV128. Paired analyses included 289 ADNI and 98 ANM participants. Test area under the receiver operating characteristic curve (ROC-AUC) values in ADNI/ANM were 0.646/0.851 for the genetic branch, 0.942/0.752 for the imaging branch, and 0.939/0.869 for generated GFV128. Generated-observed GFV128 agreement was moderate (cosine similarity, 0.590/0.589; coefficient of determination (R[2]), 0.161/0.211). Molecular importance was cohort-specific at the gene level, with no significant pathway-level convergence, whereas MRI perturbation showed cross-cohort convergence in cerebral white matter linked to distinct disease-informative molecular features. Overall, structural MRI retained disease-relevant information sufficient to generate disease-informative molecular representations, supporting IG-CVAE as a participant-paired hypothesis-generating imaging-transcriptomic framework while providing only limited evidence of participant-specific molecular correspondence without implying raw transcriptome reconstruction. The ANM test estimates should be interpreted cautiously given the small paired independent test set (n = 20).},
}

*Alzheimer Disease/genetics/diagnostic imaging
Humans
*Magnetic Resonance Imaging/methods
Autoencoder
Generative Artificial Intelligence
Neuroimaging/methods
Female

@article {pmid43028125,
year = {2026},
author = {Sahin, B and Eken, Y and Sahin, F and Karaman, T and Sezerman, OU and Ozer, S and Kaya, ZZ and Karagözlü, MZ and Serdar, MA and Serteser, M and Baykal, AT},
title = {Genotype-Associated Molecular Phenotypes Across Brain and Gut Compartments in Male 5xFAD Mice: Shared Latent Structure and the Limits of Individual-Level Inference.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43028125},
issn = {1422-0067},
support = {TSA-2024-2169//Acıbadem Mehmet Ali Aydınlar University Scientific Research Projects Commission (ABAPKO)/ ; },
mesh = {Animals ; Male ; Mice ; *Alzheimer Disease/genetics/metabolism ; *Brain/metabolism ; Phenotype ; Genotype ; Proteomics/methods ; Disease Models, Animal ; Proteome ; *Gastrointestinal Microbiome ; Mice, Transgenic ; Feces/microbiology ; Hippocampus/metabolism ; Metagenomics ; Multiomics ; },
abstract = {Whether gut and brain molecular states covary within individual animals, rather than merely co-occurring at the group level, has rarely been tested in Alzheimer's disease models. We profiled the hippocampus, cortex, cerebellum, intestine and feces of 18 male 5xFAD (5 familial AD mutations) (B6SJL background) mice and wild-type littermates at 3, 6 and 9 months by label-free proteomics, and feces additionally by shotgun metagenomics. The hippocampal proteome reproduced the amyloid-associated signature (App, Apoe, Hexb, Clu, Gfap), and protein-set analysis showed elevated microglial, lysosomal, astrocytic and endoplasmic reticulum chaperone proteins in the hippocampus and cortex, with no detectable difference in synaptic or mitochondrial sets. Fecal Shannon diversity was reduced, and the bile-acid-modifying genera Romboutsia and Turicibacter were nearly absent in all 5xFAD animals from 3 months (cage nested within genotype). Multi-omics factor analysis recovered a genotype-associated factor shared across brain and gut views (exact permutation p = 0.00125) that explained at most 6.3% of variance in any view and was preprocessing-dependent. After removal of group structure, correlation burden did not exceed a within-cell permutation null, and neither did same-animal positive controls. The 5xFAD genotype thus alters every compartment examined, and a modest latent structure links them; because the design excludes only strong or dense individual-level coupling, the null result bounds design resolution rather than showing that gut and brain are uncoupled.},
}

Animals
Male
Mice
*Alzheimer Disease/genetics/metabolism
*Brain/metabolism
Phenotype
Genotype
Proteomics/methods
Disease Models, Animal
Proteome
*Gastrointestinal Microbiome
Mice, Transgenic
Feces/microbiology
Hippocampus/metabolism
Metagenomics
Multiomics

@article {pmid43028171,
year = {2026},
author = {Simili, OAG and Carvalho, GM and Simões, RSD and Detregiachi, CRP and Pereira, ESBM and Catharin, VMCS and Silva, GAD and Miola, VB and Bishayee, A and Valenti, VE and Vécsei, L and Tanaka, M and Barbalho, SM},
title = {Pantethine and Neurodegeneration: A Coenzyme A-Centered Framework Linking Metabolism, Neuroinflammation, and Mitochondrial Dysfunction.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43028171},
issn = {1422-0067},
support = {NKFIH K138125, SZTE SZAOK-KKA No. 2022/5S729, SZTE SZAOK-KKA SZGYA No. 2023/5S775//National Research, Development and Innovation Office/ ; //Hungarian Research Network/ ; },
mesh = {Humans ; *Pantetheine/analogs & derivatives/metabolism/therapeutic use/pharmacology ; *Coenzyme A/metabolism ; *Mitochondria/metabolism/pathology/drug effects ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neuroinflammatory Diseases/metabolism ; Oxidative Stress ; Alzheimer Disease/metabolism ; Pantothenate Kinase-Associated Neurodegeneration/metabolism ; },
abstract = {Neurodegenerative diseases are a growing global health burden associated with aging and characterized by progressive neuronal dysfunction, metabolic failure, mitochondrial impairment, oxidative stress, and chronic neuroinflammation. Among the metabolic pathways implicated in these disorders, coenzyme A (CoA)-linked biology has emerged as a potentially important but still underexplored contributor to neuronal resilience and vulnerability. Pantethine, a disulfide derivative of pantetheine and a CoA-related metabolic precursor, has attracted attention because of its reported effects on cellular metabolism, redox balance, and inflammatory signaling. However, its relevance across neurodegenerative diseases remains unevenly defined, with direct support strongest in pantothenate kinase-associated neurodegeneration (PKAN) and more limited evidence in common disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). This narrative review critically examines the mechanistic and translational evidence linking pantethine to neurodegeneration. PKAN represents the most logical disease context for pantethine investigation because impaired CoA biosynthesis is proximal to disease pathogenesis, although pantethine remains investigational and its clinical efficacy has not been established. By contrast, proposed applications in AD and PD remain highly theoretical and hypothesis-generating. Nevertheless, research on pantethine and related CoA-restoring strategies may identify new intervention targets across neurodegenerative diseases and other disorders characterized by impaired cellular bioenergetics, including selected neuropsychiatric disorders. These possibilities require biomarker-informed, disease-specific studies that establish active-species exposure, target engagement, and clinically meaningful effects.},
}

Humans
*Pantetheine/analogs & derivatives/metabolism/therapeutic use/pharmacology
*Coenzyme A/metabolism
*Mitochondria/metabolism/pathology/drug effects
Animals
*Neurodegenerative Diseases/metabolism/drug therapy
*Neuroinflammatory Diseases/metabolism
Oxidative Stress
Alzheimer Disease/metabolism
Pantothenate Kinase-Associated Neurodegeneration/metabolism

@article {pmid43028201,
year = {2026},
author = {Kordas, B and Juranek, JK},
title = {Dietary Responses in the Diabetic Brain: Transcriptomic Convergence and Comparison with an Alzheimer's Disease Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43028201},
issn = {1422-0067},
support = {2023/49/N/NZ4/03958//National Science Centre/ ; 2022/47/B/NZ5/00898//National Science Centre/ ; },
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/diet therapy ; *Transcriptome ; Humans ; *Brain/metabolism ; Disease Models, Animal ; Intermittent Fasting ; Mice ; Rats ; Diet, Ketogenic ; Hippocampus/metabolism ; *Diabetes Mellitus, Experimental/genetics/metabolism/diet therapy ; Gene Expression Profiling ; Fasting ; Male ; },
abstract = {Dietary interventions alter brain gene expression in diabetes, but the extent to which their responses agree across experiments and reduce differences from controls remains unclear. Five public transcriptomic datasets were reanalyzed, spanning human cortical fractions, rat brain regions, diabetic mouse hippocampus with intermittent fasting (IF), diabetic whole brain with ketogenic diet, and APP/PS1 and wild-type hippocampus with IF. Gene and pathway comparisons assessed agreement across experiments. Statistical tests distinguished opposing disease and dietary effects from reductions in the remaining distance from controls. IF and ketogenic diet identified 6569 and 999 genes, respectively, in diabetic mice. Their effects showed modest agreement (Pearson r = 0.205), with 447 genes significant in both experiments, including 359 with matching directions. They shared 59 pathways with a matching direction at a fixed intergene correlation of 0.01; these overlaps were not supported when correlations were estimated from the data. IF responses in diabetic and APP/PS1 hippocampus agreed poorly (r = -0.056). No human genes met a per-contrast false discovery rate < 0.05. Thirteen diabetic genes showed significant opposition of disease and IF effects; neither primary fasting experiment demonstrated contraction toward controls. The results support limited agreement between the diabetic dietary experiments and little agreement in IF responses across the examined disease contexts. They do not establish transcriptomic restoration.},
}

Animals
*Alzheimer Disease/genetics/metabolism/diet therapy
*Transcriptome
Humans
*Brain/metabolism
Disease Models, Animal
Intermittent Fasting
Mice
Rats
Diet, Ketogenic
Hippocampus/metabolism
*Diabetes Mellitus, Experimental/genetics/metabolism/diet therapy
Gene Expression Profiling
Fasting
Male

@article {pmid43028204,
year = {2026},
author = {Miziak, B and Pluta, R and Czuczwar, SJ},
title = {Current Possible Newer Pharmacological Treatment Options for Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43028204},
issn = {1422-0067},
support = {Statutory grant DS/475/26 (S.J.C.).//Medical University of Lublin/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD), as a chronic neurodegenerative disorder, leads to progressive dementia. About 60-80% of dementia cases are due to AD, and their incidence increases especially after the age of 65. AD is characterized by impaired memory, abnormal behavior, and impaired thinking process, which causes limitation of daily activities and a gradual loss of independence. The costs of all dementia cases are likely to reach $2 trillion in 2030 alone. Currently available pharmacological treatment of AD is, for the most part, not causal, and does not modify the course of the disease. The data search for procognitive drugs was carried out using the PUBMED and Clinical Science databases. Among the drugs with animal data and preliminary clinical trials, the following can be distinguished: fosgonimeton, blarcamesine, bezisterim, posiphen (buntanetap) and ACD856. As a rule, promising preclinical results were not confirmed in clinical trials. Some clinical expectations may be associated with posiphen and ACD856. Based on preclinical data, the following drugs seem promising: tenuigenin, JQ1, gemfibrozil, coumarin derivatives, ponicidin, salicin, calcaratarin D, new 1,3,5-triazines or 2-aminopyrymidine carboxamide derivatives, epimedium brevicornu flavonoids, and drugs affecting the glymphatic system. In general, the above-mentioned drugs counteract the pathologies leading to the occurrence of AD.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
Animals

@article {pmid43028238,
year = {2026},
author = {Gopalakrishna, PK and Vishnumukkala, T and Hein, ZM and Karikalan, B and Chakravarthi, S and Hussan, F and Deoghare, RS and Jagadeesan, S and Krishnasamy, N and Phyu, SE and David, P and Kamaruzzaman, MA},
title = {Mitochondrial Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Primary Drivers Versus Early Amplifiers, and Emerging Mitochondria-Targeted Therapeutic Strategies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43028238},
issn = {1422-0067},
mesh = {Humans ; *Mitochondria/metabolism/pathology/drug effects ; *Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy ; Animals ; Reactive Oxygen Species/metabolism ; Mitochondrial Dynamics ; Mitophagy ; },
abstract = {Mitochondria are critical for bioenergetics, calcium and redox homeostasis, and apoptosis in neurons. Neurons are especially susceptible to mitochondrial malfunction since they are terminally differentiated and have extraordinary energy requirements. Mechanisms such as defective oxidative phosphorylation, altered fission-fusion dynamics, defective mitophagy, impaired axonal transport and excessive reactive oxygen species (ROS) generation are increasingly appreciated as important mechanisms in major neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). The review discusses the structure and function of mitochondria with emphasis on oxidative phosphorylation, ROS and reactive nitrogen species (RNS) signalling, calcium-mediated excitotoxicity, lipid metabolism, and apoptotic and non-apoptotic cell-death mechanisms including necroptosis, ferroptosis, pyroptosis and parthanatos. In particular, disease-specific processes are highlighted, such as impaired mitophagy by amyloid β/tau in AD, PTEN-induced kinase 1 (PINK1)/Parkin dysfunction and complex I inhibition in PD, Superoxide Dismutase 1 (SOD1)/C9orf72-associated mitochondrial defects in ALS, and bioenergetic dysfunction by mutant huntingtin in HD. Therapeutic approaches include mitochondria-targeted antioxidants, fusion and biogenesis enhancers, fission inhibitors, inflammasome modulators, Mitochondrial Permeability Transition Pore (mPTP) inhibitors and gene therapy. Also highlighted are recent advancements such as Ubiquitin-Specific Peptidase 30 (USP30) inhibition, intercellular mitochondrial transfer and regulatory approval of a mitochondria-targeted peptide, together with evidence supporting causality and hurdles underpinning clinical translation. Graded against human-genetic, patient-tissue and model-based evidence, mitochondrial dysfunction is best supported as a primary driver in PD and genetic ALS, and as an early amplifier of proteinopathic or mutant-huntingtin toxicity in sporadic AD and HD.},
}

Humans
*Mitochondria/metabolism/pathology/drug effects
*Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy
Animals
Reactive Oxygen Species/metabolism
Mitochondrial Dynamics
Mitophagy

@article {pmid43028256,
year = {2026},
author = {Zhou, X and Wang, Z and Jiang, H},
title = {Single-Chain Variable Fragments Targeting Plasma Exosome Amyloid-β Peptide Subtypes for Diagnosis of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {21},
pages = {},
pmid = {43028256},
issn = {1422-0067},
mesh = {Humans ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/diagnosis/blood ; *Exosomes/metabolism ; Female ; Biomarkers/blood ; *Peptide Fragments/blood ; *Single-Chain Antibodies/immunology ; Male ; Aged ; Immunoassay/methods ; Sensitivity and Specificity ; },
abstract = {The diagnostic value of the Aβ1-42/Aβ1-40 ratio in peripheral blood as a biomarker for Alzheimer's disease (AD) remains a subject of considerable interest. However, this ratio in plasma exosomes is still underestimated. To investigate the potential clinical performances, this study has established a chemiluminescence immunoassay (CLIA) for the specific detection of Aβ1-42 and Aβ1-40 in plasma exosomes using single-chain variable fragments (scFv). Plasma samples from 20 AD patients and 20 non-AD individuals were detected by the established scFv-based CLIA, with the traditional monoclonal antibody (mAb)-based CLIA as the reference method. The results demonstrated that the plasma exosome Aβ1-42/Aβ1-40 ratio in AD patients (0.70 ± 0.35) was significantly lower than that in the non-AD control group (1.82 ± 0.79, p < 0.001). In comparison with the mAb-based assay, the scFv-based CLIA exhibited superior analytical performance, with a lower limit of detection (1 pg/mL vs. 50 pg/mL) and higher specificity (cross-reactivity rate < 5%). When the Aβ1-42/Aβ1-40 ratio of 1.075 was set as the cutoff value, the scFv-based assay achieved a diagnostic sensitivity of 90.0%, which was numerically higher than that of the mAb-based assay (85.0%), with comparable specificity (90.0% vs. 90.0%). Generally, this study has developed a highly sensitive and specific scFv-based method for the detection of plasma exosome Aβ subtypes, which supports that the plasma exosome Aβ1-42/Aβ1-40 ratio is a potential non-invasive biomarker for differentiating clinically diagnosed AD from non-AD controls in this pilot cohort.},
}

Humans
*Amyloid beta-Peptides/blood
*Alzheimer Disease/diagnosis/blood
*Exosomes/metabolism
Female
Biomarkers/blood
*Peptide Fragments/blood
*Single-Chain Antibodies/immunology
Male
Aged
Immunoassay/methods
Sensitivity and Specificity

@article {pmid43028433,
year = {2026},
author = {Korkmaz, MH and Bingöl, Ö and The Alzheimer's Disease Neuroimaging Initiative, },
title = {FDNet: A Lightweight Feature-Dominated U-Net for Hippocampus Segmentation in Brain MRI.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {21},
pages = {},
pmid = {43028433},
issn = {2075-4418},
abstract = {Background/Objectives: Hippocampus segmentation in brain MRI is challenging because the structure is small, irregularly shaped, and poorly contrasted against surrounding tissue. Increasingly complex U-Net variants improve accuracy at computational cost. We investigated whether modifying the relative contribution of encoder features within skip connections can improve performance without additional attention or gating modules. Methods: We propose FDNet, a lightweight feature-dominated U-Net that concatenates multiple identical copies of encoder feature maps with the corresponding decoder features. Three variants (FDNetX2, FDNetX3, and FDNetX4) were evaluated on sagittal MRI slices from ADNI, the Medical Segmentation Decathlon, and IBSR using five-fold cross-validation, assessed with overlap metrics and per-slice false-positive/false-negative counts. To address potential subject-level leakage in the slice-level evaluation, a subject-grouped assessment with a fixed held-out test set was additionally conducted on ADNI, with re-implemented baselines and nnU-Net v2. Results: Under the slice-level protocol, FDNet achieved Dice coefficients of 0.9339 on ADNI, 0.9470 on Decathlon, and 0.9477 on IBSR, outperforming re-implemented U-Net, Attention U-Net, and SegNet baselines with substantially fewer parameters. Under the subject-grouped protocol, the best FDNet variant reached a held-out test Dice of 0.9050 versus 0.9019 for nnU-Net. All variants significantly outperformed the three baselines after Holm correction (adjusted p < 0.0001); their advantage over nnU-Net was not significant. Conclusions: Repeated encoder features within skip connections can provide competitive hippocampus segmentation with a relatively small parameter budget. Because all results come from curated research datasets without external or cross-dataset validation, they indicate competitive performance under the evaluated conditions rather than clinical readiness.},
}

