@article {pmid37496245,
year = {2024},
author = {Singh, M and Panda, SP},
title = {The Role of Monosodium Glutamate (MSG) in Epilepsy and other Neurodegenerative Diseases: Phytochemical-based Therapeutic Approa-ches and Mechanisms.},
journal = {Current pharmaceutical biotechnology},
volume = {25},
number = {2},
pages = {213-229},
doi = {10.2174/1389201024666230726161314},
pmid = {37496245},
issn = {1873-4316},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/chemically induced/metabolism ; *Sodium Glutamate/adverse effects ; Animals ; *Epilepsy/drug therapy/chemically induced/metabolism ; *Phytochemicals/therapeutic use/pharmacology ; Glutamic Acid/metabolism ; },
abstract = {Epilepsy is a common neurological disease affecting 50 million individuals worldwide, and some forms of epilepsy do not respond to available treatments. Overactivation of the glutamate pathway and excessive entrance of calcium ions into neurons are proposed as the biochemical mechanisms behind epileptic seizures. However, the overactivation of neurons has also been associated with other neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, Huntington's, and multiple sclerosis. The most widely used food ingredient, monosodium glutamate (MSG), increases the level of free glutamate in the brain, putting humans at risk for NDDs and epilepsy. Glutamate is a key neurotransmitter that activates nerve cells. MSG acts on glutamate receptors, specifically NMDA and AMPA receptors, leading to an imbalance between excitatory glutamate and inhibitory GABA neurotransmission. This imbalance can cause hyperexcitability of neurons and lead to epileptic seizures. Overuse of MSG causes neuronal cells to become overexcited, which in turn leads to an increase in the flow of Ca[2+] and Na[+] ions, mutations, and upregulation in the enzymes superoxide dismutase 1 (SOD-1) and TDP43, all of which contribute to the development of NDDs. While TDP43 and SOD-1 protect cells from damage, a mutation in their genes makes the proteins unprotective and cause neurodegeneration. Yet to what extent mutant SOD1 and TDP43 aggregates contribute to neurotoxicity is generally unknown. This study is focused on neuroprotective herbal medications that can pass the blood-brain barrier and cure MSGinduced NDDs and the factors that influence MSG-induced glutaminergic, astrocyte, and GABAergic neuron abnormalities causing neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/drug therapy/chemically induced/metabolism
*Sodium Glutamate/adverse effects
Animals
*Epilepsy/drug therapy/chemically induced/metabolism
*Phytochemicals/therapeutic use/pharmacology
Glutamic Acid/metabolism

@article {pmid37537932,
year = {2024},
author = {Semwal, BC and Singh, B and Murti, Y and Singh, S},
title = {Therapeutic Potential of Ascorbic Acid in the Management of Alzheimer's Disease: An Update.},
journal = {Current pharmaceutical biotechnology},
volume = {25},
number = {2},
pages = {196-212},
doi = {10.2174/1389201024666230804102617},
pmid = {37537932},
issn = {1873-4316},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Ascorbic Acid/therapeutic use/pharmacology ; Humans ; Animals ; *Antioxidants/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {BACKGROUND: Ascorbic acid is a potent natural antioxidant that protects against oxidative stress and performs various bodily functions. It is commonly found in fruits and vegetables.

OBJECTIVE: The manuscript has been written to provide valuable insights into ascorbic acid in managing Alzheimer's disease.

METHODS: The data has been gathered from web sources, including PubMed, Science Direct, Publons, Web of Science, and Scopus from 2000-2022 using AA, ascorbic acid, Alzheimer's diseases, memory, dementia, and antioxidant keywords.

RESULTS: In the present manuscript, we have summarized the impact of ascorbic acid and its possible mechanism in Alzheimer's disease by, outlining the information currently available on the behavioral and biochemical effects of ascorbic acid in animal models of Alzheimer's disease as well as its usage as a therapeutic agent to slow down the progression of Alzheimer disease in human beings. Oxidative stress plays a significant role in the advancement of AD. AA is a wellknown antioxidant that primarily reduces oxidative stress and produces protein aggregates, which may help decrease cognitive deficits in Alzheimer's disease. The current paper analyses of ascorbic acid revealed that deficiency of ascorbic acid adversely affects the central nervous system and leads to cognitive defects. However, the results of clinical studies are conflicting, but some of the studies suggested that supplementation of ascorbic acid improved cognitive deficits and decreased disease progression.

CONCLUSION: Based on clinical and preclinical studies, it is observed that ascorbic acid supplementation improves cognitive deficits and protects the neurons from oxidative stress injury.},
}

*Alzheimer Disease/drug therapy/metabolism
*Ascorbic Acid/therapeutic use/pharmacology
Humans
Animals
*Antioxidants/therapeutic use/pharmacology
Oxidative Stress/drug effects