@article {pmid43028460,
year = {2026},
author = {Rahmani, AH and Sarwar, T},
title = {Lipidomics in Brain Health and Neurodegenerative Diseases: Mechanisms, Biomarkers, and Therapeutic Perspectives.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {21},
pages = {},
pmid = {43028460},
issn = {2075-4418},
abstract = {Lipids constitute nearly half of the brain's dry weight and play a crucial role in maintaining the function of the central nervous system (CNS). Beyond their well-known function as structural components of cellular membranes and energy storage, lipids are now identified as dynamic bioactive mediators that regulate neuronal signaling, synaptic plasticity, membrane integrity and neuroinflammatory responses. Emerging evidence demonstrates that altered lipid homeostasis is associated with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). In this review, we highlight key pathophysiological mechanisms, including dysregulation of lipid transport by cholesterol and apolipoprotein E4 (ApoE4), which may influence the aggregation of amyloid-β in AD. We discuss sphingolipid dysregulation and impaired glucocerebrosidase activity in modulating α-synuclein pathology in PD. Furthermore, we emphasize the importance of polyunsaturated fatty acids (PUFAs) and their oxidized forms in the regulation of oxidative stress, ferroptosis, and neuronal cell death in ALS and HD. Besides mechanistic information, this review also highlights the recent advancements in modern lipidomic technologies, such as high-resolution mass spectrometry and multi-omics integration, which have facilitated the comprehensive characterization of disease-associated lipid alterations. Emerging lipid signatures, including alterations in ceramide, cholesterol metabolism and lipid droplet biogenesis in glial cells, are being investigated as candidate biomarkers and therapeutic targets. Collectively, we outline a strategy for exploiting the brain lipidome to explore the potential for personalized disease-modifying strategies against neurodegeneration by integrating mechanistic, diagnostic and therapeutic insights.},
}

@article {pmid43029376,
year = {2026},
author = {Wang, Y and Cheng, J and Liu, T and Li, S and Wang, Q and Shao, K and Yang, G and Li, P},
title = {Harnessing Nanozyme Catalytic Activities for Multi-Target Intervention in Neurodegenerative Pathology.},
journal = {Nanomaterials (Basel, Switzerland)},
volume = {16},
number = {21},
pages = {},
pmid = {43029376},
issn = {2079-4991},
support = {2025M783015//China Postdoctoral Science Foundation/ ; 2025SZRJJ2142//Hangzhou Municipal Natural Science Foundation/ ; 32401061//National Natural Science Foundation of China/ ; },
abstract = {The therapeutic landscape for neurodegenerative diseases (NDs), including Alzheimer's and Parkinson's disease, remains challenging due to their complex, multifactorial pathogenesis and the limited efficacy of conventional therapies that primarily offer symptomatic relief. The emergence of nanozymes, nanomaterials with intrinsic enzyme-mimicking activities, presents a promising opportunity for multi-targeted intervention. This review comprehensively explores the rational design and therapeutic mechanisms of nanozymes in combating core pathological features of NDs, such as oxidative stress, protein aggregation, and neuroinflammation. We critically assess their remarkable ability to cross the blood-brain barrier and execute synergistic functions, including reactive oxygen species scavenging, misfolded protein degradation, and modulation of microglial activation. Furthermore, we provide a detailed analysis of the application and efficacy of nanozymes across major NDs, alongside a discussion on pharmacokinetics, biosafety, and prevailing challenges. By delineating the structure-enzyme-mimicking activity relationships and cellular-level mechanisms, this review aims to establish a foundational framework for the future development of nanozyme-based neuroprotective strategies, supporting ongoing efforts toward disease-modifying interventions for NDs.},
}

@article {pmid43030106,
year = {2026},
author = {Choquet de Isla, J and Riscart-López, J and Sánchez-Gomar, I and Bández-Ruiz, M and Rosety-Rodríguez, I and Brenes-Martín, F and Bazán, NG and Navarro Quiroz, E and Rosety-Rodríguez, MÁ and Geribaldi-Doldán, N},
title = {A Scoping Review of Creatine Supplementation in Alzheimer's Disease: Evidence from Preclinical and Clinical Studies.},
journal = {Nutrients},
volume = {18},
number = {21},
pages = {},
pmid = {43030106},
issn = {2072-6643},
support = {FEDER-UCA-2024-A2-58//European Regional Development Fund/ ; },
mesh = {*Alzheimer Disease/drug therapy ; *Creatine/administration & dosage ; Humans ; Animals ; *Dietary Supplements ; Female ; Disease Models, Animal ; *Neuroprotective Agents/administration & dosage ; Male ; Cognition/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Background/Objectives: Although creatine supplementation has a theoretical rationale for neuroprotection, public interest has outpaced available scientific evidence. Alzheimer's disease (AD), a major and growing global health concern, is among the neurodegenerative diseases proposed to benefit from creatine supplementation. This scoping review systematically maps the existing literature on creatine supplementation for AD to identify gaps that limit translational progress. Methods: Following JBI methodology and PRISMA-ScR guidelines, a search in five electronic databases was conducted for preclinical and clinical studies evaluating creatine interventions in AD. The methodological quality of the studies was appraised using the SYRCLE and NIH tools, respectively. Results: Nine unique studies were included. The preclinical models investigated neuron apoptosis, oxidative stress, neuroinflammation, mitochondrial function, cognitive outcomes, and pathophysiological clearance. Conversely, clinical studies were limited to a pilot trial that suggested preliminary tolerability but could not establish causality. This review identifies six limitations within the current evidence: (1) a reliance on acute or non-transgenic animal models that lack construct validity; (2) a need to address sexual dimorphism; (3) a lack of studies exploring administration routes to bypass the blood-brain barrier; (4) a complete lack of independent randomized controlled trials (RCTs), with all clinical evidence originating from a single research group; (5) an absence of research assessing creatine as a preventive strategy; and (6) a shortage of assessment regarding physical syndromes, such as frailty. Conclusions: The scientific evidence for creatine in AD remains preliminary. Future research should prioritize progressive transgenic models, evaluate noninvasive administration routes, investigate effects on frailty, assess long-term preventive efficacy, account for sex as a variable, and transition to rigorous RCTs.},
}

*Alzheimer Disease/drug therapy
*Creatine/administration & dosage
Humans
Animals
*Dietary Supplements
Female
Disease Models, Animal
*Neuroprotective Agents/administration & dosage
Male
Cognition/drug effects
Oxidative Stress/drug effects

@article {pmid43030126,
year = {2026},
author = {Cho, KH and Lee, YB and Kang, MJ and Yadav, D},
title = {Efficacy and Safety of Cuban Policosanol on Cognitive Function and Antioxidant Status in Adults with Subjective Memory Decline: A 12-Week Randomized, Double-Blinded, Placebo-Controlled Multicenter Trial.},
journal = {Nutrients},
volume = {18},
number = {21},
pages = {},
pmid = {43030126},
issn = {2072-6643},
mesh = {Humans ; Double-Blind Method ; *Fatty Alcohols/adverse effects/therapeutic use/pharmacology/administration & dosage ; Aged ; Male ; Middle Aged ; Female ; *Antioxidants/metabolism ; *Cognition/drug effects ; *Memory Disorders/drug therapy/blood ; Superoxide Dismutase/blood ; Aged, 80 and over ; Biomarkers/blood ; Cognitive Dysfunction/drug therapy ; Cognitive Enhancement ; Treatment Outcome ; },
abstract = {Objectives: Early non-pharmacological interventions for people with subjective memory decline (SMD) are increasingly advocated in preventing age-related cognitive decline and potentially delaying progression to mild cognitive impairment or dementia. In this multicenter clinical trial (RAYDELP1), we evaluated the efficacy and safety of sugarcane-derived Cuban policosanol (PCO) on cognitive function, superoxide dismutase (SOD) activity, inflammatory markers, and metabolic panels in adults aged 55-85 years with subjective cognitive complaints. Methods: A 12-week, randomized, double-blinded, placebo-controlled trial was conducted at Gachon University Gil Medical Center and Seoul Veterans Hospital in adults with SMD complaints. Individuals were randomized equally into three groups: placebo, PCO 20 mg group, or PCO 40 mg group. Assessment of cognitive function was performed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) and the Korean Mini-Mental State Examination (K-MMSE). All measurements, including SOD activity, inflammatory markers, and metabolic parameters, were analyzed in blood samples at baseline and after 12 weeks. For an exploratory subgroup analysis, participants receiving statins and those with potential ceiling effects or greater cognitive impairment based on K-MMSE scores were excluded. The K-MMSE range of 18-26 was used as an exploratory criterion to reduce heterogeneity in baseline cognitive scores, resulting in a refined analysis population of 56 participants. Results: In the refined SMD population, SOD activity increased significantly in the PCO 40 mg group after 12 weeks (mean change, +0.16 ± 0.25 U/mL; p = 0.0109) with increasing HDL-C, whereas changes in the placebo groups were not statistically significant (+0.08 ± 0.24 U/mL, p = 0.1873) with decreasing HDL-C. HDL-C levels increased in a dose-dependent manner in both the PCO 20 mg (+0.78 ± 5.1 mg/dL) and PCO 40 mg (+2.2 ± 6.7 mg/dL) groups within and between the groups. Both PCO groups showed significant differences compared with placebo in the between-group analysis and baseline-adjusted ANCOVA (p = 0.0124 and p = 0.0142, respectively). K-MMSE place-orientation scores improved significantly from baseline within both PCO groups (20 mg: 0.94 ± 0.87, p = 0.0003; 40 mg: 0.47 ± 0.77, p = 0.0155), whereas no significant within-group change was observed in the placebo group. Similarly, ADAS-Cog 11 language scores improved significantly within both PCO groups (20 mg: -1.17 ± 1.92, p = 0.0194; 40 mg: -0.95 ± 1.58, p = 0.0176). The 20 mg PCO group also showed a significant within-group decrease in Visual CPT false-alarm errors (-3.83 ± 7.13, p = 0.0357). However, between-group comparisons and baseline-adjusted ANCOVA did not demonstrate statistically significant differences in the selected cognitive outcomes. Conclusions: In the analyzed study population, HDL-C levels increased numerically in both PCO groups in a dose-dependent manner. The PCO 40 mg group showed a significant within-group increase in serum SOD activity, while improvements in selected cognitive domains were observed within both 20 mg and 40 mg PCO groups. However, no significant differences were found in between-group or ANCOVA analyses. PCO was well tolerated, and further clinical studies are warranted to confirm these exploratory findings and clarify its potential effects on cognitive function and enhancement of HDL quantity and quality.},
}

Humans
Double-Blind Method
*Fatty Alcohols/adverse effects/therapeutic use/pharmacology/administration & dosage
Aged
Male
Middle Aged
Female
*Antioxidants/metabolism
*Cognition/drug effects
*Memory Disorders/drug therapy/blood
Superoxide Dismutase/blood
Aged, 80 and over
Biomarkers/blood
Cognitive Dysfunction/drug therapy
Cognitive Enhancement
Treatment Outcome

@article {pmid43030141,
year = {2026},
author = {Dragan, J and Koziorowska-Gawron, E and Pietkiewicz, M and Pokryszko-Dragan, A},
title = {Therapeutic Potential of Tea and Its Compounds in the Central Nervous System Disorders.},
journal = {Nutrients},
volume = {18},
number = {21},
pages = {},
pmid = {43030141},
issn = {2072-6643},
support = {SUBZ.A520.26.030//Wroclaw Medical University/ ; },
mesh = {Humans ; *Tea/chemistry ; *Central Nervous System Diseases/drug therapy ; Animals ; Antioxidants/pharmacology ; Polyphenols/pharmacology ; *Camellia sinensis/chemistry ; *Plant Extracts/pharmacology/therapeutic use ; Anti-Inflammatory Agents/pharmacology ; Neuroprotective Agents ; Neurodegenerative Diseases/drug therapy ; },
abstract = {Due to increasing prevalence and burden of the central nervous system (CNS) disorders and challenges associated with their treatment, there is ongoing search for new therapeutic targets, frequently conducted in the area of natural products. Tea (derived from Camellia sinensis) contains a wide range of bioactive compounds (polyphenols, alkaloids and amino acids) which positively affect general health and function of many systems, including CNS. The aim of this narrative review was to present up-to-date evidence of beneficial effects of tea and its compounds on CNS functions and to outline the most promising perspectives for their utility in management of neurological conditions. Based on extensive literature search, the authors demonstrate biochemical properties of tea-derived substances, molecular mechanisms of their antioxidative, anti-inflammatory and cytoprotective activity, as well as pathways of their specific impact on CNS. The evidence is presented from experimental and clinical studies investigating effects of tea and its compounds on the prevention or amelioration of neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Huntington's disease), multiple sclerosis, cerebrovascular disease and brain tumors. Finally, limitations and barriers to these investigations are discussed and their emerging future directions are suggested.},
}

Humans
*Tea/chemistry
*Central Nervous System Diseases/drug therapy
Animals
Antioxidants/pharmacology
Polyphenols/pharmacology
*Camellia sinensis/chemistry
*Plant Extracts/pharmacology/therapeutic use
Anti-Inflammatory Agents/pharmacology
Neuroprotective Agents
Neurodegenerative Diseases/drug therapy

@article {pmid43030219,
year = {2026},
author = {Potu, BK and Arulkandan, A and Gopalakrishna, PK and Thanu, AS and Omar, NA and Nasr El-Din, WA and Vishnumukkala, T},
title = {Anatomical and Molecular Foundations of the Gut-Brain Axis in Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Translation.},
journal = {Nutrients},
volume = {18},
number = {21},
pages = {},
pmid = {43030219},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/therapy/microbiology/metabolism/physiopathology ; Animals ; *Gastrointestinal Microbiome/physiology ; Dysbiosis ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; Probiotics ; *Gastrointestinal Tract ; },
abstract = {Alzheimer's disease (AD) is a complex disease that involves systemic, vascular, and metabolic components affecting the brain, in addition to amyloid-beta (Aβ) and tau pathology. The microbiota-gut-brain axis, a bidirectional communication network between the gastrointestinal tract and the central nervous system, involving neural, immune, endocrine, and metabolic pathways, has arisen as a mechanistically plausible and clinically relevant contributor to AD pathogenesis among these systemic contributors. This review integrates information from human observational research, preclinical transgenic and germ-free models, and clinical trials to assess how gut dysbiosis, intestinal barrier dysfunction, and microbial metabolites converge on amyloidogenic and tau-associated pathways. In preclinical models, disruption of intestinal barrier integrity is proposed to allow translocation of lipopolysaccharide and bacterial amyloids into the systemic circulation, activating Toll-like receptor and NLRP3 inflammasome signaling that may prime microglia and astrocytes towards a chronic neuroinflammatory state. Further, dysbiosis-mediated changes in short-chain fatty acid, tryptophan-kynurenine, and bile acid metabolism may influence amyloid precursor protein processing, microglial clearance capability, and tau phosphorylation. Preclinical germ-free and fecal-transfer investigations provide fundamental evidence for these pathways in rodent models, while human case-control and Mendelian randomization data indicate converging yet diverse associations that have not yet established underlying directionality in human disease. Therapeutic modulation of the axis has shown promising early phase and observational signals using probiotics, synbiotics, dietary pattern interventions, fecal microbiota transplantation and pharmacological targeting of the GLP-1 pathway; however, the phase 3 EVOKE and EVOKE+ trials of oral semaglutide did not meet their primary cognitive endpoint, and heterogeneity of trials, short follow-up, and inconsistent reporting of biomarkers currently preclude definitive conclusions. We conclude that the microbiota-gut-brain axis is a biologically plausible and therapeutically tractable component of AD pathophysiology, but translation from mechanistic plausibility to clinical utility will depend upon longitudinal, biomarker-anchored and adequately powered interventional trials in genetically and microbiologically diverse populations. Because diet is among the most readily modifiable determinants of gut microbiome composition and function, this review prioritizes dietary patterns, prebiotic fibers, and probiotic or synbiotic supplementation as practical strategies for investigating the microbiota-gut-brain axis in AD. Their disease-modifying efficacy remains unproven; therefore, mechanistic and pharmacological approaches are discussed as complementary avenues for informing future research.},
}

Humans
*Alzheimer Disease/therapy/microbiology/metabolism/physiopathology
Animals
*Gastrointestinal Microbiome/physiology
Dysbiosis
*Brain/metabolism
*Brain-Gut Axis/physiology
Probiotics
*Gastrointestinal Tract

@article {pmid43030267,
year = {2026},
author = {Chamut, S and Nowak, H and Dadras, S and Kumari, R and Castrejón-Pérez, RC and Pontes Monteiro, J and Briggs Early, K and Chamut, D and Morris, M and Pico, J and Glittenberg, M and Habs-Hd Study Team, and Weisskopf, M},
title = {Mapping the Oral-Nutrition-Brain Axis in Aging: A Scoping Review of Evidence Linking Oral Health, Nutrition, and Cognitive Outcomes.},
journal = {Nutrients},
volume = {18},
number = {21},
pages = {},
pmid = {43030267},
issn = {2072-6643},
support = {/NH/NIH HHS/United States ; },
mesh = {Humans ; *Oral Health ; *Nutritional Status ; *Aging/physiology ; *Brain/physiology ; *Cognition/physiology ; Aged ; Biomarkers/blood ; Female ; Aged, 80 and over ; Male ; },
abstract = {Background: Oral health, nutrition, and neurocognitive health are increasingly recognized as components of healthy aging; however, their multidimensional relationships and plausible biological connections relevant to Alzheimer's disease and related dementia (AD/ADRD) risk remain incompletely characterized. Objective: To systematically map evidence linking oral conditions and function, nutrition-related factors and biomarkers, and neurocognitive outcomes in adults aged ≥65 years, and conceptualize an integrative Oral-Nutrition-Brain Axis (ONBA). Methods: This scoping review followed Joanna Briggs Institute methodology and PRISMA-ScR guidance. Five electronic databases were searched for studies published from 2010 through June 2025. Evidence was harmonized across oral and functional indicators, nutritional/metabolic/inflammatory biomarkers, and neurological and cognitive outcomes. Results: Of 3415 records identified, 1988 unique records were screened, and 120 studies met eligibility criteria. Evidence was predominantly observational and geographically concentrated in East Asia. Periodontal inflammation, compromised dentition, impaired functional occlusion and masticatory performance were consistently associated with nutritional vulnerability, poorer cognitive performance, cognitive decline, and adverse AD/ADRD outcomes. Co-occurring nutritional and systemic markers included low body weight, hypoalbuminemia, low serum vitamin B12 and folate, hyperhomocysteinemia, and elevated inflammatory biomarkers. Mapped findings aligned across three proposed conceptual frameworks: inflammatory-microbial, nutritional-metabolic, and sensorimotor deafferentation axes. Studies incorporating neuroimaging biomarkers or integrating all three ONBA domains simultaneously remained limited. Conclusions: Oral health and functional dentition may represent key modifiable proxies associated with nutritional and neurocognitive vulnerability in older adults. Longitudinal studies incorporating harmonized oral, nutritional, inflammatory, and neurological phenotypes are needed to clarify temporal sequence, evaluate potential explanatory relationships, and inform multi-domain risk assessment for healthy cognitive aging.},
}

Humans
*Oral Health
*Nutritional Status
*Aging/physiology
*Brain/physiology
*Cognition/physiology
Aged
Biomarkers/blood
Female
Aged, 80 and over
Male

@article {pmid43030309,
year = {2026},
author = {Drăgoi, CM and Nicolae, AC and Dumitrescu, IB},
title = {The Circadian Diet in Age-Related Neurodegeneration: Nutrient Timing, Sleep, and Mitochondrial Mechanisms.},
journal = {Nutrients},
volume = {18},
number = {21},
pages = {},
pmid = {43030309},
issn = {2072-6643},
mesh = {Humans ; *Circadian Rhythm/physiology ; *Mitochondria/metabolism/physiology ; Animals ; *Sleep/physiology ; *Neurodegenerative Diseases/physiopathology ; *Diet ; Intermittent Fasting ; Nutrients ; *Aging/physiology ; Parkinson Disease/physiopathology ; },
abstract = {Circadian rhythms coordinate sleep-wake regulation, endocrine secretion, nutrient handling and cellular energy metabolism. Circadian and sleep disturbances are associated with metabolic and cardiovascular morbidity and with neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), although whether restoring circadian alignment modifies neurodegeneration remains uncertain. This narrative review examines chrononutrition within the broader context of sleep regulation, physical activity and circadian care, distinguishing evidence from cellular and animal models, observational studies and clinical trials. Meal timing and dietary composition act as signals to peripheral clocks, while NAD[+], sirtuins and AMP-activated protein kinase link nutrient availability with clock regulation and mitochondrial metabolism. We appraise time-restricted eating, protein distribution, NAD[+] precursors, tryptophan- and melatonin-containing foods, magnesium, omega-3 fatty acids, polyphenols and fermentable fiber. Experimental findings provide mechanistic plausibility, but metabolic improvements and target engagement have not translated into demonstrated neuroprotection. Clinical application must account for levodopa-protein interactions, undernutrition, frailty and sarcopenia. Adequately powered trials with circadian-phase assessment, controlled energy intake and clinically meaningful neurological outcomes are required before a "circadian diet" can be established as a disease-modifying intervention.},
}

Humans
*Circadian Rhythm/physiology
*Mitochondria/metabolism/physiology
Animals
*Sleep/physiology
*Neurodegenerative Diseases/physiopathology
*Diet
Intermittent Fasting
Nutrients
*Aging/physiology
Parkinson Disease/physiopathology

@article {pmid43030335,
year = {2026},
author = {Bartosz, G and Sadowska-Bartosz, I},
title = {Ergothioneine: A Natural Antioxidant Claimed to Prevent Neurodegeneration.},
journal = {Nutrients},
volume = {18},
number = {21},
pages = {},
pmid = {43030335},
issn = {2072-6643},
mesh = {*Ergothioneine/pharmacology/therapeutic use ; Humans ; *Antioxidants/pharmacology/therapeutic use ; Animals ; *Neurodegenerative Diseases/prevention & control ; *Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects ; Alzheimer Disease/prevention & control ; NF-E2-Related Factor 2/metabolism ; Parkinson Disease/prevention & control ; },
abstract = {Ergothioneine (ET) is an exogenous thiol antioxidant present mainly in mushrooms and, in smaller amounts, in various other food products as well. Numerous beneficial health effects of ET have been reported, suggesting that ET is a vitamin-like compound. Evidence that ET prevents and inhibits the development of neurodegenerative diseases, especially Alzheimer's disease and Parkinson's disease, has been accumulated based on studies of cellular and animal models, as well as epidemiologic and interventional studies in humans. The mechanism of the neuroprotective action of ET remains to be elucidated. Apart from the direct antioxidant effect, ET was found to stimulate an endogenous antioxidant defense through the activation of Nrf2 signaling while also affecting other signaling pathways. The accumulating literature data suggest that an ET-rich diet could be recommended for the prevention of neurodegeneration in the general population, but such a recommendation, though noteworthy, is not yet adequately supported by the limited human intervention data, and further studies are needed.},
}

*Ergothioneine/pharmacology/therapeutic use
Humans
*Antioxidants/pharmacology/therapeutic use
Animals
*Neurodegenerative Diseases/prevention & control
*Neuroprotective Agents/pharmacology
Signal Transduction/drug effects
Alzheimer Disease/prevention & control
NF-E2-Related Factor 2/metabolism
Parkinson Disease/prevention & control

@article {pmid43030714,
year = {2026},
author = {Balgetir, F and Barua, PD and Shen, J and Narasimhan, P and Shivshankar, S and Dogan, S and Tasci, I and Tasci, B and Baygin, M and Tuncer, T and Kobayashi, M},
title = {Self-Organized Explainable Symbolic EEG Feature Engineering Using Directed Lobish and Previous-Next Pattern: A Proof-of-Concept Study on Dementia Classification.},
journal = {Journal of clinical medicine},
volume = {15},
number = {21},
pages = {},
pmid = {43030714},
issn = {2077-0383},
abstract = {Objective: Dementia is a prevalent neurological disorder, and accurate detection is essential for timely intervention. This study aims to design an interpretable symbolic feature engineering framework for EEG-based dementia classification and to examine how its performance depends on the validation protocol. Methods: We used a publicly available EEG dementia dataset including Alzheimer's disease (AD), frontotemporal dementia (FD), and healthy controls. A self-organized explainable feature engineering (SOXFE) model was introduced with five phases: (i) feature extraction using Bipartite Channel Transformer (BCT) and Previous-Next Pattern (PNPat), (ii) feature selection via cumulative weight-based iterative neighborhood component analysis (CWINCA), (iii) explainable output generation using Directed Lobish (DLob), (iv) classification through an ensemble tkNN classifier, and (v) information fusion with combinational majority voting (CMV). Performance was evaluated with segment-wise 10-fold cross-validation, leave-one-subject-out (LOSO) cross-validation, and nested participant-grouped 10-fold cross-validation. Results: Segment-wise 10-fold cross-validation, which allowed segments of one participant in both training and test folds, yielded accuracies of 99.12-99.74%. Participant-independent accuracy was substantially lower: 51.19-63.81% for LOSO and 49.00-62.50% for nested participant-grouped validation at the segment level. Participant-level LOSO accuracy equaled the majority-class rate for dementia versus healthy controls (67.05%) and fell below it for AD versus FD (57.63% versus 61.02%). No exact McNemar comparison showed an accuracy advantage over the majority-class baseline. DLob outputs were produced as feature-level visualizations. Conclusions: The findings support the feasibility of interpretable, algorithm-derived symbolic feature representations. They do not establish reproducible disease-related EEG characteristics or clinical diagnostic utility. DLob outputs describe the channel transitions used by the model. Independent cohorts and stronger participant-independent performance are required before clinical application.},
}

@article {pmid43030797,
year = {2026},
author = {Lee, JE and Lee, GT and Cho, HA},
title = {Extreme Heat Exposure and Dementia-Related Mortality: A Systematic Review and Meta-Analysis.},
journal = {Journal of clinical medicine},
volume = {15},
number = {21},
pages = {},
pmid = {43030797},
issn = {2077-0383},
support = {NRF-2025S1A5A2A03017422//National Research Foundation/ ; },
abstract = {Background/Objectives: The world is undergoing rapid population aging while experiencing more frequent and intense heatwaves driven by climate change. People living with dementia-who can have impaired thermoregulation, a reduced ability to perceive and respond to heat, and high care dependency-may be especially susceptible to heat, but the evidence on mortality has not been synthesized. We conducted a systematic review and meta-analysis to quantify the association between heatwave exposure and dementia-related mortality. Methods: PubMed, Web of Science Core Collection, ProQuest Dissertations & Theses Global, and APA PsycINFO were searched from inception to 15 June 2026; the searches were rerun on 15 October 2026 and supplemented by citation searching and by a PubMed search without the older-adult concept block. The review is reported according to PRISMA 2020 (PROSPERO CRD420261436457, registered after the searches had been run). Observational studies reporting relative effect estimates for mortality during defined heatwave or extreme heat events, among people with diagnosed dementia or for deaths attributed to dementia in mortality records, were eligible. Risk of bias was assessed with an adapted ROBINS-E approach and the certainty of evidence with GRADE. Odds ratios (ORs) from time-stratified case-crossover analyses, which estimate rate ratios, were pooled in a random-effects model with restricted maximum-likelihood estimation and Hartung-Knapp 95% confidence intervals (CIs); heterogeneity was described with Cochran's Q, I[2], and a 95% prediction interval. The primary analysis was restricted to studies with a dementia-specific outcome definition and an estimate of the total heatwave association and used one study from each pair of studies based on the same mortality data. Results: Six studies conducted in China and Australia met the eligibility criteria, one of them identified only by the supplementary search; three contributed to the primary analysis, and three were used in sensitivity analyses only. All study-level estimates exceeded unity, but the pooled association was imprecise and not statistically significant (OR 1.84, 95% CI 0.54-6.25), with high heterogeneity (I[2] = 94.9%; 95% prediction interval 0.21-16.31). In sensitivity analyses that retained at least three studies, pooled ORs ranged from 1.50 to 1.84; analyses reduced to two studies had uninformative CIs. The CI excluded the null when an alternative national study was substituted (OR 1.76, 95% CI 1.13-2.72), when all six estimates were pooled without regard to overlapping data (OR 1.57, 95% CI 1.15-2.15), or when the conventional DerSimonian-Laird method was used. No included study compared dementia with non-dementia deaths, and only one was restricted to adults aged 60 years or older; the others were predominantly older or did not report age. The certainty of evidence was very low. Conclusions: The evidence is inconclusive regarding the magnitude and consistency of an association between heatwaves and dementia-related mortality. The study-level estimates point in the same direction, but the pooled estimate is an average across highly heterogeneous settings, is too imprecise to establish an effect, and cannot show whether the relative increase exceeds that for other deaths; evidence specific to older adults with dementia is largely indirect. Including people with dementia in heat-health action plans remains a reasonable precaution, and independent, methodologically harmonized primary studies are needed.},
}

@article {pmid43031254,
year = {2026},
author = {Desai, NM and Shou, H and Hillman, N and Melhem, R and Beason-Held, LL and Resnick, SM and , and , and Davatzikos, C and Shinohara, RT},
title = {Harmonization of Longitudinal Multi-Scanner Neuroimaging Data With Nonlinear Biological Associations.},
journal = {Human brain mapping},
volume = {47},
number = {16},
pages = {},
doi = {10.1002/hbm.70687},
pmid = {43031254},
issn = {1097-0193},
support = {R01MH112847/MH/NIMH NIH HHS/United States ; R01MH123550/MH/NIMH NIH HHS/United States ; R01MH12355/MH/NIMH NIH HHS/United States ; R01NS112274/NS/NINDS NIH HHS/United States ; U24NS13041/NS/NINDS NIH HHS/United States ; U01AG068057/AG/NIA NIH HHS/United States ; RF1AG054409/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Neuroimaging/methods/standards ; Nonlinear Dynamics ; *Alzheimer Disease/diagnostic imaging/pathology ; Longitudinal Studies ; *Brain/pathology/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Aging/pathology ; Aged ; Male ; Female ; *Image Processing, Computer-Assisted/methods ; },
abstract = {The aggregation of neuroimaging data across multiple sources, typically scanners or imaging sites, has the potential to improve statistical power when conducting inference. The added benefits of increased sample size to inference, however, can be obstructed by unwanted source-specific technical variability that increases difficulty in estimating biological signals of interest. To address this issue, recent methods based on ComBat, a batch-correction procedure originally developed for genomics, have been developed for both cross-sectional and longitudinal neuroimaging data. While these approaches have successfully removed technical batch-specific variability, they restrict their consideration to linear biological associations. In this article we introduce a ComBat-based method to harmonize longitudinal multisource imaging data that can account for nonlinear biological associations of interest. We demonstrate via simulation that, in the presence of nonlinear biological signal, our method outperforms existing ComBat-based approaches designed for longitudinal imaging data, particularly in settings where observed values of relevant biological covariates lack substantial overlap across sources. Using volumetric measurements for 504 subjects combined from both the Baltimore Longitudinal Study of Aging (BLSA) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), we identify the presence of both additive and multiplicative study-specific effects for a substantial number of brain regions and demonstrate the effective removal of their presence on data harmonized by our method. The flexibility of the proposed method towards capturing many types of biological associations makes it a versatile procedure that can be used to harmonize longitudinal biomedical data.},
}

Humans
*Neuroimaging/methods/standards
Nonlinear Dynamics
*Alzheimer Disease/diagnostic imaging/pathology
Longitudinal Studies
*Brain/pathology/diagnostic imaging
*Magnetic Resonance Imaging/methods
Aging/pathology
Aged
Male
Female
*Image Processing, Computer-Assisted/methods

@article {pmid43031302,
year = {2026},
author = {Zhu, N and Xu, H and Eriksdotter, M},
title = {Oral anticoagulation and cognitive outcomes in atrial fibrillation and Alzheimer's disease: considerations for longitudinal analyses.},
journal = {European heart journal},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurheartj/ehag930},
pmid = {43031302},
issn = {1522-9645},
support = {FoUI-1002840//Center for Innovative Medicine/ ; AF-1032116//Swedish Alzheimer's Foundation/ ; M24-0221//Åke Wiberg Foundation/ ; 2022-01428//Swedish Research Council/ ; M-2024-2526//Petrus and Augusta Hedlund Foundation/ ; 2024-1370//Magnus Bergvall Foundation/ ; //Swedish Kidney Foundation/ ; 2024-03599//Karolinska Institutet internal funds/ ; FO2024-0339//Swedish Brain Foundation/ ; //Stockholm County Council/ ; //Karolinska Institutet/ ; 2021-02680//VINNOVA/ ; //Mats Paulsson Foundation/ ; },
}

@article {pmid43031372,
year = {2026},
author = {Karakasis, P},
title = {Oral anticoagulation and cognitive outcomes in atrial fibrillation and Alzheimer's disease.},
journal = {European heart journal},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurheartj/ehag926},
pmid = {43031372},
issn = {1522-9645},
}

@article {pmid43031658,
year = {2026},
author = {Shen, Z and Niu, Y and Chen, H and Pan, M and Yang, F and Li, M and Zhang, C and Zhou, Y and Yan, J},
title = {SEL1L: molecular gatekeeper of the endoplasmic reticulum quality control network.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {251},
number = {},
pages = {11350},
pmid = {43031658},
issn = {1535-3699},
mesh = {Humans ; *Endoplasmic Reticulum/metabolism ; *Endoplasmic Reticulum-Associated Degradation/physiology ; Neurodegenerative Diseases/metabolism ; Ubiquitin-Protein Ligases/metabolism ; *Proteins/metabolism/genetics ; Animals ; },
abstract = {SEL1L (suppressor/enhancer of lin-12-like) is an endoplasmic reticulum (ER) transmembrane protein that serves as a key regulatory molecule in the endoplasmic reticulum-associated degradation (ERAD) pathway, playing a central role in maintaining intracellular protein homeostasis. This paper provides a systematic review of SEL1L's structural characteristics, the molecular mechanisms by which it forms a functional complex with the E3 ubiquitin ligase HMG-CoA reductase degradation protein 1 (HRD1, encoded by SYVN1) to synergistically execute ERAD, and its pathophysiological significance in the onset and progression of various diseases. Research indicates that SEL1L dysfunction is closely associated with pathogenic protein aggregation in neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), protein homeostasis imbalances during tumorigenesis, cellular metabolic dysregulation in metabolic disorders (e.g., diabetes, lipid metabolism disorders), and immune system dysfunction. Furthermore, the expression levels or variants of SEL1L exhibit specific alterations across different tumor tissues, suggesting its potential as a disease biomarker and therapeutic target. This paper aims to synthesize existing research, elucidate the 'gatekeeper' role of SEL1L in multiple physiological and pathological processes, and explore the prospects for developing novel therapeutic strategies by targeting the SEL1L-HRD1 complex and related pathways.},
}

Humans
*Endoplasmic Reticulum/metabolism
*Endoplasmic Reticulum-Associated Degradation/physiology
Neurodegenerative Diseases/metabolism
Ubiquitin-Protein Ligases/metabolism
*Proteins/metabolism/genetics
Animals

@article {pmid43031667,
year = {2026},
author = {Oh, C and Kim, IS},
title = {Speech acoustics, prefrontal activation, and their coupling during affective prosody production in dementia of the Alzheimer's type.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1937665},
pmid = {43031667},
issn = {1663-4365},
abstract = {INTRODUCTION: Affective prosody, the expression of emotion through speech, is often disrupted in dementia of the Alzheimer's type (DAT), yet its acoustic and neural bases remain poorly understood. Extending our earlier single-group investigation, we compared individuals with DAT and cognitively healthy older adults across speech acoustics, prefrontal activation, and their coupling.

METHODS: Ten individuals with DAT and ten cognitively healthy older adults of similar mean age produced spontaneous happy, sad, and neutral speech while prefrontal cortical activity was recorded using functional near-infrared spectroscopy (fNIRS). Acoustic features were extracted and analyzed alongside cortical activation and speech-brain activation coupling.