@article {pmid42554889,
year = {2026},
author = {Shi, C and Liu, Y and Zhu, Y},
title = {DNA Sensing Pathways in Innate Immunity: Implications for Alzheimer's Disease Progression and Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42554889},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/immunology/therapy/pathology ; *Immunity, Innate/immunology ; Animals ; *Disease Progression ; *Signal Transduction ; Innate Immunity Recognition ; *DNA/metabolism/immunology ; cGAS-STING Signaling Pathway ; Toll-Like Receptor 9/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; },
abstract = {DNA sensors are emerging regulators of innate immune activation in Alzheimer's disease (AD). In addition to detecting microbial DNA, these pattern-recognition receptors can respond to cytosolic or endosomal self-DNA generated by DNA damage, mitochondrial dysfunction, impaired DNA repair, cellular stress, or neuronal injury. Aberrant activation of DNA-sensing pathways may amplify neuroinflammation through type I interferon (IFN-I) signaling, inflammasome activation, pyroptosis, and microglial dysfunction, thereby contributing to amyloid pathology, tau-related inflammation, synaptic loss, and cognitive decline. In this review, we summarize current evidence linking major DNA sensors, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9) to AD pathogenesis. We emphasize the strongest available evidence for cGAS-STING and AIM2, discuss the context-dependent roles of TLR9, and highlight less-established sensors requiring further validation. Finally, we evaluate therapeutic strategies targeting DNA-sensing pathways, including pathway inhibition and controlled immune activation, and discuss translational challenges such as blood-brain barrier penetration, off-target effects, dose dependency, and disease-stage-specific modulation.},
}

Humans
*Alzheimer Disease/immunology/therapy/pathology
*Immunity, Innate/immunology
Animals
*Disease Progression
*Signal Transduction
Innate Immunity Recognition
*DNA/metabolism/immunology
cGAS-STING Signaling Pathway
Toll-Like Receptor 9/metabolism
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase

@article {pmid42554922,
year = {2026},
author = {Fang, Y and Zhou, R},
title = {Two-stage deep learning framework for the restoration of incomplete-ring PET images.},
journal = {Medical & biological engineering & computing},
volume = {},
number = {},
pages = {},
pmid = {42554922},
issn = {1741-0444},
support = {12175212//Innovative Research Group Project of the National Natural Science Foundation of China/ ; },
abstract = {Positron Emission Tomography (PET) is an important molecular imaging tool widely used in medicine. Traditional PET systems rely on complete detector rings for full angular coverage and reliable data collection. However, incomplete-ring PET scanners have emerged due to hardware failures, cost constraints, or specific clinical needs. Standard reconstruction algorithms often suffer from performance degradation with these systems because of reduced data completeness and geometric inconsistencies. We present a two-stage deep-learning framework that, without incorporating any time-of-flight (TOF) information, restores high-quality images from data with about 50% missing coincidences-double the loss levels previously addressed by CNN-based methods. The pipeline operates in two stages: a projection-domain Attention U-Net first predicts the missing sections of the sinogram by leveraging spatial context from neighbouring slices, after which the completed data are reconstructed with OSEM algorithm and passed to a cascaded U-Net & warm-start diffusion model for image refinement. This module starts the reverse diffusion process from the U-Net coarse prediction rather than pure Gaussian noise. Using 613 simulated brain volumes from real scans (196 healthy brain samples, 217 Alzheimer's disease samples, and 200 Mild Cognitive Impairment samples), the results show that our model successfully preserves most anatomical structures and tracer distribution features with PSNR of 38.18 to 38.59 dB and SSIM of 0.9904 to 0.9925. Our two-stage deep-learning framework effectively restores high-quality PET images from over 50 % incomplete-ring data, achieving near-complete anatomical fidelity and robust performance without requiring TOF information.},
}

@article {pmid42554925,
year = {2026},
author = {Lin, K and Sachdev, PS and Jiang, J and , },
title = {The Associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-beta across the Alzheimer's disease spectrum.},
journal = {Brain imaging and behavior},
volume = {20},
number = {4},
pages = {},
pmid = {42554925},
issn = {1931-7565},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology/metabolism/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/blood ; *White Matter/diagnostic imaging/pathology/metabolism ; Female ; *Cerebrovascular Circulation/physiology ; Male ; Cross-Sectional Studies ; Positron-Emission Tomography ; Aged ; Magnetic Resonance Imaging ; Brain/diagnostic imaging/pathology/metabolism ; Longitudinal Studies ; Aged, 80 and over ; Perfusion Magnetic Resonance Imaging ; Biomarkers/blood ; },
abstract = {Although the associations between cerebrovascular dysfunctions and Alzheimer's disease are increasingly appreciated, the relationship of cerebral blood flow and white matter hyperintensities with tau and amyloid-β pathology remains unclear, particularly in the longitudinal context. This study investigated cross-sectional and longitudinal associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-β pathology using multimodal imaging and blood biomarkers in 179 participants from the ADNI3 cohort. Participants underwent structural (T1-weighted, T2-weighted FLAIR) and arterial spin labelling perfusion MRI, tau and amyloid-β PET, and plasma assay tests for amyloid-β 42, amyloid-β 40, and phosphorylated tau-217. Tau from PET was negatively associated with cerebral blood flow both cross-sectionally and longitudinally in the posterior brain, independent of amyloid-β quantified from PET. Higher white matter hyperintensities volumes were associated with higher levels of tau and amyloid-β at baseline, but the associations were significantly attenuated after further adjusting for amyloid-β and tau, respectively. Plasma amyloid-β 42/40 ratio was negatively associated with white matter hyperintensity volumes both cross-sectionally and longitudinally. In conclusion, tau pathology showed spatially specific associations with cerebral hypoperfusion, independent of amyloid-β, particularly in posterior regions. The attenuation of associations of white matter hyperintensities with amyloid-β and tau after adjustment may reflect shared disease-related variance rather than distinct independent effects.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology/metabolism/pathology
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism/blood
*White Matter/diagnostic imaging/pathology/metabolism
Female
*Cerebrovascular Circulation/physiology
Male
Cross-Sectional Studies
Positron-Emission Tomography
Aged
Magnetic Resonance Imaging
Brain/diagnostic imaging/pathology/metabolism
Longitudinal Studies
Aged, 80 and over
Perfusion Magnetic Resonance Imaging
Biomarkers/blood