RESULTS: The groups differed reliably in the formant domain, while intensity, fundamental frequency, and formant structure varied by affective condition. Overall prefrontal activation did not differ between groups, but group-by-emotion interactions revealed opposite response directions: healthy adults generally showed increased activation during affective speech, whereas individuals with DAT showed decreased activation. Seven of eight contrasts survived correction for multiple comparisons. The pattern was replicated in total hemoglobin and remained robust to the removal of individual participants. Speech-brain activation coupling also differed between groups, with large effect sizes (Cohen's q = 0.64-0.66), although these exploratory effects did not survive correction for multiple comparisons.

DISCUSSION: DAT was characterized not by uniform reduction but by reorganization of the relationship between affective speech and its cortical support. Joint analysis of acoustic and neural signals may provide a more comprehensive understanding of affective communication in dementia, while the exploratory coupling findings require confirmation in a larger sample.},
}

@article {pmid43032132,
year = {2026},
author = {Margetts-Smith, G and Andrianova, L and Plant, AK and Kohli, S and Sampaio-Baptista, C and Randall, AD and Aggleton, JP and Witton, J and Craig, MT},
title = {Anterior thalamic nucleus inputs to the retrosplenial cortex are unperturbed in the hAPP-J20 mouse model of Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {6},
pages = {fcag417},
doi = {10.1093/braincomms/fcag417},
pmid = {43032132},
issn = {2632-1297},
abstract = {Alzheimer's disease is a neurodegenerative condition characterized by progressive loss of memory and general decline in cognitive function. Although research has traditionally focused on the hippocampus and entorhinal cortex, other regions important for memory and spatial navigation, such as the anterior thalamic nuclei and retrosplenial cortex, are also affected. The retrosplenial cortex is an important brain region for both memory and spatial navigation, and displays dysfunction in humans during prodromal phases of Alzheimer's Disease. The anterior thalamic nuclei provide a major input to the retrosplenial cortex, with loss of this input to the retrosplenial cortex causing a dramatic reduction in the expression of the immediate-early gene product c-Fos. The anterior thalamic nuclei to retrosplenial cortex connection may thus present a new target for therapeutic intervention in Alzheimer's Disease. Here, we set out to determine whether Alzheimer's-like pathology perturbed projections from the anterior thalamic nuclei to retrosplenial cortex in the hAPP-J20 amyloidopathy mouse model, using optogenetic activation of thalamic inputs combined with ex vivo patch clamp electrophysiology. We found that the retrosplenial cortex displayed an age-dependent decline in basal c-Fos activity, with no additional effect of amyloid pathology on c-Fos expression. At all-time points (3, 6 and 9 months) measured, we found no evidence of impairments in the synaptic strength or efficacy of the anterior thalamic nuclei projections to either granular or dysgranular subdivisions of the retrosplenial cortex. We conclude that, in the hAPP-J20 mouse model, this pathway is unaffected by amyloid-β overexpression.},
}

@article {pmid43032557,
year = {2026},
author = {Ng, TKS and Dennis, KR and Beck, T and Bond, J and Krueger, KR and Desai, P and Wilson, RS and Evans, DA and Rajan, KB},
title = {Neurofilament light chain as a potential mediator of the longitudinal association between depressive symptoms and cognitive aging.},
journal = {Brain, behavior, & immunity - health},
volume = {58},
number = {},
pages = {101398},
doi = {10.1016/j.bbih.2026.101398},
pmid = {43032557},
issn = {2666-3546},
abstract = {Depressive symptoms have long been associated with cognitive decline (CD) and Alzheimer's disease (AD), yet the biological processes connecting affective distress to later cognitive vulnerability remain poorly understood. Serum neurofilament light chain (NfL) is a circulating marker of neuroaxonal injury. We tested whether serum neurofilament light chain (NfL), a sensitive marker of neuroaxonal degeneration and an emerging biomarker in late-life depression, mediates the prospective association between depressive symptoms and subsequent adverse cognitive outcomes. We analyzed 921 Black and White community-dwelling older adults from the Chicago Health and Aging Project (CHAP; 1993-2012) with baseline depressive symptom scores (T1), serum NfL measured at the next wave (T2), and global cognition assessed across three waves (T1-T3; mean interval 6.34 years), with cognition at T3 serving as the primary outcome in the mediation analyses. A subsample of 445 participants had clinically adjudicated incident AD at T3 (79 AD cases). Mixed-effects models examined the association between baseline depressive symptoms and CD, followed by longitudinal mediation models using a temporally ordered T1→T2→T3 framework with 1000 simulations. Sensitivity analyses excluded baseline AD to assess model robustness. In mixed-effects models, higher baseline depressive symptoms were associated with accelerated CD in Models 1-2, with similar but nonsignificant associations after full adjustment (Model 3: β = -0.0041; p = 0.0581) and additional adjustment for NfL (Model 4: β = -0.0040; p = 0.0647). Mediation analyses identified significant indirect pathways through NfL linking depressive symptoms with poorer subsequent cognitive performance (indirect effect: -0.0046; 95% CI: -0.0089 to -0.0014; p = 0.004; 18.05% mediated) and accelerated CD (indirect effect: -0.0010; 95% CI: -0.0021 to -0.0002; p = 0.008; 10.49% mediated). Findings were robust to the exclusion of baseline AD. In the subsample with clinical AD diagnoses, NfL also mediated the prospective association between depressive symptoms and incident AD (indirect effect: 0.0033; 95% CI: 0.0000 to 0.0073; p = 0.046; 16.15% mediated), with attenuated significance in fully adjusted models consistent with the smaller sample and limited number of incident AD cases. These findings provide longitudinal evidence that depressive symptoms are associated with adverse cognitive outcomes, with indirect pathways through NfL accounting for part of these associations. These temporally ordered associations suggest that NfL may index a potential neurobiological pathway linking depressive symptoms with cognitive aging NfL may represent a biologically grounded marker for early risk detection and intervention in late-life depressive symptoms with implications for cognitive decline.},
}

@article {pmid43032635,
year = {2026},
author = {Wang, RY and Wozniak, G and Wang, X and Mustafa, M and El-Khatib, M and Kahn, E and Heutink, P and Long, H and Kenkare-Mitra, S and Rosenthal, A and Khan, Z and Kuhn, JA and Gulbranson, DR},
title = {Integrative analysis of pooled CRISPR screens provide functional insights into AD GWAS risk genes.},
journal = {iScience},
volume = {29},
number = {11},
pages = {118170},
doi = {10.1016/j.isci.2026.118170},
pmid = {43032635},
issn = {2589-0042},
abstract = {Microglia pathways such as lipid transport and metabolism, phagocytosis, and lysosomal function are implicated Alzheimer's disease (AD) pathology, but the mechanisms underlying these pathways remain poorly understood. To map these pathways, custom CRISPR activation and interference (CRISPRa/i) libraries were constructed targeting 203 microglial and genome-wide association study (GWAS)-associated risk genes. Pooled CRISPRa/i screens in THP-1 cells identified core functional regulators of lipid metabolism and lysosomal function, a subset of which were validated in primary macrophages. We also captured transcriptomic changes caused by these genes by performing Perturb-seq in primary macrophages. Through non-negative matrix factorization, we identified five gene programs altered by our perturbation library. We then used an integrative analysis of functional screen data with Perturb-seq data that enabled us to uncover novel functions and genetic relationships between perturbations. This multidimensional resource links genetic perturbations to phenotypes and transcriptional programs, establishing a scalable framework for systematic gene discovery in neurodegeneration and beyond.},
}

@article {pmid43032671,
year = {2026},
author = {Sun, MY and Wang, Y and Jiang, J and Feng, S and Sun, YG},
title = {Current status and trends of gut microbiota in the study of cognitive impairment in the elderly.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1910406},
doi = {10.3389/fmicb.2026.1910406},
pmid = {43032671},
issn = {1664-302X},
abstract = {BACKGROUND: Cognitive impairment in older persons has become a major public health concern as the world's population ages more quickly. A reduction in thinking, learning, and memory skills that affects a person's day-to-day activities or social functioning is referred to as cognitive impairment. The connection between gut microbiota and cognitive decline has attracted a lot of interest lately. However, this rapidly expanding interdisciplinary field presents an increasingly complex knowledge structure, with existing evidence being highly fragmented and subject to significant methodological and sample size limitations.

GOAL: This study adopts a bibliometrics perspective, summarising and outlining the current state and developmental trends within the field to provide a reference framework and recommendations for subsequent research.

METHOD: Based on the Web of Science Core Collection (WoSCC) database and Scopus database. In WOSCC database, literature related to gut microbiota and cognitive impairment in the elderly from 1995 to 8 September 2025 was retrieved. Similarly, search for relevant literature from 1995 to 2025 in the Scopus database. Bibliometric analysis was conducted using VOSviewer software to examine data on countries, institutions, authors, journals, keywords, citations, and generate visual maps.

RESULT: A total of 406 relevant publications were retrieved from the WOSCC database. The overall publication trend is increasing. China is the country with the most published papers, and Nanjing Medical University and Zhejiang University are joint top institutions in terms of output, while in the WOS database, Hariom Yadav is the most prolific author, while Luo Ailin has the highest total link strength. In the Scopus database, Zhang, Y is the most prolific author, while Hisada, T et al. have the highest total link strength. The most common keyword is gut microbiota, followed by Alzheimer's disease, aging, probiotics, dementia, and neuroinflammation. In addition, a total of 180 relevant literatures were retrieved from the Scopus database. Among them, the most common keywords are intestine flora, aged, cognitive defect, cognition, and gastrointestinal microbiome.

CONCLUSION: Research into the relationship between the gut microbiota and cognitive impairment is advancing steadily, yet there remains a need to strengthen collaboration between authors and institutions across different regions. Sustained interaction and exchange are essential to further explore the mechanisms of action of the gut microbiota. Based on the identified research hotspots and gaps, we suggest that future investigations could benefit from integrating multi-omics approaches to explore potential biomarkers and nutritional intervention strategies. However, these directions remain speculative and should be pursued through rigorous experimental and clinical research.},
}

@article {pmid43033017,
year = {2026},
author = {Bohlken, J and Riedel-Heller, S and Kostev, K},
title = {Primary non-adherence to anti-dementia drugs, antidepressants, antipsychotics and benzodiazepines in individuals with dementia in Germany: A cohort study of primary care prescriptions.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261507606},
doi = {10.1177/13872877261507606},
pmid = {43033017},
issn = {1875-8908},
abstract = {BackgroundIndividuals with dementia frequently receive psychotropic and anti-dementia medication. Primary non-adherence (PNA), the failure to dispense a newly initiated medication, is an early and overlooked treatment barrier.ObjectiveTo estimate PNA at treatment initiation across four medication classes in dementia, to analyse subsequent prescriptions separately, and to identify associated patient factors.MethodsRetrospective cohort study using German primary care records linked to pharmacy dispensing data. Individuals aged 65 years and older with dementia who initiated anti-dementia drugs, antidepressants, antipsychotics, or benzodiazepines and related sedatives in general practices were included. Treatment initiation required 365 days of prior observation and no dispensing of the same class in that period. PNA was defined as failure to dispense within 30 days. Generalized estimating equations accounted for repeated observations within patients.ResultsAmong 10,746 initiations from 8634 individuals (mean age 83.4 years; 64.3% women), PNA occurred in 13.4% (95% CI 11.8-15.1) of anti-dementia drug, 11.5% (10.2-12.9) of antidepressant, 8.7% (7.9-9.5) of antipsychotic and 25.7% (23.8-27.7) of benzodiazepine initiations. Compared with antipsychotics, odds were higher for anti-dementia drugs (OR 1.54; 1.30-1.82), antidepressants (1.29; 1.11-1.51) and benzodiazepines (3.63; 3.14-4.20). Results were homogeneous across age cohorts (interaction p = 0.97). Among 180,796 subsequent prescriptions, non-dispensing was lower than at initiation except for benzodiazepines (31.5%).ConclusionsPNA at initiation was moderate for anti-dementia drugs, antidepressants and antipsychotics, and considerably higher for benzodiazepines and related sedatives. The latter warrants investigation into access barriers, preferences, safety concerns, and incomplete capture of privately issued prescriptions.},
}

@article {pmid43033029,
year = {2026},
author = {Ou, C and Chen, B and Yu, H and Deng, J and Long, H},
title = {Integrated single-cell RNA sequencing and two-sample Mendelian randomization reveal CD4[+] T cell-expressed COMT and JUN as shared candidate genes for Alzheimer's disease and type 2 diabetes mellitus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261506457},
doi = {10.1177/13872877261506457},
pmid = {43033029},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are high-burden diseases; T2DM independently elevates AD risk via shared pathogenesis, yet their shared peripheral immune pathways and genetically supported cell-specific targets remain undefined.ObjectiveTo identify shared immune subsets, key genes and candidate compounds for AD and T2DM via integrated scRNA-seq and two-sample Mendelian randomization.MethodsWe constructed an integrated multi-omics framework combining peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) and two-sample Mendelian randomization (2SMR) using 10 public GEO datasets, with core analyses covering cell annotation, cell-cell communication profiling, differential expression analysis, eQTL-based 2SMR, in silico gene function prediction, and molecular docking with dynamics simulation for compound screening.ResultsCD4[+] T cells were inferred as the most abundant adaptive immune subset and a potential intercellular communication hub in peripheral blood of both AD and T2DM. Dual scRNA-seq/2SMR screening identified consistently upregulated shared candidate genes COMT and JUN, validated at single-cell and bulk transcriptome levels; myricetin and tauroursodeoxycholic acid were screened as candidate compounds with high predicted binding affinity to the encoded proteins. The 100 ns molecular dynamics simulation confirmed favorable structural stability of the COMT-myricetin complex (RMSD ∼1.2 Å).ConclusionsAs an exploratory bioinformatics investigation, this study proposes a testable hypothesis that CD4[+] T cells and the COMT/JUN axis may act as a potential shared immune regulatory node in the concurrent pathogenesis of AD and T2DM, differing from the canonical T cell-driven pathological process in classic autoimmune diseases. All findings remain preliminary and require dedicated experimental validation.},
}

@article {pmid43033031,
year = {2026},
author = {Zhang, M and Chen, Y and Sheng, Z and Yu, W and Guo, F and Lü, Y and , },
title = {Potential synergy of cerebrospinal fluid TREM2 and BDNF/TrkB pathways promote mild depressive symptoms in Alzheimer's disease through tau pathology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261503497},
doi = {10.1177/13872877261503497},
pmid = {43033031},
issn = {1875-8908},
abstract = {BackgroundEarly identification of Alzheimer's disease (AD) remains challenging. Mild depressive symptoms (MDSs) during the prodromal stage accelerate cognitive decline, but the underlying mechanisms remain unclear. Neuroinflammation and neurotrophic support are implicated in cognitive impairment, yet the interaction between triggering receptor expressed on myeloid cells 2 (TREM2)-mediated neuroimmune dysregulation and brain derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) deficits has not been established.ObjectiveThis study aimed to investigate whether alterations in cerebrospinal fluid (CSF) TREM2/sTREM2 and BDNF/TrkB interact to affect cognition in patients with AD and MDSs and whether tau pathology mediates this relationship, using observational data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).MethodsADNI data collected from 2005 to 2013 included 653 eligible participants. CSF TREM2, sTREM2, BDNF, TrkB, Aβ42, pTau181, and tTau levels, neuropsychiatric measures, and cognitive scores were analyzed using analysis of covariance, stratified analyses, mediation analyses, and multivariable linear regression adjusted for age, sex, education, and APOE ε4 status.ResultsCSF BDNF, TREM2, and sTREM2 levels varied significantly with age. sTREM2 appeared protective in early but not late disease stages. Reduced BDNF/TrkB signaling was associated with MDSs and poorer memory and executive function. Mediation analyses indicated that MDS-related cognitive impairment was partly mediated by TREM2/sTREM2-associated neuroinflammation and BDNF/TrkB dysfunction, particularly with elevated tau pathology.ConclusionsTREM2-mediated neuroimmune dysfunction and impaired BDNF/TrkB support may jointly exacerbate tau-related cognitive decline in preclinical AD with MDSs. This immune-neurotrophic interaction may promote dysfunctional microglial activation, excessive inflammation, and reduced clearance, offering a potential mechanism linking depressive symptoms to accelerated AD progression and informing early risk stratification and targeted intervention.},
}

@article {pmid43033032,
year = {2026},
author = {Gurney, ZC and Yokota, S and Vita, AJ and Jargowsky, J and Shumer, GD and Fang, H and Mahmoudi, E},
title = {Economics of dementia care across five developed countries: A scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261505501},
doi = {10.1177/13872877261505501},
pmid = {43033032},
issn = {1875-8908},
abstract = {BackgroundAs the global population ages, the number of people living with dementia is rising rapidly, creating substantial economic challenges for healthcare systems, caregivers, and societies worldwide.ObjectiveWe examined the economics of dementia care across five developed countries to identify potentially transferable care practices and policy approaches relevant to the U.S.MethodsWe conducted a scoping review of studies involving adults with dementia that assessed dementia care, healthcare utilization, or costs in Canada, France, Germany, China, and Japan. Searches were performed in Ovid MEDLINE and Ovid Embase for January 2017-December 2023.ResultsOf 12,286 titles and abstracts screened, 266 articles underwent full-text review, and 63 met inclusion criteria. Studies were categorized into three areas: prescription drug use, direct medical costs, and economic impacts of care models or policies. We found that use of antidementia medications generally decreases with increasing dementia severity. Higher severity and greater burden of comorbidity were associated with increased costs, largely driven by frequent hospitalizations and long-term care. Policies incentivizing informal caregiving were associated with delayed long-term care but may reduce caregivers' labor-force participation, while in-kind, service-based models showed more consistent evidence of delaying costly institutional care. Evidence on integrated care models was mixed.ConclusionsRising dementia-related healthcare costs in aging populations represent a shared global challenge. Aligning reimbursement policies, care models, and service delivery with disease severity and care needs can improve efficiency, equity, and sustainability.},
}