@article {pmid42554945,
year = {2026},
author = {Yang, S and Li, Y and Guo, Y and Li, Y and Li, M and Li, H and Zhang, Y},
title = {GPR146 Deficiency Enhances Microglial Phagocytosis and Blood-Brain Barrier-Associated Markers in an Acute Amyloid-β Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42554945},
issn = {1559-1182},
mesh = {Animals ; *Blood-Brain Barrier/metabolism/pathology ; *Amyloid beta-Peptides/metabolism/toxicity ; *Receptors, G-Protein-Coupled/deficiency/metabolism ; *Microglia/metabolism/pathology ; *Phagocytosis/drug effects ; *Biomarkers/metabolism ; Disease Models, Animal ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Signal Transduction ; },
abstract = {Dysregulation of brain cholesterol homeostasis is increasingly recognized as a critical driver of Alzheimer's disease (AD) pathogenesis. G protein-coupled receptor 146 (GPR146) has emerged as a pivotal regulator of systemic cholesterol metabolism; however, its role in the central nervous system and AD remains elusive. Here, we report that GPR146 deficiency in mice modulates ERK/PKA signaling without affecting baseline physiology or general behavior. Following intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)42 oligomers, GPR146 was associated with altered Aβ42-evoked ERK/PKA/Akt signaling both in vivo and in vitro. Mechanistically, Gpr146 ablation potentiated microglial Aβ phagocytosis, which correlated with the transcriptional upregulation of phagocytic receptors, including TREM2, GPR34, P2Y6, and CR3, alongside increased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Moreover, GPR146 deficiency was linked to elevated levels of blood-brain barrier (BBB)-associated markers Cldn-5 and Glut-1 protein levels, while attenuating Aβ‑induced inflammatory responses in brain endothelial cells. At the metabolic level, GPR146 knockout modulated the expression of key enzymes governing glucose (GLUT1, GLUT3, G6PD, PFK, HK) and lipid (HMGCS1, ACACA, FASN, SCD1) metabolism and markedly reduced Aβ‑elicited lipid droplet accumulation in the cortex and hippocampus. Collectively, our findings establish GPR146 as a novel neurometabolic regulator whose deficiency correlates with enhanced Aβ phagocytosis, maintenance of BBB-associated proteins, and altered cerebral metabolism, thereby presenting a potential therapeutic axis for early AD intervention.},
}

Animals
*Blood-Brain Barrier/metabolism/pathology
*Amyloid beta-Peptides/metabolism/toxicity
*Receptors, G-Protein-Coupled/deficiency/metabolism
*Microglia/metabolism/pathology
*Phagocytosis/drug effects
*Biomarkers/metabolism
Disease Models, Animal
Mice, Knockout
Mice, Inbred C57BL
Male
Signal Transduction

@article {pmid42554959,
year = {2026},
author = {Welsh, TJ and Chen, Y and Kennelly, SP and Quinn, TJ and Religa, D and Shenkin, SD and Soysal, P and Roitto, HM},
title = {From memory clinics to Brain Health Services: implications for older adults and the future of cognitive care in Europe.},
journal = {European geriatric medicine},
volume = {},
number = {},
pages = {},
pmid = {42554959},
issn = {1878-7649},
abstract = {AIM: To explore the implications of transitioning from traditional memory clinics to Brain Health Services (BHS) for older adults, and to advocate for a geriatric-informed, equitable, and function-oriented approach to brain health care.

METHODS: This perspective article draws on discussions within the EuGMS Brain Health and Dementia Specialist Interest Group and relevant literature to examine the implications of emerging Brain Health Services for older adults.

RESULTS: The emergence of Brain Health Services represents a significant shift in cognitive healthcare, moving beyond traditional memory clinic models focussed primarily on dementia diagnosis and management towards prevention, risk reduction, and maintenance of cognitive function. Potential benefits include earlier engagement with cognitive care, multidomain lifestyle interventions, reduction of stigma surrounding dementia, and facilitation of access to emerging disease-modifying therapies. However, substantial challenges remain. Biomarker-driven approaches may overemphasise Alzheimer's disease-centric frameworks despite the high prevalence of mixed pathologies and complex comorbidity in older adults. Ethical concerns surrounding risk disclosure, inequitable access, and resource allocation are also considerable, particularly if services disproportionately benefit younger, healthier, or socioeconomically advantaged populations.