@article {pmid43033224,
year = {2026},
author = {Sathe, A and Chatterjee, A and Shashikumar, N and Pechman, KR and Schilling, K and Landman, BA and Gaynor, LS and Bolton, CJ and Zhang, P and Hohman, TJ and Jefferson, AL and Bender, AR and Archer, DB},
title = {Fixel-based analysis identifies selective vulnerability of non-dominant fiber populations in aging and mild cognitive impairment.},
journal = {Brain structure & function},
volume = {231},
number = {9},
pages = {},
pmid = {43033224},
issn = {1863-2661},
mesh = {Humans ; *Aging/pathology ; *White Matter/pathology/diagnostic imaging ; *Cognitive Dysfunction/pathology/diagnostic imaging/psychology ; Diffusion Tensor Imaging/methods ; Female ; Aged ; Male ; *Brain/pathology/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; Aged, 80 and over ; Image Processing, Computer-Assisted ; },
abstract = {Fixel-based analysis (FBA) resolves fiber-specific white matter properties within crossing-fiber regions, where conventional diffusion tensor imaging is limited. We applied single-shell three-tissue constrained spherical deconvolution to diffusion MRI from 295 older adults in the Vanderbilt Memory and Aging Project cohort, quantifying fiber density (FD), fiber-bundle cross-section (FC), and their composite (FDC) across the primary (N1), secondary (N2), and tertiary (N3) fiber populations within each white matter voxel. White matter was stratified into crossing-fiber complexity strata defined by the number of distinct bundles per voxel, and covariate-adjusted models examined associations with age, cognitive status, and cognition. FC declined with age most steeply in the non-dominant fiber populations. In these populations, FC was lower in participants with mild cognitive impairment than in cognitively unimpaired participants, and higher FC was associated with better executive function. The age-related decline in non-dominant FC did not vary across crossing-fiber complexity, indicating that fiber-population identity, rather than local architecture, organizes age-related vulnerability. FD and FDC showed age associations that became more positive as complexity increased, with the N1 FD association reversing from negative in the least complex regions to positive in the most complex. This behavior is consistent with how density is estimated in multi-fiber voxels rather than with fiber loss, identifying FC as the more interpretable metric in crossing-fiber regions. These findings identify fiber cross-section in the non-dominant fiber populations as a sensitive marker of white matter aging and cognitive status and provide a framework for fiber-specific analysis in existing single-shell cohorts.},
}

Humans
*Aging/pathology
*White Matter/pathology/diagnostic imaging
*Cognitive Dysfunction/pathology/diagnostic imaging/psychology
Diffusion Tensor Imaging/methods
Female
Aged
Male
*Brain/pathology/diagnostic imaging
Diffusion Magnetic Resonance Imaging
Aged, 80 and over
Image Processing, Computer-Assisted

@article {pmid43033255,
year = {2026},
author = {Ali, S and Ullah, A},
title = {Neuropharmacology of omega-3 long-chain polyunsaturated fatty acids in neurodegenerative diseases: mechanisms, multi-omics evidence, and clinical translation.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {43033255},
issn = {1432-1912},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, involve progressive neuronal dysfunction associated with neuroinflammation, oxidative stress, mitochondrial impairment, defective proteostasis, and synaptic failure. Although symptomatic treatment remains central, anti-amyloid therapies can modestly slow clinical decline in selected patients with early Alzheimer's disease. This review critically evaluates the neuropharmacological evidence for omega-3 long-chain polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and the barriers to their clinical translation. We narratively synthesized preclinical, observational, and interventional clinical evidence, focusing on membrane organization, inflammatory resolution, mitochondrial and redox homeostasis, autophagy, proteostasis, neuronal signaling, and factors contributing to heterogeneous clinical outcomes. Preclinical studies support context-dependent effects of DHA and EPA on neuronal membranes, inflammatory signaling, mitochondrial function, redox balance, autophagy, and synaptic plasticity. Human evidence is less consistent: observational studies generally report favorable associations between omega-3 status and neurological outcomes, whereas randomized trials show null, modest, or subgroup-dependent effects. Outcomes vary with disease stage, baseline omega-3 status, formulation, dose, treatment duration, genotype, and endpoint selection. Uncertain central nervous system exposure and limited pharmacokinetic and target-engagement data remain major translational barriers. Omega-3 long-chain polyunsaturated fatty acids are biologically plausible neuropharmacological modulators, but current evidence does not establish DHA or EPA as broadly effective disease-modifying treatments for neurodegenerative diseases. Future trials should prioritize early-stage, biomarker-stratified populations, pharmacologically characterized formulations, adequate treatment duration, and clinically meaningful progression-related outcomes.},
}

@article {pmid43033321,
year = {2026},
author = {Liu, T and Chen, X},
title = {Multilayer Transcriptomic Analysis Prioritizes RAE1 and SLC25A46 as Alzheimer's Disease Candidate Genes Related to Nucleocytoplasmic Transport and Mitochondrial Homeostasis.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {43033321},
issn = {1559-1166},
mesh = {*Alzheimer Disease/genetics/metabolism ; Humans ; *Mitochondria/metabolism/genetics ; Homeostasis ; Active Transport, Cell Nucleus ; *Transcriptome ; Gene Expression Profiling ; },
abstract = {Regional and cellular heterogeneity complicates transcriptomic candidate prioritization in Alzheimer's disease (AD). We integrated donor-adjusted differential expression, exploratory co-expression analysis, donor-grouped nested machine learning, external evaluation, and single-nucleus and spatial localization. Differential screening used false discovery rate < 0.05 and absolute log2 fold change > 0.10. We also examined functional enrichment, immune context, pseudotime, cell communication, virtual knockout, and exploratory compound screening and docking. Among 173 tissue samples from 63 donors, 356 genes met the screening criteria; 44 of 113 algorithm combinations yielded complete evaluations. RAE1 was downregulated across four discovery regions and both external cohorts, with areas under the receiver operating characteristic curve (AUC) of 0.662 (95% confidence interval 0.429-0.894) and 0.863 (0.693-1.000). The frozen Stepglm[forward] model yielded external AUCs of 0.5154 and 0.8875. SLC25A46 showed opposite discovery and external expression directions. Genome-wide enrichment identified 754 Gene Ontology terms and 62 Kyoto Encyclopedia of Genes and Genomes pathways, including negatively enriched mitochondrial energy and RNA-processing programs. Localization across 61,472 nuclei and 25,293 spatial spots, together with virtual perturbation, defined cellular contexts. R-547, JNJ-7,706,621, and roscovitine provided single-engine docking leads. These findings prioritize RAE1 for nucleocytoplasmic RNA-transport research and SLC25A46 as a context-dependent mitochondrial-homeostasis candidate. The compound results provide leads for target-binding and cellular functional studies.},
}

*Alzheimer Disease/genetics/metabolism
Humans
*Mitochondria/metabolism/genetics
Homeostasis
Active Transport, Cell Nucleus
*Transcriptome
Gene Expression Profiling

@article {pmid43033470,
year = {2026},
author = {Cheli, VT and Angeliu, CG and Paez, PM},
title = {Mechanisms and Functional Outcomes of Astrocytic Ca[2+] Signaling.},
journal = {ASN neuro},
volume = {18},
number = {1},
pages = {2752345},
doi = {10.1080/17590914.2026.2752345},
pmid = {43033470},
issn = {1759-0914},
mesh = {*Astrocytes/metabolism ; Humans ; Animals ; *Calcium Signaling/physiology ; *Calcium/metabolism ; *Brain/metabolism ; },
abstract = {Astrocytic calcium (Ca[2+]) signaling is a central regulator of brain function, enabling astrocytes to integrate neuronal, vascular, and metabolic information across multiple spatial and temporal scales. Rather than passive support cells, astrocytes generate dynamic Ca[2+] signals ranging from localized microdomain transients in perisynaptic processes to propagating intercellular waves. These signals arise from coordinated activity of plasma membrane channels, ligand-gated and G protein-coupled receptors, and intracellular Ca[2+] handling systems. Through these mechanisms, astrocytic Ca[2+] dynamics regulate essential processes including gliotransmitter release, synaptic modulation and plasticity, neurovascular coupling, and metabolic support. This multiscale signaling framework positions astrocytes as active hubs within the tripartite synapse and neurovascular unit, shaping both local circuit activity and global brain states. Notably, distinct signaling modalities-particularly microdomain events-function as key computational units that enable astrocytes to decode synaptic inputs. Disruption of Ca[2+] homeostasis transforms this system into a driver of pathology. Dysregulated signaling promotes astrogliosis, neuroinflammation, excitotoxicity, and impaired neurovascular and metabolic coupling, and is implicated across disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, stroke, and chronic pain. In this review, we highlight key knowledge gaps, including how microdomain and global Ca[2+] signals are integrated, how Ca[2+] dynamics couple to astrocytic metabolism and gliotransmission, and how these processes are reorganized across physiological and disease states. Addressing these challenges will be essential for deciphering astrocytic signaling logic and identifying precise pharmacological targets.},
}

*Astrocytes/metabolism
Humans
Animals
*Calcium Signaling/physiology
*Calcium/metabolism
*Brain/metabolism

@article {pmid43033473,
year = {2026},
author = {Basha, S and Chattopadhyay, A and Pai, AR and Mahato, KK},
title = {Emerging Insights into Autophagy-Lysosomal Dysfunction in Age-Related Neurodegenerative Disorders.},
journal = {ASN neuro},
volume = {18},
number = {1},
pages = {2759459},
doi = {10.1080/17590914.2026.2759459},
pmid = {43033473},
issn = {1759-0914},
mesh = {Humans ; *Autophagy/physiology ; *Neurodegenerative Diseases/metabolism/pathology/physiopathology ; *Lysosomes/metabolism/pathology ; *Aging/metabolism/pathology ; Animals ; Neurons/metabolism ; },
abstract = {Ageing is associated with changes in autophagic-lysosomal quality control, but these changes are not uniform and do not necessarily indicate reduced autophagy. This narrative review uses a clearance-bottleneck framework to examine how defects in pathway capacity, cargo recognition, autophagosome formation, trafficking, or lysosomal degradation may affect the ageing nervous system. It integrates evidence on lysosomal function and biogenesis, nutrient-sensing and transcriptional regulation, macroautophagy, chaperone-mediated autophagy, protein turnover, and organelle quality control. The review considers how these processes intersect with protein aggregation, mitochondrial dysfunction, synaptic regulation, and inflammatory communication among neurons, microglia, and astrocytes. Findings across Alzheimer's disease and tauopathies, Parkinson's disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington's disease/polyglutamine disorders are compared with attention to cargo, cellular context, model, and evidence from human studies. Methodological limitations are emphasized, particularly the inability of autophagy markers alone to establish completed flux. Therapeutic studies are evaluated separately for rescue, human target engagement, and clinical benefit. Evidence does not establish that precision correction of a defined neuronal autophagy defect improves clinical outcomes. The framework identifies priorities for validating clearance defects and testing interventions.},
}

Humans
*Autophagy/physiology
*Neurodegenerative Diseases/metabolism/pathology/physiopathology
*Lysosomes/metabolism/pathology
*Aging/metabolism/pathology
Animals
Neurons/metabolism

@article {pmid43033633,
year = {2026},
author = {Li, W and Zhou, Q and Li, B and Shi, G and Xin, J and Xie, N and Chen, C},
title = {Structured home-based interventions for people with dementia: A systematic review and meta-analysis.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {75},
number = {},
pages = {104446},
doi = {10.1016/j.gerinurse.2026.104446},
pmid = {43033633},
issn = {1528-3984},
abstract = {BACKGROUND: Dementia is a progressive neurodegenerative disorder causing cognitive decline and behavioral and psychological symptoms (BPSD), burdening patients and caregivers. Pharmacological treatments have limited efficacy and side effects, highlighting the need for non-pharmacological strategies.

AIM: To evaluate the effects of Structured Home-based Interventions on cognitive function and neuropsychiatric symptoms-including overall BPSD, anxiety, and depression-in people with dementia.

METHODS: Following PRISMA, we searched PubMed, Embase, Cochrane Library, Web of Science, and four Chinese databases from inception to October 24, 2025, for randomized controlled trials comparing Structured Home-based Interventions with usual care or wait-list controls. Quality was assessed using RoB 2.0; random-effects meta-analyses used Stata 18.0.

RESULTS: Thirty-five RCTs (N > 5,000) were included. Structured Home-based Interventions improved cognition (SMD = 0.82, 95% CI: 0.54 to 1.10, P < 0.001), with integrated multicomponent and cognitively oriented interventions showing the largest effects. Overall neuropsychiatric symptoms showed a small reduction (SMD = -0.18, 95% CI: -0.34 to -0.01, P < 0.05). Anxiety (SMD = -1.15, 95% CI: -2.29 to -0.01) and depression (SMD = -0.76, 95% CI: -1.40 to -0.12) improved more, but heterogeneity and limited robustness warrant caution.

CONCLUSION: These findings suggest the potential value of Structured Home-based Interventions, especially integrated multicomponent models, and may inform future community dementia services. However, given substantial heterogeneity, limited robustness for some outcomes, and very low certainty of evidence for anxiety and depressive symptoms, broad implementation requires caution, and further validation is warranted. Nurses may play a key role in training family caregivers.

PROSPERO: CRD420251178386.},
}

@article {pmid43033680,
year = {2026},
author = {Joshi, K and Dabhi, R and Joshi, D and Prajapati, O and Pathak, D and Mehta, R and Shah, A and Yadav, R and Thakur, B and Darreh-Shori, T and Vijayvargia, R and Yadav, MR and Murumkar, P},
title = {Design, synthesis and biological evaluation of novel vicinal diarylpyrazole- benzylpiperidine/carbamate hybrids as MAO-B inhibitors.},
journal = {Bioorganic & medicinal chemistry},
volume = {144},
number = {},
pages = {118841},
doi = {10.1016/j.bmc.2026.118841},
pmid = {43033680},
issn = {1464-3391},
abstract = {We report the design, synthesis, and biological evaluation of two distinct series of vicinal diaryl pyrazole-based hybrids incorporating benzylpiperidine (37-67) and carbamate (68-91) moieties as multifunctional agents for Alzheimer's disease. All compounds were evaluated for in vitro monoamine oxidase-B (MAO-B) inhibition, with initial screening at 10 μM showing >90% inhibition for the majority of compounds. Compounds (42 and 90) were identified as potent MAO-B inhibitors, with IC50 values of 109.3 ± 20.78 and 92.86 ± 7.66 nM, respectively. Structure-activity relationship analysis revealed that unsubstituted aryl groups at the C-3,4 positions of the pyrazole core were the most potent, followed by methoxy and chloro substitutions, while bulky substituents reduced potency. Carbamate derivatives (68-91) exhibited improved MAO-B inhibition relative to benzylpiperidine analogues (37-67), with phenyl and benzyl carbamate substitutions being most favorable. The compounds showed moderate acetylcholinesterase (AChE) inhibition, with compounds (83 and 90) displaying 89.5% and 94.7% inhibition at 10 μM, respectively. Compounds (42 and 90) also demonstrated low neurotoxicity in STHdh[Q7/Q7] neuronal cells (MTT assay) and exhibited effective chelation of Zn[2+], Cu[2+], and Fe[2+] ions. Molecular docking studies supported these findings, revealing key interactions within the MAO-B and AChE active sites. These results identify vicinal diaryl pyrazole-based hybrids, particularly compound (90) containing carbamate moiety, as promising multifunctional leads for further development as anti-Alzheimer agents.},
}

@article {pmid43033909,
year = {2026},
author = {Wang, B and Wu, Z and Huang, S and Sio, C and Shen, HM and Chen, Q},
title = {Identification of mitophagy inducers for Alzheimer's disease via high-throughput endogenous ATP5B tagging system.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.11.015},
pmid = {43033909},
issn = {2090-1224},
abstract = {INTRODUCTION: Mitophagy, the selective clearance of defective mitochondria via the autophagy-lysosome pathway, is essential for maintaining mitochondrial health and cellular homeostasis. Dysregulation of mitophagy is strongly implicated in aging-related pathologies, including neurodegenerative diseases (Alzheimer's, Parkinson's), cancer, and metabolic disorders, highlighting the significance of elucidating its regulatory mechanisms. While existing methods using exogenous reporters enable genome-wide and high-throughput screening for mitophagy regulators, they constrain discoveries to specific pathways and introduce artifacts through ectopic expression.

OBJECTIVES: To overcome these limitations, we developed an effective and rapid platform for identifying mitophagy modulators by targeting endogenous proteins.

METHODS: Using CRISPR-Cas9 technology, we engineered HeLa cells expressing small molecular tags (GFP or NanoLuc) fused to the C-terminal of ATP5B, a mitochondrial inner membrane protein. Genome-wide screening for mitophagy regulatory genes were performed using a genome-wide CRISPR library coupled with flow cytometry. Additionally, an FDA-approved kinase inhibitor library was used to screen for mitophagy inducers. To evaluate the efficacy of a screened drug in Alzheimer's disease, cognitive behavior, pathological features and mitophagy events in 3 × Tg-AD mice with or without treatment were examined using the Morris water maze assay, enzyme-linked immunosorbent assay (ELISA) and transmission electron microscopy (TEM).

RESULTS: These ATP5B-tagging cells provided a robust readout of mitophagy and enabled high-throughput genetic or pharmacological screening. With this platform, we identified several promising genes that regulate mitophagy and are significantly associated with Alzheimer's disease. Moreover, the FDA-approved drug Flupentixol emerged as a novel mitophagy inducer that acts by promoting adenosine monophosphate-activated protein kinase (AMPK) localization to mitochondria and exhibited strong therapeutic potential in a model of Alzheimer's disease.

CONCLUSION: This study establishes a novel system for identifying mitophagy modulators, with the potential to accelerate the discovery of therapeutic strategies for Alzheimer's disease.},
}

@article {pmid42996291,
year = {2026},
author = {Badea, A and Xu, J and Laskowitz, DT and Badea, CT},
title = {APOE ε4 Modifies the Association of Left Atrial Remodeling With Brain Aging.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42996291},
support = {RF1 AG057895/AG/NIA NIH HHS/United States ; N01 HC025195/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; R01 CA302738/CA/NCI NIH HHS/United States ; 75N92025D00012/HL/NHLBI NIH HHS/United States ; R01 HL107385/HL/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; R56 AG066184/AG/NIA NIH HHS/United States ; R01 AG066184/AG/NIA NIH HHS/United States ; R01 AG070149/AG/NIA NIH HHS/United States ; U19 AG023122/AG/NIA NIH HHS/United States ; R01 HL179758/HL/NHLBI NIH HHS/United States ; },
abstract = {INTRODUCTION: Whether APOE ε4 modifies relationships between subclinical cardiac phenotypes and brain structure is unknown.