CONCLUSIONS: Brain Health Services should be reframed through a gerontologically informed lens that prioritises function, independence, quality of life, and equitable access alongside prevention. Integration with comprehensive geriatric assessment and existing older persons' care pathways is essential. Future research should focus on pragmatic real-world evaluation, inclusive outcome measures, and personalised approaches that account for heterogeneity in ageing. Ultimately, the success of BHS will depend on their ability to support healthy ageing while remaining responsive to the lived realities and priorities of older adults.},
}

@article {pmid42554972,
year = {2026},
author = {Wang, X and Tao, Y and Li, Q and Yang, J and Liu, Q and Xu, A},
title = {The Therapeutic Efficacy of Gold Needle "Regulating Spirit" Acupuncture for Amnestic Mild Cognitive Impairment: Protocol for a Randomized Controlled Trial.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e96326},
pmid = {42554972},
issn = {1929-0748},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods/instrumentation ; *Needles ; *Gold/therapeutic use ; Aged ; Female ; Male ; Middle Aged ; Treatment Outcome ; Biomarkers/blood ; },
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), the predominant subtype of mild cognitive impairment, carries the highest risk of progression to Alzheimer disease among all mild cognitive impairment subtypes. Currently, clinical practice lacks an established, authoritative treatment method for this condition. Prior clinical evidence indicates acupuncture may enhance cognitive function in individuals with mild cognitive impairment. Further clinical evidence suggests Gold Needle therapy demonstrates significant therapeutic effects for challenging and refractory conditions; however, a critical gap exists: no clinical trials currently ascertain whether Gold Needle therapy surpasses conventional acupuncture in treating aMCI. This trial aims to rigorously evaluate the therapeutic efficacy and safety of the Gold Needle "Regulating Spirit" method for clinical symptoms in patients with aMCI, alongside investigating its underlying imaging and biochemical mechanisms.

OBJECTIVE: This proposed study aims to identify imaging and laboratory biomarkers for the early diagnosis of aMCI, thereby providing a theoretical foundation for clinical practice.

METHODS: This randomized controlled trial will recruit 90 patients diagnosed with aMCI from the Beijing Hospital of Traditional Chinese Medicine, affiliated with Capital Medical University, alongside 20 healthy volunteers. The 90 patients with aMCI will be randomly allocated to 1 of 3 groups: the Gold Needle "Regulating Spirit" group uses gold-based needles, the general acupuncture "Regulating Spirit" group, or a sham acupuncture control group. The Gold Needle "Regulate Spirit" group uses gold-based needles, the general acupuncture "Regulate Spirit" group uses standard needles, and the sham acupuncture group administers Park needles. Participants will undergo 3 sessions per week of their assigned acupuncture or placebo treatment over a continuous 12-week period.

RESULTS: This study was initiated on September 1, 2023. As of October 30, 2025, 110 eligible participants had been enrolled, and data collection had been completed in full. Data analysis is currently underway, and the preliminary results are expected to be available by June 2025. We hypothesize that, compared with the filiform needle-based mind-regulating acupuncture group, the golden needle-based mind-regulating acupuncture group will demonstrate superior efficacy in improving cognitive impairment. This superiority will be reflected in multiple key outcome measures, including Montreal Cognitive Assessment and Mini-Mental State Examination scores, plasma biomarkers, and functional magnetic resonance imaging findings.

CONCLUSIONS: We anticipate that by the end of the trial, we will be able to definitively ascertain whether the gold acupuncture needle technique for "regulating spirit" offers a significant advantage in treating aMCI, and further investigate the nature of this therapeutic benefit, to offer a more efficacious intervention for the clinical management of aMCI and the prevention of Alzheimer disease.},
}

Humans
*Cognitive Dysfunction/therapy
*Acupuncture Therapy/methods/instrumentation
*Needles
*Gold/therapeutic use
Aged
Female
Male
Middle Aged
Treatment Outcome
Biomarkers/blood

@article {pmid42554979,
year = {2026},
author = {Fang, JR and Vogel, AP and Velakoulis, D and Yuan, Y and Nayler, D and Loi, SM and Joubert, L},
title = {Interventions for caregivers of persons with young-onset dementia in hospital environments: A systematic scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469822},
doi = {10.1177/13872877261469822},
pmid = {42554979},
issn = {1875-8908},
abstract = {BackgroundCaregivers of patients with young-onset dementia (YOD), most commonly Alzheimer's disease and frontotemporal dementia, face unique challenges balancing employment, childcare, finances, and complex care responsibilities. Tailored interventions delivered in hospital environments may provide timely support and optimize caregiver preparedness, but evidence regarding these interventions remains limited.ObjectiveTo map and synthesize evidence on interventions supporting caregivers of individuals with YOD within hospital environments offering diagnostic services, multidisciplinary care, and opportunities for caregiver engagement. Intervention types, delivery modes, outcomes, and evidence gaps will be highlighted.MethodsA systematic scoping review adhering to PRISMA-ScR guidelines was conducted. Medline, Embase, PsycINFO, EBM Reviews, SocINDEX, CINAHL, and Scopus were searched for studies published up to 2025. Peer-reviewed studies in English describing or evaluating interventions for YOD caregivers were included. Data on study characteristics, intervention type, delivery, outcomes, and key findings were extracted and synthesized narratively.ResultsEight studies met the inclusion criteria. Interventions were largely focused on psychoeducation and support groups. Most studies targeted spouses with few including other caregiver types. Interventions addressed caregiver functions such as task management, safety, information, and caregiver needs related to emotional support and burden reduction, but rarely were both comprehensively addressed. Quantitative outcomes were mixed while qualitative findings consistently reported improved preparedness, support, and coping.ConclusionsEvidence on caregiver interventions in hospital environments is limited and largely exploratory. Future work should embed supports within diagnostic pathways, incorporate structured assessment, tailor interventions by subtype and caregiver role, and use outcome measures sensitive to early, meaningful changes.},
}

@article {pmid42554980,
year = {2026},
author = {Goldstein, FC and Hales, CM and Parker, MW and Trammell, AR and Manzanares, CM and Heldenberg, SC and Hanfelt, JJ and Levey, AI and Lah, JJ},
title = {Performance of the participant self-rating version of the Quick Dementia Rating System in a racially diverse cohort of non-demented older adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471427},
doi = {10.1177/13872877261471427},
pmid = {42554980},
issn = {1875-8908},
abstract = {BackgroundEarly detection of clinical Alzheimer's disease and related dementias is a public health priority. The Clinical Dementia Rating is used for staging but is time intensive. The Quick Dementia Rating System (QDRS) is a brief, self-administered alternative, although studies have focused on informant rather than patient ratings.ObjectiveThis study evaluated the clinical utility of the QDRS Participant Self-Rating version for classifying cognitive status of White and Black/African Americans.MethodsParticipants (79 White, 95 Black/African American) enrolled in the Goizueta Alzheimer's Disease Research Center with Clinical Dementia Rating (CDR) Global scores of 0.0 or 0.5 completed the QDRS. Concordance rates and associations with the Montreal Cognitive Assessment (MoCA) were examined.ResultsAgreement between QDRS and CDR Global scores was 69% (κ = 0.36), and comparable between racial groups. QDRS Sum of Boxes demonstrated moderate correlations with CDR Sum of Boxes for the full sample and each group. Participants classified as impaired on the QDRS had lower MoCA Total and Memory Index scores, with similar effect sizes between racial groups. ROC analyses demonstrated good discrimination of CDR 0.0 versus 0.5 for the overall sample (AUC = 0.789, SE = 0.040, 95% CI = 0.711-0.866) and for White (AUC = 0.792, SE = 0.055, 95% CI = 0.683-0.900) and Black/African American participants (AUC = 0.777, SE = 0.058, 95% CI = 0.663-0.891). Positive predictive value of the QDRS Global score was 50%, and negative predictive value was 85%.ConclusionsThe QDRS Participant Self-Rating version is a clinically useful prescreening tool to rule out cognitive impairment in both White and Black/African American persons with early cognitive impairment.},
}

@article {pmid42554985,
year = {2026},
author = {Sánchez-Juan, P and García-Arcelay, E and Almagro, M and Balasa, M and Piñol-Ripoll, G and Boada, M and Landete, L and Abellan, I and Berbel, A and Espejo, B and Baquero, M and Marin, J and Franco-Macias, E and Villarejo-Galende, A and Viñuela Fernández, F and Feria Vilar, I and Perez-Vieitez, C and Rodríguez-Espinosa, N and Puig-Pijoan, A and Bargay Pizarro, E and Rodríguez-Rodríguez, E and Rodrigo, J and Maurino, J and Manzano, S},
title = {Burden, perception of stigma, and gender differences among informal care partners of individuals with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474135},
doi = {10.1177/13872877261474135},
pmid = {42554985},
issn = {1875-8908},
abstract = {BackgroundCaring for individuals with mild cognitive impairment (MCI) is increasingly recognized as a significant clinical challenge. However, the latent burden, driven by perceived stigma and gender-specific vulnerabilities, remains poorly characterized during these early stages of cognitive decline.ObjectiveThis study aimed to evaluate the prevalence of care partner strain and affiliate stigma, and to identify independent correlates of psychological distress and protective factors among informal care partners of individuals with MCI.MethodsWe conducted a multicenter, observational, cross-sectional study across 19 memory clinics in Spain. Care partners (n = 196) were evaluated using the Zarit Burden Interview, Affiliate Stigma Scale, and validated instruments assessing resilience, relationship quality, coping strategies, and psychological distress. Multivariate logistic regression models identified independent predictors of burden and stigma.ResultsSignificant care partner strain affected 59.7% of the cohort, while 39.3% perceived themselves as stigmatized. Multivariate analysis revealed that high burden was independently associated with anxiety symptoms (OR = 1.13, p = 0.017) and perceived stigma (OR = 1.07, p = 0.007). High resilience served as the primary determinant protecting the 60.7% of partners who did not report significant stigma (OR = 1.05, p < 0.001). Compared to their male counterparts, female care partners were significantly younger and reported higher levels of burden, anxiety, and stigma.ConclusionsCare partner strain and affiliate stigma are correlated phenomena that emerge long before formal patient dependency. These findings underscore the need for gender-sensitive clinical frameworks and specific interventions that actively strengthen resilience immediately upon MCI diagnosis to mitigate early psychological deterioration.},
}