METHODS: In Framingham Heart Study Offspring participants, we related antecedent echocardiographic remodeling (Examinations 4-6) to repeated brain MRI, and cardiac magnetic resonance phenotypes to regional cortical morphometry, testing cardiac × APOE ε4 interactions with false-discovery-rate (FDR) correction and permutation testing of the regional screen.

RESULTS: APOE ε4 modified the association between antecedent left atrial (LA) remodeling and subsequent lateral ventricular expansion (β=-0.00858, P=1.45×10[-4], q=0.0023; N=1,305; 3,787 MRI observations), the only FDR-significant result of 16 longitudinal tests, including with participant-specific MRI-time slopes (q=0.034); it weakened when intracranial volume × MRI time was modeled. Four regional ventricular cardiac × APOE ε4 interactions met within-family FDR criteria, but their number was consistent with chance (permutation P=0.70). Maximum LA volume index showed an APOE ε4-dependent association with left middle-occipital cortical-thickness variability (whole-brain q=0.017; permutation P=0.041) that persisted after ventricular adjustment. Cardiac phenotypes and trajectories showed no FDR-significant APOE ε4-dependent associations with plasma Aβ42/40, p-tau181, GFAP, or NfL, and adjustment for these biomarkers changed the regional interactions by at most 3.2%. Allen Human Brain Atlas data showed cholesterol-biosynthesis enrichment in the right superior frontal cortex, implicated by the LV end-systolic volume interaction, but without convergent pathway evidence.

DISCUSSION: APOE ε4 modified atrial-brain relationships, with the strongest evidence linking antecedent atrial remodeling to later ventricular expansion. Replication with prespecified models is needed.},
}

@article {pmid43020063,
year = {2026},
author = {Daniel, SF and Lee, C and Mollenkopf, T and Lee, M and Arbuckle, J and Fiabane, E and Gabitto, MI and Johansen, N and Kapen, I and Kraft, AW and Lai, HY and Li, SY and McGinty, R and Miller, JA and Welch-Moosman, S and Otto, S and Sawyer, L and Shepard, N and Thompson, CL and Tjärnberg, A and Waters, J and Zhen, X and Macosko, E and Lein, E and Ng, L and Zeng, H and Mufti, S and Yao, Z and Hawrylycz, M},
title = {MapMyCells: High-performance mapping of cell-by-gene data to reference brain taxonomies.},
journal = {Cell reports methods},
volume = {},
number = {},
pages = {101650},
doi = {10.1016/j.crmeth.2026.101650},
pmid = {43020063},
issn = {2667-2375},
abstract = {Single-cell reference mapping is increasingly central to translating heterogeneous datasets into consistent representations of cell identity. As cell-type atlases expand in scale and complexity, mapping new data to shared references enables reproducible annotation, cross-study integration, and accumulation of biological knowledge. We present MapMyCells, an open-source, high-performance framework for mapping diverse single-cell omics datasets to hierarchical reference taxonomies with minimal preprocessing. MapMyCells currently supports six diverse brain references spanning whole mouse and human brain, Alzheimer's disease and aging cohorts, developing mouse cortex, and a cross-species basal ganglia taxonomy. Across these references, MapMyCells accurately recovers cell identities at broad and intermediate taxonomic levels, remains robust with reduced informative gene panels, and supports transcriptomic, epigenomic, and spatial datasets. Benchmarking shows competitive accuracy with substantially lower computational requirements, enabling datasets and taxonomies containing thousands of cell types to be analyzed on standard workstations. MapMyCells provides a scalable framework for unified, extensible brain cell atlases.},
}

@article {pmid43020064,
year = {2026},
author = {Wang, N and Cardenas, C and Nieto-Caballero, VE and Turner, D and Feinberg, H and Yuan, D and Scott, N and DeBerardine, M and Dan, S and Caceres, L and Schembri, J and Chang, WJ and Yao, Z and Lee, C and Pillow, JW and Krienen, FM},
title = {PIANO enables generative modeling of gene expression and scales multi-omics integration to 100 million cells.},
journal = {Cell reports methods},
volume = {},
number = {},
pages = {101661},
doi = {10.1016/j.crmeth.2026.101661},
pmid = {43020064},
issn = {2667-2375},
abstract = {Single-cell RNA technologies enable the routine acquisition of transcriptomic atlases. However, these molecular profiles are influenced by overlapping sources of variation. Since these covariates confound comparisons, data integration is the first step in most analyses. Three challenges remain: correcting strong batch effects, scaling to millions of cells, and modeling how covariates influence gene expression. To address these challenges, we developed PIANO, probabilistic inference autoencoder networks for multi-omics, a deep learning framework whose central feature is a generative model of gene expression data. Additionally, PIANO achieves robust integrations and trains 10× faster than previous methods. PIANO accurately integrates single-cell data across species and across single-cell and spatial transcriptomics modalities. As practical applications, PIANO models spatially resolved gene expression during Alzheimer's disease progression in human brains and integrates over 100 million cancer cells to model drug perturbations. In summary, PIANO's integration and generative modeling capabilities will empower novel insights for a wide range of future studies.},
}

@article {pmid43020165,
year = {2026},
author = {Yan, M and Tian, L and Gao, W},
title = {Modular nanoplatforms for precision diagnosis and therapy of Alzheimer's disease.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {},
number = {},
pages = {103047},
doi = {10.1016/j.nano.2026.103047},
pmid = {43020165},
issn = {1549-9642},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder whose pathological heterogeneity and restrictive blood-brain barrier (BBB) limit conventional diagnosis and therapy. This review presents a pathology- and function-oriented framework for modular AD nanotheranostics, linking key biomarkers and pathological processes to molecular recognition, brain delivery, therapeutic intervention, responsive release, and treatment monitoring. Major BBB-crossing strategies are critically evaluated, emphasizing the distinction between endothelial uptake and genuine brain-parenchymal delivery. Closed-loop nanoplatforms are organized into sensing, BBB-crossing, lesion-targeting, therapeutic, stimuli-responsive, imaging/monitoring, and feedback-adjustment modules, with representative material systems compared according to these functions. Most current platforms remain monitoring-enabled theranostic systems rather than true closed-loop systems. Clinical translation will require simplified biodegradable designs, rigorous verification of parenchymal delivery, standardized manufacturing, long-term safety evaluation, biomarker-guided patient selection, and predefined feedback rules linking treatment response to therapeutic adjustment.},
}

@article {pmid43020291,
year = {2026},
author = {Anbar, HS and Lozon, Y and Khodr, V and Jabr, R and Elnazier, M and Zarzour, T and Nasir, R and Ahmed, S and Malahifci, R and El Gamal, MI and Abdullatif, M and Ahmed, M and Dohle, W and Potter, BVL and Hassan, HM},
title = {Irosustat and STX140 improve cognitive function and modulate amyloid, oxidative stress, and inflammatory pathways in experimental Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118618},
doi = {10.1016/j.bcp.2026.118618},
pmid = {43020291},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is currently the most prevalent neurodegenerative disorder affecting the geriatric population. The pathology of AD has been described as neuronal loss caused by the accumulation of beta-amyloid plaques and the formation of neurofibrillary tangles resulting from tau protein phosphorylation. This study aimed to investigate the therapeutic potential of steroid sulfatase inhibition using two drugs, the clinical steroid sulfatase inhibitor Irosustat and the multi-targeting preclinical candidate STX140, in scopolamine-induced AD in male Wistar rats compared to Donepezil as a standard drug. Behavioral tests such as the Open Field Test, Elevated Plus Maze Test, and Morris Water Maze Test were conducted to confirm the disease state and assess any improvement. At the end of the study, the animals were dissected to collect blood and brain samples for morphological, histological, immunohistochemical, biochemical, quantitative polymerase chain reaction and western blotting analyses. Treatment with Irosustat or STX140 improved learning, memory, and cognitive function compared with the disease group. The treated groups showed lowered brain tissue Aβ-40 & 42 levels, acetylcholinesterase activity, oxidative stress, and inflammatory markers. Morphological assessments showed that the drugs protected against brain atrophy and neuronal loss. Irosustat and STX140 are therefore promising therapeutic candidates for the management of Alzheimer's Disease.},
}

@article {pmid43020849,
year = {2026},
author = {Lee, J and Nichols, E and Adar, SD and Knapp, D and Atshan, S and Avendano, M and Bindas, A and Brauer, M and Brook, JR and Chang, HH and Chiang, YY and Choi, H and Doiron, D and Flood, S and Fransz-Myers, MM and Gross, AL and Hayes-Larson, E and Claus Henn, B and Hicken, M and Keller, KP and Kezios, KL and Kieny, C and Lane, KJ and Luben, TJ and Meijer, E and Narayanan, S and Shih, RA and Szpiro, AA and Thorpe, LE and Van Riper, D and Weerman, B and Weiss, J and Wellenius, GA and Weuve, J},
title = {Understanding the exposome across the life course to promote healthy aging: consensus recommendations from the Gateway Exposome Coordinating Center.},
journal = {Nature aging},
volume = {6},
number = {11},
pages = {2379-2392},
pmid = {43020849},
issn = {2662-8465},
support = {U24AG088894//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {Humans ; Aging ; Consensus ; *Environmental Exposure ; *Exposome ; *Healthy Aging ; },
abstract = {Healthy aging is shaped by the exposome-the accumulation of exposures experienced across the life course arising from intersections of the natural, physical, social, community and policy environments in which people age. This Consensus Statement reports recommendations from the Gateway Exposome Coordinating Center to accelerate life-course research on the exposome's impacts on healthy aging, including Alzheimer's disease and related dementias. Recommendations centered on five themes are presented: the promotion of interdisciplinary collaboration; the integration of life-course perspectives on the timing, accumulation and sequencing of exposures; systematically quantifying and incorporating broader contexts of time and place into health research; the adoption of mechanistic thinking to develop pathway-relevant exposure metrics; and leveraging new data streams, including wearable sensors, administrative records and remote sensing, to improve exposure measurement. These priorities emphasize harmonized measures, transparent methods and attention to bias, with the goal of identifying actionable intervention and policy targets across diverse populations that can shape individuals' exposures, lived experiences, behaviors and, ultimately, health as they age.},
}

Humans
Aging
Consensus
*Environmental Exposure
*Exposome
*Healthy Aging

@article {pmid43021327,
year = {2026},
author = {Son, HJ and Lee, NH and Kim, H and Myeong, SH and Kang, JH and Lee, NK and Lee, SY and Jang, H and Seo, SW and Chang, JW and Na, DL and Kim, HJ},
title = {Ethionamide preconditioning enhances the therapeutic efficacy of human mesenchymal stromal cells in an Alzheimer's disease model.},
journal = {Stem cell research & therapy},
volume = {17},
number = {1},
pages = {},
pmid = {43021327},
issn = {1757-6512},
support = {RS-2026-25485281//National Research Foundation of Korea (NRF)/ ; SMX1250981, SMO1264024//Samsung Medical Center/ ; RS-2022-KH127216//the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare/ ; },
mesh = {*Alzheimer Disease/therapy/pathology/metabolism ; Animals ; Humans ; *Mesenchymal Stem Cells/drug effects/metabolism/cytology ; *Mesenchymal Stem Cell Transplantation/methods ; Disease Models, Animal ; Mice ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Microglia/metabolism/drug effects/pathology ; },
abstract = {BACKGROUND: Mesenchymal stromal cells (MSCs) are promising therapeutic candidates for neurodegenerative diseases, including Alzheimer's disease (AD). However, their limited survival and functionality in pathological environments hinder their therapeutic efficacy. The primary objective of this study was to evaluate the therapeutic efficacy of ethionamide (ETH)-preconditioned MSCs (ETH-MSCs) in mitigating AD pathology.

METHODS: Wharton's jelly-derived MSCs (WJ-MSCs) were preconditioned with ethionamide, and their therapeutic efficacy was evaluated in both in vitro and in vivo AD models. In vitro, ETH-MSCs were assessed for their ability to modulate microglial inflammation and promote amyloid-β (Aβ) clearance under AD-like conditions. For in vivo studies, ETH-MSCs were injected into the lateral ventricles of 5xFAD transgenic mice. The effects of ETH-MSC administration on glial activation (GFAP and Iba1 expression) and Aβ deposition were evaluated.

RESULTS: In vitro, ETH-MSCs reduced pro-inflammatory cytokine secretion by microglia and enhanced Aβ clearance in neurons. In vivo, ETH-MSCs treatment significantly decreased GFAP and Iba1 expression, indicating reduced astroglial and microglial activation, and reduced amyloid plaque burden in 5xFAD mice. Repeated ETH-MSCs injections further boosted Aβ clearance, demonstrating a cumulative therapeutic benefit.

CONCLUSIONS: Ethionamide preconditioning significantly enhances the neuroprotective and amyloid-clearing capabilities of WJ-MSCs. These findings suggest the potential of ETH-MSCs as an effective therapeutic strategy for AD, with superior efficacy compared to naïve MSCs in both in vitro and in vivo models.},
}

*Alzheimer Disease/therapy/pathology/metabolism
Animals
Humans
*Mesenchymal Stem Cells/drug effects/metabolism/cytology
*Mesenchymal Stem Cell Transplantation/methods
Disease Models, Animal
Mice
Amyloid beta-Peptides/metabolism
Mice, Transgenic
Microglia/metabolism/drug effects/pathology

@article {pmid43021380,
year = {2026},
author = {Zattoni, M and Aigner, L},
title = {Disentangling the role of adaptive immunity in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {43021380},
issn = {1750-1326},
mesh = {*Alzheimer Disease/immunology ; Humans ; *Adaptive Immunity/immunology ; Animals ; Immunity, Innate ; },
abstract = {Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by progressive synaptic and neuronal loss, amyloid-β deposition, hyperphosphorylated tau accumulation, and chronic neuroinflammation, traditionally attributed primarily to the innate immune system. Increasing evidence, however, implicates the adaptive immune system as an active contributor to AD pathogenesis and progression. This emerging perspective has stimulated the development of immunomodulatory strategies aimed at mitigating cognitive decline and neuropathological hallmarks of the disease. In this review, we examine how adaptive immune responses change throughout the course of AD, integrating findings from both human studies and animal models while emphasizing the temporal dynamics of these alterations. We critically evaluate areas of consensus and controversy in the field, highlighting how differences in experimental models, disease stages, and methodological approaches contribute to divergent findings. Finally, we assess current therapeutic strategies targeting adaptive immunity, discussing their potential mechanisms of action and identifying key therapeutic windows and routes of administration that may maximize efficacy. By providing a comprehensive overview of adaptive immune involvement in AD, this review aims to inform the development of more precise and effective immunomodulatory interventions.},
}

*Alzheimer Disease/immunology
Humans
*Adaptive Immunity/immunology
Animals
Immunity, Innate

@article {pmid43021430,
year = {2026},
author = {Lees, AJ},
title = {Love in the time of Alzheimer: Gabriel García Márquez's pact with solitude.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag402},
pmid = {43021430},
issn = {1460-2156},
}

@article {pmid43021519,
year = {2026},
author = {Triposkiadis, F and Xanthopoulos, A},
title = {EXPRESS: The Medin-Aorta-Brain Axis: Linking Vascular Aging to Alzheimer's Disease.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261508312},
doi = {10.1177/0271678X261508312},
pmid = {43021519},
issn = {1559-7016},
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of cerebral amyloid-β (Aβ). Medin amyloid is present in the aging aorta and has been linked to cerebrovascular dysfunction. We hypothesize that medin contributes to AD pathogenesis through a systemic aorta-brain axis. Aortic medin may promote aortic stiffening, thereby increasing cerebral pulsatile load and impairing perivascular clearance. Furthermore, cerebral medin co-localizes with Aβ, exacerbating neurovascular injury. This hypothesis requires validation. We outline falsifiable predictions, a staged biomarker framework, and the interpretation of circulating medin levels. Medin targeting may be a strategy to maintain vascular compliance and reduce Aβ aggregation, pending safety studies.},
}

@article {pmid43021531,
year = {2026},
author = {Verma, A and Kundu, S and Jaiswal, S and Khanna, P},
title = {Vegetarian dietary patterns are not associated with lower odds of noncommunicable diseases among patients presenting to a tertiary care center in North India: a cross-sectional survey.},
journal = {Clinical nutrition research},
volume = {15},
number = {4},
pages = {253-260},
doi = {10.7762/cnr.2025.0010},
pmid = {43021531},
issn = {2287-3732},
abstract = {OBJECTIVE: Noncommunicable diseases (NCDs) present a huge global burden, accounting for approximately 7.3 trillion cases and 43.8 million deaths in 2021. In India, 68% of all deaths are caused by NCDs. Carbohydrate intake has been associated with NCD development. Standard Indian diets mainly comprise carbohydrates. In this study, we aimed to analyze the association of vegetarian versus omnivorous diets with the odds of developing NCDs in patients visiting the emergency department.

METHODS: Over 18 months, a cross-sectional epidemiological survey-based study was conducted among patients aged >18 years presenting to our department with documented comorbid conditions (e.g., diabetes mellitus [DM], hypertension, heart disease, hypothyroidism, Alzheimer disease, and cancer). These patients completed a 32-item questionnaire survey regarding dietary and lifestyle choices. Associations between comorbidity status and dietary variables were evaluated by bivariate analysis. Additionally, unadjusted odds ratio (OR) and adjusted OR for DM, hypertension, and heart disease were calculated.

RESULTS: This study included 11,011 patients, of which 55.31% were males and 68.91% were >55 years old. Furthermore, 65.87% were vegetarians, whereas 28.97% were omnivores. Hypertension, DM, and heart disease were found in 62.6%, 49.9% and 26.0%, respectively, while 58% had combinations of NCDs. Adjusted for age, sex, smoking, sugar, alcohol, exercise, and packaged food, OR (omnivore vs. vegetarian) was 0.94 (95% confidence interval [CI], 0.86-1.03; P=0.180), 0.91 (95% CI, 0.83-1.00; P=0.052) and 1.02 (95% CI, 0.92-1.13; P=0.690) for DM, hypertension, and heart disease, respectively.

CONCLUSION: Most patients with NCDs followed a vegetarian dietary pattern, which was not associated with lower odds of developing NCDs.},
}

@article {pmid43021542,
year = {2026},
author = {Makarios, SN and Shukla, R and Yadav, H and Jain, S},
title = {Periodontitis as a Modifiable Risk Factor for Dementia: Mechanistic Pathways Linking Oral Inflammation to Neurodegeneration.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-8},
doi = {10.1017/cjn.2026.10704},
pmid = {43021542},
issn = {0317-1671},
abstract = {Emerging evidence increasingly implicates chronic periodontal disease as a contributor to age-related cognitive decline and dementia, including Alzheimer's disease (AD). Periodontitis is defined by persistent oral microbial dysbiosis, ulcerated gingival epithelium, repeated bacteremia and sustained systemic inflammatory signaling - factors that plausibly influence neuroimmune pathways and cerebrovascular integrity. This review synthesizes findings from epidemiological studies, systematic reviews, mechanistic analyses and experimental models to examine the biological links between oral inflammation and neurodegeneration. Collectively, the literature suggests a stepwise oral-brain axis: first gingival inflammation promotes local and systemic pro-inflammatory cytokine release, second repeated bacteremia allows oral pathogens and microbial byproducts to enter circulation, third these signals and agents access and compromise the blood-brain barrier, then fourth microglia in the brain become primed and hyper-reactive and at last enhanced neuroinflammation accelerates amyloid-β and tau pathology. Although causal inference remains limited by the predominance of observational data, emerging intervention studies and mechanistic evidence suggest that periodontal health is a potentially modifiable factor in dementia prevention strategies.},
}

@article {pmid43021763,
year = {2026},
author = {Sun, YZ and Yi, Y and He, Y and Chen, DD and Liu, MX and Zhang, XL},
title = {Dual Roles of Cathepsins in Neuroinflammation: From Pathogenic Mediators to Therapeutic Targets in Neurological Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X505934261026094642},
pmid = {43021763},
issn = {1875-6190},
abstract = {Neurological diseases are a series of disorders that affect the brain, spinal cord, and peripheral nervous system, posing a significant threat to human health. Persistent neuroinflammation is a critical factor in the occurrence of neurological diseases, although the underlying mechanisms are highly complex. Recent evidence increasingly demonstrates that cathepsins play an important role in the initiation and progression of neuroinflammation. Significant alterations in the expression, activity, and intracellular localization of cathepsins occur during the pathogenesis of neurological disorders. Therefore, the pathophysiological roles of cathepsins have attracted considerable attention in neuroscientific research. This review provides a critical overview of current knowledge on cathepsins in neurological diseases, with particular attention to their roles in neuroinflammation. Besides, this review highlights the interplay between cathepsins and key neural cells in the nervous system (including microglia, astrocytes, oligodendrocytes, and neurons) as well as signaling molecules as a mechanistic framework. This study elucidates the mechanism of cathepsin-mediated neuroinflammation and details their roles in different types of neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury, and multiple sclerosis (MS). Although treatments are available for some neurological disorders, this review will examine cathepsin-mediated neuroinflammation in depth to assess its potential as a clinically significant therapeutic target.},
}

@article {pmid43021770,
year = {2026},
author = {Jiang, P and Guo, X and Wang, L and Huang, W and Xie, H and Gao, X},
title = {Under-recognized Autoimmune Encephalitis in Patients with Alzheimer's Disease: A Case Series Emphasizing EEG Screening.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050509968261027101230},
pmid = {43021770},
issn = {1875-5828},
abstract = {INTRODUCTION: AD and AE present overlapping cognitive decline, often causing misdiagnosis and delayed immunotherapy. AD has an insidious onset and slow progression with typical Aβ and tau abnormalities, while AE manifests subacute neuropsychiatric symptoms and inflammatory imaging or CSF changes. Rapid cognitive decline in AD patients with superimposed AE is easily misdiagnosed as simple neurodegeneration. EEG is a convenient non-invasive test that can serve as a screening tool to trigger further autoimmune evaluation in AD patients with unexplained rapid deterioration. This case series reports two verified AD patients complicated with anti-LGI1 encephalitis and probable seronegative AE. It adds to the literature on the pathological coexistence and interaction of AD and AE, highlights the underutilized diagnostic value of EEG, and supports routine EEG screening for rapidly progressive AD cognitive decline.

CASE PRESENTATION: Two biomarker-confirmed AD female patients with comorbid AE were included. The 75-year-old patient had 4 years of cognitive decline (baseline MMSE=10), with typical AD imaging and biomarker abnormalities, positive anti-LGI1 IgG and abnormal EEG, diagnosed with AD combined with LGI1 encephalitis. She received IVIg, rituximab, anti-amyloid and anti-dementia treatment. MMSE improved from 10 to 18 at 1 month but fluctuated thereafter (MMSE 11-12, MoCA 3-9) with treatment pause and irregular adherence; serum LGI1 antibody and AD biomarkers remained normal throughout. The 62-year-old patient had 7 years of cognitive decline, personality changes, and hallucinations (MMSE=0, MoCA=0). She was diagnosed with probable seronegative AE complicated with AD based on AD imaging changes, positive CSF indicators, and positive TBA findings. Treatment with telitacicept and lecanemab was associated with modest cognitive improvement (MMSE +3, MoCA +2) at short-term follow-up.

CONCLUSION: Rapid cognitive exacerbation in AD patients should not be attributed to natural neurodegeneration. Routine EEG is an essential noninvasive tool for cognitive evaluation in AD. EEG abnormalities in AD patients require comprehensive autoimmune examinations. Concurrent AE is a reversible and treatable factor worsening AD cognitive impairment. Combined immunotherapy and anti-amyloid treatment can significantly improve patient cognition and biomarkers. EEG should be a routine screening item for rapidly progressive AD. Autoimmune inflammation may accelerate AD progression, providing new insights for AD immunological pathogenesis and targeted therapy research.},
}

@article {pmid43021771,
year = {2026},
author = {Akter, H and Siddique, MAB and Tufael, and Debnath, A and Debnath, N},
title = {Impact of Nursing Interventions on Cognitive Decline and Quality of Life in Alzheimer's Disease: A Comprehensive Mini-Review.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050514304261027040607},
pmid = {43021771},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive worsening with severe cognitive impairment and poor quality of life. The nursing interventions of cognitive stimulation, medication management, and holistic care are significant for cognitive outcomes and the emotional well-being of AD patients. The purpose of this mini-review is to determine the efficacy of nursing interventions in slowing cognitive decline and improving quality of life experienced by people with Alzheimer's. An extensive literature search was carried out, including works that affected cognitive functioning, psychological well-being, and life satisfaction as a whole. Cognitive stimulation therapy (CST), medication adherence, and family-centered care were key interventions that were shown to have a significant effect on cognitive performance, helping decrease neuropsychiatric symptoms (anxiety and depression) and encouraging social interaction and independence. The results presented in the evidence indicate that holistic models of care that incorporate emotional and social support are highly effective in improving patients' cognitive and psychological health. Nevertheless, resource shortages, staff training, and caregiver burnout continue to be serious impediments to the successful implementation of these interventions. Nursing interventions play a critical role in enhancing cognitive and emotional health among AD patients. These interventions should be refined, and their benefits and long-term effects studied to inform best practices in AD care in future research.},
}

@article {pmid43021956,
year = {2026},
author = {Zhang, X and Wu, Y and Han, J and Zhao, Z and Yao, Y and Sun, Y and Wang, X},
title = {Recent advances in the pharmacological effects and mechanisms of borneol and borneol-containing formulations in central nervous system diseases.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1950139},
pmid = {43021956},
issn = {1663-9812},
abstract = {Borneol is an aromatic medicinal agent widely used in traditional Chinese medicine, both as a standalone component and as an ingredient in multi-herb formulations. Its pharmacological relevance to central nervous system (CNS) disorders has attracted increasing attention, particularly in Alzheimer's disease, Parkinson's disease, epilepsy, ischemic stroke, and glioma. Accumulating evidence indicates that borneol may influence multiple pathophysiological processes, including brain-barrier function and drug delivery, neuroinflammation and oxidative stress, neurotransmitter homeostasis and neuronal excitability, cellular injury and death, and the clearance of pathological substances and post-injury repair. Here, we integrate and compare these mechanisms across disease contexts. Notably, although several actions of borneol appear to converge across CNS disorders, others are strongly disease- and context-dependent; for example, its effects on brain-barrier permeability, oxidative stress, and cell death may differ in direction according to disease pathology and therapeutic intent. Pharmacokinetic studies support measurable brain exposure to borneol, yet direct comparative evidence of pharmacological activity, brain disposition, and human pharmacokinetics among borneol preparations of different botanical origins and stereochemical configurations remains scarce. Borneol-containing formulations also exhibit multi-level pharmacological effects; however, because most studies lack borneol-alone, borneol-depleted, or add-back controls, these effects cannot be unequivocally attributed to borneol itself. Overall, the current evidence base remains dominated by cellular and animal studies, with several proposed mechanisms inferred primarily from changes in molecular expression or computational predictions. Robust causal validation, high-quality clinical evidence, and long-term safety data are still limited. Future studies should therefore define the dose-exposure-response relationships and disease-specific therapeutic windows of different borneol preparations, establish the independent contribution of borneol within complex formulations, and determine its genuine therapeutic value and long-term safety through rigorous mechanistic and clinical investigation.},
}

@article {pmid43021970,
year = {2026},
author = {Gau, SY and Lo, SW and Hsu, C and Tu, YF and Su, YJ and Chen, CC and Wu, MC and Mitsukura, Y and Chang, HC},
title = {PCSK9 inhibitor use and risk of dementia and neurodegenerative diseases in adults aged 50 Years and older: a global electronic health record study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1942691},
pmid = {43021970},
issn = {1663-9812},
abstract = {BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors achieve profound lipid lowering, yet their long-term neurocognitive effects remain uncertain. Evidence from randomized trials is limited by short follow-up and lack of dedicated neurodegenerative endpoints.

METHODS: We performed a retrospective target trial emulation using the TriNetX Global Collaborative Network. Adults aged ≥50 years with hyperlipidemia initiating PCSK9 inhibitors or comparator lipid-lowering therapies between 2015 and 2024 were included. Active-comparator cohorts were constructed against statins, ezetimibe, and fenofibrate or cholestyramine with mutual exclusion of prior exposure. Propensity score matching at a 1:1 ratio balanced demographics, body mass index, socioeconomic indicators, healthcare utilization, and cardiometabolic comorbidities. Outcomes included incident all-cause dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, and other neurodegenerative disorders. Sensitivity analyses incorporated lag periods, varying follow-up durations, alternative matching strategies, and intention-to-treat analyses. Cross-dataset validation was additionally conducted using the US Collaborative Network to assess reproducibility under independent data settings. Hazard ratio along with 95% confidence interval were evaluated in each analysis.

RESULTS: Among 31,604 matched PCSK9 inhibitor-statin pairs, PCSK9 inhibitor use was associated with lower risks of all-cause dementia (HR 0.454; 95% CI 0.394-0.522), Alzheimer's disease (HR 0.553; 95% CI 0.433-0.705), vascular dementia (HR 0.536; 95% CI 0.402-0.714), Parkinson's disease (HR 0.686; 95% CI 0.544-0.865), and other neurodegenerative disorders (HR 0.730; 95% CI 0.645-0.825). Results were consistent across comparator therapies, cross-dataset validation and sensitivity analyses.

CONCLUSION: PCSK9 inhibitor use was associated with lower observed risks of neurodegenerative outcomes across multiple analyses and datasets. These findings support a potential association but do not establish causality and require confirmation in prospective trials.},
}

@article {pmid43022016,
year = {2026},
author = {Bednorz, A and Religa, D},
title = {Sex-specific personality metatrait profiles and their associations with APOE, PICALM variants, and cognitive performance in healthy middle-aged adults: a cluster-based analysis.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1933176},
pmid = {43022016},
issn = {2673-6217},
abstract = {INTRODUCTION: APOE ε4 is the strongest common genetic risk factor for late-onset Alzheimer's disease, while PICALM rs3851179 has been associated with amyloid-β clearance. Personality can be summarized into two higher-order metatraits: Stability, reflecting emotional and behavioral regulation, and Plasticity, reflecting cognitive flexibility. This study examined whether genetic associations with episodic memory and fluid intelligence differ across Stability-Plasticity personality clusters in cognitively healthy middle-aged adults.

MATERIAL AND METHODS: The sample comprised 192 participants. NEO-FFI personality traits were standardized to derive the metatraits Stability and Plasticity. Sex-stratified agglomerative hierarchical clustering (Ward's linkage) identified two personality profiles characterized by relatively higher or lower levels of both metatraits. Cognitive outcomes included the California Verbal Learning Test (CVLT) and Raven's Progressive Matrices (RPM). Sex-stratified regression models examined associations between APOE ε4 carrier status, PICALM rs3851179 GG genotype, age, education, and cognitive performance.

RESULTS: After false discovery rate correction, significant associations were observed only in females. In the low Stability-low Plasticity cluster, the APOE × age interaction was negatively associated with CVLT Recognition performance (pFDR = 0.019; R[2] = 0.254). In the high Stability-high Plasticity cluster, models incorporating APOE and/or PICALM status were significantly associated with CVLT Recognition performance (R[2] = 0.583-0.619, pFDR = 0.010-0.019). For fluid intelligence, significant negative APOE × age and APOE × age × education interactions, as well as a negative APOE × PICALM × age interaction, were observed in the respective models (R[2] = 0.553-0.696, pFDR = 0.001-0.019).

CONCLUSION: Personality metatraits were associated with variability in APOE-related cognitive outcomes, particularly among females. These findings suggest that personality structure can contribute to individual differences in cognitive aging pathways associated with genetic risk. However, the results should be interpreted considering the cross-sectional design and limited sample size.},
}

@article {pmid43022197,
year = {2026},
author = {Khan, SH and Iqbal, R and Alqahtani, S and Shan, RU and Alhefdhi, A and Alkhamees, B and Gasmi, K and Ali, A},
title = {Efficient neuroanalytic local-global learning with dual-branch CNN-lightweight Swin Transformer for Alzheimer's disease analysis.},
journal = {Frontiers in computational neuroscience},
volume = {20},
number = {},
pages = {1972923},
pmid = {43022197},
issn = {1662-5188},
abstract = {Alzheimer's disease (AD) is one of the main causes of dementia, where early detection is critical for postponing the progression of the disease and timely treatment. Recent computer-aided diagnosis using deep learning with structural MRI has shown optimal performance; however, the rising number of model parameters and high computational requirements make the deployment challenging in resource-limited environments. This study proposes an efficient deep learning framework named "NeuroCST" based on a dual-branch network architecture incorporating an enhanced EfficientNet-based CNN and a Lightweight Swin Transformer working independently to capture local and global information of AD. The enhanced Efficient Convolution branch extracts fine-grained morphological features using depthwise separable convolution and residual learning for texture capturing. Consequently, the customized SwinLite Transformer branch models global contextual dependencies using Efficient SwinLite Transformer blocks with attention, shifted-window partitioning, and MLP. These dual-branch diverse feature vectors are then concatenated and processed by a spatial attention mechanism, NeuroCST-SA, for optimal pixel selection to reduce redundancy and discriminate minor contrast and texture inter-class variation. The proposed NeuroCST is evaluated on the public Kaggle AD dataset, which contains 6,400 original and 33,984 augmented MRI images (40,384 in total) in four classes: Mild Demented, Moderate Demented, Non-Demented, and Very Mild Demented. The NeuroCST-SA performs better on diverse experimental setups, both augmented and original, than existing CNNs and ViTs, achieving 98.42% accuracy, 98.50% sensitivity, 98.60% precision, and an F1-score of 98.55% (mean, with a standard deviation of 2.49% across holdout cross-validation). The base NeuroCST model has 15.3 million parameters and 5.2 GFLOPs, and the NeuroCST-SA variant has 14.8 million parameters, 4.9 GFLOPs, and a processing time of 11.4 ms per image. The performance demonstrates the effective integration of CNN and transformer in capturing diverse local-global features for robust AD classification.},
}

@article {pmid43022201,
year = {2026},
author = {Singaravel, V},
title = {Optogenetics in neurobiology and neurodegenerative disorders: from neural circuit mechanisms to precision neuromodulation.},
journal = {Frontiers in medical technology},
volume = {8},
number = {},
pages = {1958917},
pmid = {43022201},
issn = {2673-3129},
abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and stroke, are characterized by progressive neuronal dysfunction, synaptic impairment and neural circuit degeneration, leading to severe cognitive and motor deficits. Although considerable progress has been made in understanding their molecular pathology, the circuit level mechanisms driving disease onset and progression remain incompletely understood. Optogenetics, which combines microbial opsins, genetic engineering and optical stimulation, enables reversible, cell-specific control of neuronal activity with millisecond precision and has transformed neuroscience from observational analysis to causal investigation of neural circuits. This review summarizes recent advances in the molecular basis of optogenetics, microbial opsins, gene delivery strategies and optical stimulation technologies, together with their applications in basic neurobiology and neurodegenerative disease research. We discuss how optogenetics has advanced understanding of neural circuit organization, synaptic plasticity, memory, neurodevelopment, sleep regulation, protein aggregation, synaptic dysfunction, neuroinflammation, mitochondrial impairment, oxidative stress and regulated cell death. Although these studies have generated important mechanistic insights and demonstrated functional improvements in experimental models, translation into human therapies remains investigational due to challenges associated with gene delivery, long-term opsin expression, immune compatibility and optical accessibility. Emerging therapeutic strategies, including closed-loop neuromodulation, wireless photostimulation, artificial intelligence-assisted neural decoding, nanotechnology enabled light delivery and brain computer interfaces, are critically evaluated with emphasis on their current evidence status, translational challenges and limitations for clinical implementation. Collectively, optogenetics provides an unprecedented platform for deciphering disease mechanisms and evaluating circuit-based neuromodulation strategies, while continued technological and biological validation will determine its future role in precision therapies for neurodegenerative disorders.},
}

@article {pmid43022223,
year = {2026},
author = {Liu, W and Xu, B and Yang, C and Li, G and Yang, X},
title = {Xanthohumol promotes cognitive function-associated neuroprotein changes in two mouse models of Alzheimer's disease.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {1113-1121},
pmid = {43022223},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that progressively impairs cognitive function for which there is no effective treatment. Natural dietary compounds such as xanthohumol (Xn) potentially offer a new therapeutic approach in AD. We aim to employ quantitative proteomic techniques to investigate the effects of Xn on cognitive impairment in two established murine models of AD. Treatment with 0.5 mg/kg Xn significantly improved the ability of stimulating learning and memory and cognitive function of 3 ×Tg AD mice while 5 mg/kg Xn ameliorated cognitive decline in APP/PS1 mice. We identified two common differential proteins and 12 pathways in the hippocampi of 3 ×Tg AD mice and 70 common differential proteins and 22 pathways in APP/PS1 mice. Moreover, Nine common signaling pathways mainly involved in energy metabolism, neurodegenerative disease, cardiovascular disease and cancer. So multi high-throughput proteomic analyses of hippocampus add to the scientific basis for development of effective drugs for AD, one candidate of which is Xn.},
}

@article {pmid43022324,
year = {2026},
author = {Bayram, E and Carter, DJ and Litvan, I},
title = {Sex differences in clinical profile across Lewy body disease pathology stages.},
journal = {Aging brain},
volume = {10},
number = {},
pages = {100175},
pmid = {43022324},
issn = {2589-9589},
abstract = {BACKGROUND: Sex impacts clinical profile for people with limbic, neocortical LB pathology, and AD pathology contributes to heterogeneity. Amygdala, olfactory, and brainstem LB can also underlie LB disease and sex differences for these pathology stages are unclear.