@article {pmid42554989,
year = {2026},
author = {Qiu, J and Zhang, Y and Shang, Y and Shang, Q and Li, L and Chen, Y and Dai, S and Ai, M and Xi, X and Huang, W and Zhang, J and Liu, X},
title = {Impact of SARS-CoV-2 infection on the progression of Alzheimer's disease: A prospective cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469118},
doi = {10.1177/13872877261469118},
pmid = {42554989},
issn = {1875-8908},
abstract = {BackgroundSARS-CoV-2 infection is associated with neurological sequelae and may accelerate Alzheimer's disease (AD) progression through neuroinflammation and protein aggregation. However, longitudinal evidence regarding the cognitive impact of COVID-19 in patients with AD remains scarce, and this interaction requires further clarification.ObjectiveTo explore whether COVID-19 accelerates cognitive decline in patients with AD.MethodsA total of 120 participants were enrolled, including 63 in the COVID-19 group and 57 in the non-COVID-19 group. The primary outcomes were disease decline and disease deterioration over three months, assessed using CDR-SB. Disease deterioration indicated clinically meaningful worsening, whereas disease decline captured subtler progression. Multivariable logistic regression adjusted for demographic, clinical, lifestyle, genetic, and disease severity factors. Overlap-Weighted Propensity Score Matching was additionally performed to reduce confounding during the 3-month follow-up.ResultsCOVID-19 significantly increased the risk of disease decline (OR = 10.39, 95% CI:3.87 to 27.87, p < 0.001) and disease deterioration (OR = 10.37, 95% CI: 2.71 to 39.65, p = 0.001). APOE ε4 carrier status was associated with a higher risk of deterioration (OR = 1.72), while those with unknown APOE status exhibited an even greater risk (OR = 5.20, 95% CI:1.32 to 20.53, p = 0.019). Secondary analyses confirmed that COVID-19 patients experienced significantly greater increases in CDR-SB scores compared to non-COVID-19 patients.ConclusionsSARS-CoV-2 infection was associated with greater short-term cognitive worsening over a three-month period in patients with AD, underscoring its potential public health relevance and the need for early surveillance to guide timely clinical management.},
}

@article {pmid42554990,
year = {2026},
author = {Baird, KT},
title = {Thermodynamic impedance mismatch in neurodegeneration: A biophysical framework for the prediction of amyloid-related imaging abnormalities.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474112},
doi = {10.1177/13872877261474112},
pmid = {42554990},
issn = {1875-8908},
abstract = {Amyloid-related imaging abnormalities (ARIA) represent a significant iatrogenic complication of anti-amyloid monoclonal antibody therapies. To address this, we propose the Impedance Mismatch Theory as a theoretical framework and hypothesis, reframing neurodegeneration as a network-level thermodynamic failure characterized by localized thermal runaway (Neural Physiological Load Index (NLI) greater than or equal to 1.0). Within this framework, amyloid-β (Aβ) is modeled not only in its established biological context, but as a potential thermodynamic heat sink and bio-conductive electrical shunt deployed to protect hyper-metabolic neural hubs. Utilizing the Pennes bioheat equation, we formalize the NLI and map its theoretical values to absolute [1]H-magnetic resonance spectroscopy thermometry signatures. Our model suggests that clearing Aβ in the setting of unresolved energetic mismatch could contribute to localized mechanical and thermal instability. We hypothesize that these upstream physical dynamics precipitate the downstream inflammatory cascades clinically observed as ARIA. If validated, these theoretical considerations suggest that effective disease modification may require thermodynamic normalization as a prerequisite to, or in parallel with, plaque clearance.},
}

@article {pmid42554993,
year = {2026},
author = {Palmer, AM and Francis, PT and Sims, NR},
title = {Fifty years of the cholinergic hypothesis: David Bowen's legacy in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag261},
pmid = {42554993},
issn = {1460-2156},
}

@article {pmid42555084,
year = {2026},
author = {Knox, S and Dooley, M and Cutty, M and Simpson, KN},
title = {Beyond binary classification: A tiered claims-based algorithm for Alzheimer's disease and related dementias in Medicare.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471874},
doi = {10.1177/13872877261471874},
pmid = {42555084},
issn = {1875-8908},
abstract = {BackgroundAdministrative data is widely used to identify Alzheimer's disease and related dementias (ADRD), yet commonly applied algorithms (e.g., the Chronic Conditions Warehouse [CCW] algorithm) rely on binary classification that may obscure heterogeneity in likelihood and care needs.ObjectiveTo examine whether a tiered ADRD classification algorithm using Medicare home health data yields cohorts with more clearly distinguishable clinical and sociodemographic characteristics compared with the CCW-27 algorithm.MethodsWe conducted a retrospective cohort study of 2,252,040 Medicare Fee-for-Service beneficiaries with home health encounters. The novel algorithm applied episode-level and individual-level criteria to classify individuals into one of three mutually exclusive groups (ADRD-highly likely, ADRD-possible, ADRD-unlikely). Using descriptive statistics, we compared socio-demographic characteristics and OASIS-based cognitive and functional measures across groups defined by the novel algorithm and the CCW-27 algorithm.ResultsThe CCW-27 algorithm classified 34.3% of individuals as ADRD-positive, whereas the novel algorithm classified 7.6% as ADRD-highly likely, 29.3% as ADRD-possible, and 63.1% as ADRD-unlikely. The ADRD-highly likely group demonstrated greater cognitive and functional impairment than the CCW-27 ADRD-positive group. Discordant classifications revealed important sociodemographic differences: individuals classified as ADRD-highly likely by the novel algorithm but ADRD-negative by the CCW-27 algorithm were more frequently Medicare/Medicaid dual-eligible (52.9%) and non-White (39.5%) than concordant and alternative discordant groups.ConclusionsA tiered claims-based ADRD classification provides greater resolution than binary approaches and reveals clinically and sociodemographically distinct groups within the Medicare home health population. Such approaches may support more nuanced characterization of ADRD when clinical gold standards are unavailable.},
}