METHODS: Data were obtained from National Alzheimer's Coordinating Center for 198 females and 314 males with LB pathology and available data on AD pathology staging. Main and interaction effects of sex and LB pathology group for clinical diagnosis, cognitive, behavioral, and motor outcomes were assessed with logistic and linear regression models, with and without AD pathology staging as a covariate. Sex differences within individual LB pathology groups were also assessed.

RESULTS: Females were less likely to have spouses/partners as informants, had less advanced LB pathology stage, and more advanced ADNC stage. Females were less likely to have RBD and a clinical diagnosis of LB dementia, including after adjustment for AD pathology stage. Advancing LB pathology was associated with a greater reduction in the likelihood of clinical AD diagnosis and a greater increase in the likelihood of auditory hallucinations in males than females, after adjustment for AD pathology stage. Females with neocortical LB pathology were less likely than males to have RBD.

CONCLUSIONS: Lower likelihood of RBD in females was particularly evident at the neocortical LB pathology stage. Clinical correlates of LB pathology may differ by sex, and these sex differences may not be fully explained by AD co-pathology. Considering sex and co-pathology is important for both diagnostic and therapeutic approaches to LB disease.},
}

@article {pmid43022368,
year = {2026},
author = {Taouili, R and Lefebvre, C and Oosterlynck, M and Bouillet, T and Eddarkaoui, S and Musiol, D and Formentin, C and Accart, B and Maurage, CA and Colin, M and Buée, L and Halliez, S},
title = {Deciphering early tau pathology events using an Alzheimer's disease-seeded organotypic hippocampal slice culture model.},
journal = {iScience},
volume = {29},
number = {11},
pages = {118083},
pmid = {43022368},
issn = {2589-0042},
abstract = {In Alzheimer's disease, the spreading of the tau pathology through the brain is assumed to rely on pathological species of tau acting as seeds. To better understand the underlying mechanisms, we need models allowing us to study tau seeding in a brain-like environment. We developed an ex vivo model based on organotypic hippocampal slice cultures prepared from transgenic mouse pups expressing human pro-aggregative mutant tau. We show for the first time that human brain-derived tau seeds are able to potentiate tau pathology in such cultures. Moreover, tau seeds are generated ex vivo, completing the validation of the model. Then, we shed light on the initial events of tau seeding: tau pathology appears sequentially, first in neurites and then in cell bodies, and misfolding (MC1+) precedes pathological phosphorylation (pS422, pT217). Altogether, this makes the present model a highly valuable bioassay to decipher the molecular and cellular mechanisms leading to tau pathology development.},
}

@article {pmid43022413,
year = {2026},
author = {Shan, Q and Li, J and Wang, Y and Gupta, S and Song, L and Zhang, W and Su, F and Guo, Y},
title = {Brain-computer interfaces for neurodegenerative diseases: A comprehensive review of closed-loop systems from diagnosis to neural rehabilitation.},
journal = {iScience},
volume = {29},
number = {11},
pages = {118073},
pmid = {43022413},
issn = {2589-0042},
abstract = {Brain-computer interface (BCI) technology serves as an important bridge between the nervous system and external devices and has shown considerable promise for the diagnosis and treatment of neurodegenerative diseases, whose global burden continues to increase: in 2021, more than 57 million people were living with dementia worldwide, with Alzheimer's disease (AD) accounting for approximately 60-70% of cases, while an estimated 11.77 million people were living with Parkinson's disease (PD) in 2021, according to the Global Burden of Disease Study 2021. This growing disease burden, together with the progressive loss of cognitive, motor, and communicative functions, highlights the need for more precise approaches to early detection, functional assistance, and individualized intervention. Conventional diagnostic and therapeutic approaches remain poorly suited to early detection and timely intervention. This paper analyzes the development of BCI technology, from the first detection of electroencephalogram (EEG) signals to the parallel development of invasive and non-invasive systems, and outlines the basic principles of signal acquisition, processing, and decoding, together with the relative advantages and limitations of different approaches. It then focuses on the use of BCI in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), covering early diagnosis, functional reconstruction, and neuromodulation. The article also discusses the difficulties encountered by BCI technology in terms of technological realization, clinical translation, and ethical considerations, as well as several future research directions, including multimodal fusion, adaptive algorithms, closed-loop control systems, and personalized treatment so as to drive the applications of BCI in precision medicine and in neurological diseases.},
}

@article {pmid43022451,
year = {2026},
author = {Ma, T and Li, Y and Ding, Y and Liu, S and Gao, C and Li, X and Tong, Z and Lv, Y},
title = {Correction: New insight into Alzheimer's disease: small molecule-Aβ in the brain transport and peripheral organ clearance.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {2029384},
doi = {10.3389/fragi.2026.2029384},
pmid = {43022451},
issn = {2673-6217},
abstract = {[This corrects the article DOI: 10.3389/fragi.2026.1921485.].},
}

@article {pmid43022618,
year = {2026},
author = {Jiang, Y and Wu, L and Li, W and Li, L and Huang, Z and Gui, Y and Wang, JZ and Liu, R and Jing, CH and Wang, X},
title = {Tau spread plays an etiopathogenic connection between seizures and Alzheimer's disease.},
journal = {iScience},
volume = {29},
number = {11},
pages = {117747},
pmid = {43022618},
issn = {2589-0042},
abstract = {Patients with Alzheimer's disease (AD) display heightened seizure susceptibility, in which neuronal hyperactivity during seizures correlates with exacerbated Tau pathology and cognitive impairment. This study integrated public transcriptomic datasets with machine learning approaches, suggesting Tau spread as a key biological association between seizure activity and AD. We validated activity-dependent Tau release under epileptic stimulation using primary neurons and human induced pluripotent stem cells (hiPSC)-derived neuronal models. Further validation in an AAV-based mouse Tau propagation model revealed robust bidirectional interactions: pathological Tau overexpression worsened seizure outcomes, while seizures accelerated Tau propagation across brain regions, inducing neuronal loss and gliosis. This study characterizes the activity-regulated interplay between epileptic activity and AD-associated Tau pathology, offering a potential therapeutic target for AD comorbid with epilepsy.},
}

@article {pmid43022635,
year = {2026},
author = {Liu, Y and Yang, R and Chang, H},
title = {Neurovascular-immune-clearance remodeling in brain aging.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1950144},
pmid = {43022635},
issn = {1664-3224},
mesh = {Humans ; *Aging/immunology/pathology ; *Brain/immunology/blood supply/metabolism/pathology ; Animals ; Blood-Brain Barrier/immunology/metabolism ; Glymphatic System/immunology/metabolism ; Neuroimmunomodulation ; Biomarkers ; Cellular Senescence ; },
abstract = {Brain aging involves concurrent changes in cerebral vessels, immune regulation, and waste clearance, yet these processes are often studied separately. This fragmented approach limits understanding of how dysfunction in one system influences the others and contributes to age-related neurological disorders. This review summarizes current evidence on the neurovascular-immune-clearance axis, focusing on neurovascular unit deterioration, impaired glymphatic and meningeal lymphatic transport, neuroimmune remodeling, and the cell-specific mechanisms that connect these processes. We further compare their shared and disease-dependent roles in Alzheimer's disease, vascular cognitive impairment, and late-life depression. Available imaging, fluid, proteomic, and epigenetic biomarkers are evaluated for their ability to measure different components of this axis, and emerging interventions are organized according to their predominant effects on vascular support, clearance function, immune signaling, and cellular senescence. Current evidence indicates that brain aging is characterized by interacting and partially compensable functional bottlenecks rather than a single linear pathological pathway. Integrating these mechanisms provides a framework for interpreting heterogeneous aging phenotypes, selecting complementary biomarkers, and developing mechanism-guided interventions. Future progress will depend on longitudinal human validation and direct demonstration that target engagement produces durable neurological benefit.},
}

Humans
*Aging/immunology/pathology
*Brain/immunology/blood supply/metabolism/pathology
Animals
Blood-Brain Barrier/immunology/metabolism
Glymphatic System/immunology/metabolism
Neuroimmunomodulation
Biomarkers
Cellular Senescence

@article {pmid43022642,
year = {2026},
author = {Wang, L and Lai, W and Wei, T and Zhang, Y and Wen, Y},
title = {Physical activity in preclinical Alzheimer disease: current evidence and implications for multimodal longitudinal research.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1978500},
pmid = {43022642},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnosis/metabolism ; *Exercise/physiology ; Longitudinal Studies ; Biomarkers ; Gait/physiology ; },
abstract = {Alzheimer disease (AD) pathology may be detectable years before cognitive symptoms, but biomarker testing of cognitively unimpaired people is not recommended for routine clinical use. Objective physical activity (PA), gait, and rest-activity measures are attractive research signals because they are repeatable and relatively inexpensive; however, none are specific to AD. This narrative review examined evidence linking PA, gait, and rest-activity measures to AD-related outcomes and considered their role in multimodal longitudinal research within biomarker-characterized cohorts. Targeted searches of PubMed, Scopus, and IEEE Xplore were conducted from inception through 25 August 2026, and reference lists of pivotal studies and guidance documents were hand-searched. Priority was given to guidelines, longitudinal cohorts, randomized trials, studies using objective behavior measures and AD biomarkers, and externally evaluated prediction models. Observational evidence links higher activity with lower dementia risk, but reverse causation remains plausible. In biomarker-characterized cohorts, greater baseline step count has been associated with slower amyloid-related tau accumulation and slower cognitive and functional decline, not with lower amyloid burden. Rest-activity fragmentation has shown cross-sectional and prospective associations with amyloid-related measures, whereas a 1-year aerobic-exercise trial did not reduce amyloid accumulation. Recent multimodal AI studies demonstrate that non-PET (positron emission tomography) data can estimate amyloid and tau status. Yet, they do not establish the incremental value of free-living PA in cognitively unimpaired community samples. We therefore outline a framework for longitudinal behavioral research in cohorts whose biomarker status has been characterized independently of PA-based selection. Its primary purpose is to examine associations between behavioral measures and subsequent cognitive, functional, and tau trajectories. Whether PA improves individual prediction beyond clinical information and baseline biomarkers remains a separate, unresolved question. PA is considered a contextual behavioral measure, and the framework does not propose using it to determine eligibility for biomarker testing or research recruitment.},
}

Humans
*Alzheimer Disease/physiopathology/diagnosis/metabolism
*Exercise/physiology
Longitudinal Studies
Biomarkers
Gait/physiology

@article {pmid43022806,
year = {2026},
author = {Shan, Q and Zheng, W and Yao, W and Bai, Y and Ding, W and Wang, J and Bai, F},
title = {Developing precision nanoparticle-based drug delivery systems for Alzheimer's disease therapy.},
journal = {Materials today. Bio},
volume = {41},
number = {},
pages = {103789},
pmid = {43022806},
issn = {2590-0064},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease that has thus far suffered from unsatisfactory therapeutic outcomes. Despite ongoing research into AD pathogenesis and related drugs, few disease-modifying therapies are currently available. Moreover, efficient drug delivery is significantly hindered by low permeability of the blood-brain barrier (BBB) and non-specific distribution within the brain, further limiting the efficacy of existing anti-AD medications. Nanotechnology has recently emerged as a promising approach to overcome these challenges. This review aims to offer a comprehensive overview of recent advances in precision nanoparticle-based drug delivery systems for AD therapy. First, we outline the multiple pathological mechanisms and representative pathogenesis-inspired therapies of AD. Next, we summarize various types of nanoparticles that have been utilized in AD drug delivery, including polymeric, lipid-based, inorganic, and biomimetic nanocarriers. Subsequently, we highlight the nanoparticle-mediated strategies for cascaded precision drug delivery at different levels, focusing on both the BBB and specific pathologies or cell populations within AD lesions. Finally, we discuss potential challenges and prospects in employing precision delivery systems, aiming to accelerate the development and clinical translation of nanoparticle-based therapies for AD.},
}

@article {pmid43022882,
year = {2026},
author = {Lee, N and Youn, K and Kwon, H and Kim, DH and Ho, CT and Jun, M},
title = {Correction: Fucoxanthin attenuates carbonyl stress and neuroinflammation by modulating MGO/RAGE/NF-κB axis in Aβ-induced models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {2023015},
doi = {10.3389/fphar.2026.2023015},
pmid = {43022882},
issn = {1663-9812},
abstract = {[This corrects the article DOI: 10.3389/fphar.2026.1811183.].},
}

@article {pmid43023022,
year = {2026},
author = {Huang, H and Bao, X and Deng, Q},
title = {Long-Term Neutrophil Depletion and Flow Cytometric Analysis of Brain Neutrophils in the 5xFAD Mouse Model.},
journal = {Bio-protocol},
volume = {16},
number = {21},
pages = {e5864},
pmid = {43023022},
issn = {2331-8325},
abstract = {Neutrophils are the most abundant circulating leukocytes in human blood and have been implicated in the progression of Alzheimer's disease (AD). Elevated neutrophil numbers have been observed in the blood and brain parenchyma of AD patients and mouse models, yet their precise pathological role remains poorly understood. A major barrier to progress is the lack of validated protocols for long-term neutrophil depletion and reliable recovery of brain-infiltrating neutrophils for characterization. Here, we describe a step-by-step protocol for sustained neutrophil depletion in the 5xFAD mouse model using intraperitoneal injection of an anti-Ly6G antibody for six weeks. We used a dose-escalation strategy to maintain depletion efficiency, as neutrophil regeneration increases over time. We also applied a previously established flow cytometry method to monitor neutrophil depletion in peripheral blood, using an antibody panel designed to avoid interference from the depleting anti-Ly6G clone. Furthermore, we present an optimized brain tissue processing workflow that combines mechanical dissociation with Percoll density gradient centrifugation to collect brain-infiltrating neutrophils for downstream flow cytometric analysis. Here, this workflow was applied and validated in the 5xFAD mouse model but is not specific to AD brain tissue and may be applicable to other mouse models. Key features • Depletion of circulating neutrophils in mice. • Assessment of neutrophil depletion efficiency in mouse blood. • Processing of mouse brain parenchyma and recovery of brain-infiltrating neutrophils. • Flow cytometric analysis of neutrophils isolated from mouse brain tissue.},
}

@article {pmid43023262,
year = {2027},
author = {Chen, H and Ding, T and Zhu, Y and Yang, M and Wang, F and Chen, P and Lin, H and Kang, H and Hu, M and Zhou, J and Wang, X},
title = {Metabolic syndrome and Alzheimer's disease: Mechanistic links and precision prevention (Review).},
journal = {International journal of molecular medicine},
volume = {59},
number = {1},
pages = {},
doi = {10.3892/ijmm.2026.6051},
pmid = {43023262},
issn = {1791-244X},
mesh = {Humans ; *Alzheimer Disease/prevention & control/metabolism/etiology/pathology ; *Metabolic Syndrome/complications/metabolism/prevention & control ; Animals ; Brain/metabolism ; *Precision Medicine ; Oxidative Stress ; },
abstract = {Metabolic syndrome (MetS) is associated with increased risk of Alzheimer's disease (AD), however, the majority of previous studies regard MetS as an isolated risk factor and focus on single pathways, lacking systematic understanding of combined effects among multiple metabolic components. The present review systematically summarizes the multifaceted mechanisms by which MetS promotes AD pathology, including insulin resistance and cerebral energy dysregulation, oxidative stress and mitochondrial dysfunction, neuroinflammation and glial cell activation, vascular dysfunction and dysregulation of the renin‑angiotensin system, as well as the central convergent signaling pathway involving glycogen synthase kinase‑3β. The present review further highlights emerging regulatory mechanisms involving the gut‑brain axis, epigenetic reprogramming, sex differences and hormonal effects and senescent microenvironment. By emphasizing the peripheral‑central crosstalk and interactive amplification of MetS components, the present review aimed to position AD as a central manifestation of systemic metabolic disorders in the brain and propose a multi‑domain precision strategy integrating lifestyle intervention, metabolic drug repurposing, gut microbiota regulation, anti‑aging therapy and biomarker‑guided subtype classification for intervention against MetS‑associated AD.},
}

Humans
*Alzheimer Disease/prevention & control/metabolism/etiology/pathology
*Metabolic Syndrome/complications/metabolism/prevention & control
Animals
Brain/metabolism
*Precision Medicine
Oxidative Stress