@article {pmid42555228,
year = {2026},
author = {Kaur, G and Goyal, B},
title = {Leveraging molecular dynamics to unravel the inhibition mechanism of potential β-secretase (BACE1) inhibitors.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp01160h},
pmid = {42555228},
issn = {1463-9084},
abstract = {Alzheimer's disease (AD) remains a formidable global health challenge, driving the urgent need for potent and selective therapeutics targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme involved in the generation of amyloid-β (Aβ) peptide and a promising target for disease-modifying interventions. In this work, approximately 16 million small molecules from diverse databases were subjected to ligand-based virtual screening (LBVS), using LY3202626 as a reference compound, to identify new potent inhibitors of BACE1. LY3202626 is a highly potent, central nervous system (CNS) penetrant BACE1 inhibitor (IC50 = 0.615 nM) that has progressed to clinical trials, demonstrating efficacy at low doses against BACE1 activity. The lead candidates identified using ensemble molecular docking displayed stronger binding affinities (-11.2 to -9.6 kcal mol[-1]) to BACE1 as compared to LY3202626. Notably, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis revealed high-affinity binding of ChEMBL3667410 (C1), ChEMBL3667414 (C2), and ChEMBL3976114 (C5) with binding affinities of -32.9 ± 0.8, -33.6 ± 1.8, and -36.1 ± 1.7 kcal mol[-1], respectively, to BACE1 as compared to LY3202626 (-29.9 ± 1.8 kcal mol[-1]). Furthermore, MD simulations demonstrated enhanced structural stability and reduced residual fluctuations in BACE1 on the incorporation of C1, C2, and C5, as compared to apo-BACE1 and BACE1-LY3202626. Interestingly, the conformational snapshots, flap distances, and free energy landscape (FEL) analyses highlighted a closed flap, Val67-Glu77 (non-active) conformation in BACE1-C5 in comparison to an open flap (active) conformation in apo-BACE1, and partial restriction in the access to the active site of BACE1 due to the flap movement noticed in the presence of LY3202626, C1, and C2. Notably, conformational microstate analysis revealed key hydrogen bond interactions of C5 with the 10s loop (Gly11, Gly13), flap residues (Trp76), the catalytic residue (Asp228), Gly230, and Thr231 of BACE1, depicting its high-affinity binding to key residues of BACE1 and its potential as an effective inhibitor of BACE1 activity. The comprehensive in silico methodology in this work illuminated the inhibitory mechanism of LY3202626 and top hit compounds against BACE1 activity for the first time, which, in turn, will be highly valuable in further optimization and structural refinement using various functional group modifications to yield more potent next-generation therapeutic candidates against BACE1 in AD.},
}

@article {pmid42555262,
year = {2026},
author = {Prokopiou, PC and Van Egroo, M and Riphagen, JM and Baillet, M and Ashton, NJ and Janelidze, S and Sperling, RA and Johnson, KA and Blennow, K and Hansson, O and Zetterberg, H and Jacobs, HIL},
title = {Astrocyte reactivity modifies the effects of locus coeruleus norepinephrine-related dysfunction on tau and its impact on cognition.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71703},
pmid = {42555262},
issn = {1552-5279},
support = {WE.03-2019-02//Alzheimer Nederland/ ; R01AG062559/NH/NIH HHS/United States ; R01AG068062/NH/NIH HHS/United States ; R01AG082006/NH/NIH HHS/United States ; R21AG074220/NH/NIH HHS/United States ; R21AG081681/NH/NIH HHS/United States ; R01AG068398/NH/NIH HHS/United States ; A20211016F//BrightFocus Foundation/ ; 101109451//Marie Skłodowska Curie Actions/ ; AARF-23-1145963/ALZ/Alzheimer's Association/United States ; ZEN-21-848495/ALZ/Alzheimer's Association/United States ; 2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 2017-00915//Swedish Research Council/ ; 101053962//European Union's Horizon Europe Research and Innovation Program/ ; ALFGBG-71320//Swedish State/ ; ALFGBG-715986//Swedish State/ ; ALFGBG-965240//Swedish State/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF)/ ; RDAPB-201809-2016615//Alzheimer Drug Discovery Foundation (ADDF)/ ; JPND2021-00694//European Union Joint Programme-Neurodegenerative Disease Research/ ; JPND2019-466-236//European Union Joint Programme-Neurodegenerative Disease Research/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; AF-930351//Swedish Alzheimer Foundation/ ; AF-939721//Swedish Alzheimer Foundation/ ; AF-968270//Swedish Alzheimer Foundation/ ; FO2022-0270//Hjärnfonden, Sweden/ ; 860197//Hjärnfonden, Sweden/ ; FO2017-0243//Hjärnfonden, Sweden/ ; ALZ2022-0006//Hjärnfonden, Sweden/ ; ADSF-21-831376-C//AD Strategic Fund/ ; ADSF-21-831381-C//AD Strategic Fund/ ; ADSF-21-831377-C//AD Strategic Fund/ ; ADSF-24-1284328-C//AD Strategic Fund/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; //Stiftelsen för Gamla Tjänarinnor/ ; 860197//European Union's Horizon 2020 Research and Innovation Programme/ ; },
mesh = {*Locus Coeruleus/metabolism/physiopathology/diagnostic imaging ; Humans ; *Astrocytes/metabolism/physiology ; *tau Proteins/blood/metabolism ; Male ; Glial Fibrillary Acidic Protein/blood ; *Norepinephrine/metabolism ; Female ; *Cognition/physiology ; Aged ; *Cognitive Dysfunction/metabolism/physiopathology ; Magnetic Resonance Imaging ; Biomarkers/blood ; },
abstract = {INTRODUCTION: Animal models demonstrated that pharmacologically-induced lesioning of the locus coeruleus (LC), the brain's primary source of norepinephrine, triggered astrocyte reactivity, exacerbating Alzheimer's disease (AD) pathology and cognitive deficits. We examined whether astrocyte reactivity modulates the relationship between LC dysfunction, tau pathology, and cognitive decline in humans.

METHODS: We combined ultra-high-field LC functional imaging during an affective task with plasma biomarkers of glial fibrillary acidic protein (GFAP) and hyperphosphorylated tau (p-tau), and longitudinal cognitive data from 78 asymptomatic individuals. Associations between LC activity and norepinephrine transporter-enriched LC functional connectivity (LCFC) with p-tau, GFAP, and cognitive decline were examined.

RESULTS: Lower LC activity and LCFC were related to elevated plasma p-tau217, particularly at elevated GFAP. Lower LC FC was also associated with cognitive decline in individuals with elevated plasma p-tau217 and GFAP.

DISCUSSION: LC-norepinephrine system dysfunction may contribute to emerging tau pathology and cognitive decline, with astrocytes playing a critical gating role.},
}

*Locus Coeruleus/metabolism/physiopathology/diagnostic imaging
Humans
*Astrocytes/metabolism/physiology
*tau Proteins/blood/metabolism
Male
Glial Fibrillary Acidic Protein/blood
*Norepinephrine/metabolism
Female
*Cognition/physiology
Aged
*Cognitive Dysfunction/metabolism/physiopathology
Magnetic Resonance Imaging
Biomarkers/blood

@article {pmid42555275,
year = {2026},
author = {Qi, X and Liu, R and Belsky, DW and Tian, Q and Luo, H and Liu, Y and Xu, Z and Langa, KM and Wu, B},
title = {Edentulism, blood-based neurodegenerative biomarkers, and 10-year dementia risk: A mediation analysis in a nationally representative United States cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71731},
pmid = {42555275},
issn = {1552-5279},
support = {R01AG089856/NH/NIH HHS/United States ; //Intramural Research Program of the National Institute on Aging/ ; },
mesh = {Humans ; *Dementia/blood/epidemiology ; Biomarkers/blood ; United States/epidemiology ; Female ; Male ; Glial Fibrillary Acidic Protein/blood ; Amyloid beta-Peptides/blood ; Aged ; *Mouth, Edentulous/epidemiology/blood ; tau Proteins/blood ; Cohort Studies ; Cognitive Dysfunction/blood/epidemiology ; Risk Factors ; Neurofilament Proteins ; },
abstract = {INTRODUCTION: Tooth loss is associated with dementia risk, but mechanisms remain unclear. We examined whether blood-based neurodegenerative biomarkers mediate the edentulism-cognition association.

METHODS: Among 4238 Health and Retirement Study participants aged 50+, we linked edentulism (2012), biomarkers (neurofilament light chain [NfL], glial fibrillary acidic protein [GFAP], phosphorylated tau-181, and amyloid-β [Aβ] 42/40; 2016), and 10-year cognitive outcomes (2012-2022).

RESULTS: Edentulism was associated with higher NfL (β = 4.21) and GFAP (β = 8.06), but not pTau-181 or Aβ42/40, and predicted cognitive impairment (hazard ratio [HR] 1.49) and dementia (HR 1.28). GFAP mediated 9.8% and 12.0% of the cognitive impairment and dementia associations, respectively; NfL mediated 9.8% of the dementia association but not cognitive impairment.

CONCLUSION: In this observational cohort, elevated NfL and GFAP were associated with, and accounted for a small proportion of, the edentulism-cognition association. These associative findings support further study of oral health in dementia prevention but do not establish a causal effect.},
}

Humans
*Dementia/blood/epidemiology
Biomarkers/blood
United States/epidemiology
Female
Male
Glial Fibrillary Acidic Protein/blood
Amyloid beta-Peptides/blood
Aged
*Mouth, Edentulous/epidemiology/blood
tau Proteins/blood
Cohort Studies
Cognitive Dysfunction/blood/epidemiology
Risk Factors
Neurofilament Proteins

@article {pmid42555875,
year = {2026},
author = {Prodan, CI and Yabluchanskiy, A},
title = {The Challenge of Atypical Alzheimer Disease Phenotypes.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218533},
doi = {10.1212/WNL.0000000000218533},
pmid = {42555875},
issn = {1526-632X},
}

@article {pmid42555876,
year = {2026},
author = {Shir, D and Corriveau-Lecavalier, N and Jones, DT and Ramanan, VK and Lachner, C and Knopman, DS and Petersen, RC and Josephs, KA and Day, GS and Graff-Radford, J and Graff-Radford, NR},
title = {Eligibility for Anti-Amyloid Therapies in Patients With Biomarker-Confirmed Atypical Alzheimer Disease Phenotypes.},
journal = {Neurology},
volume = {107},
number = {5},
pages = {e218347},
pmid = {42555876},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Phenotype ; Aged ; Male ; Retrospective Studies ; Biomarkers ; Aged, 80 and over ; *Patient Selection ; Middle Aged ; *Eligibility Determination ; },
abstract = {BACKGROUND AND OBJECTIVES: Clinical trials of anti-amyloid therapies (AATs) for Alzheimer disease (AD) primarily enrolled patients with mildly symptomatic, amnestic predominant presentations. The applicability of eligibility criteria to atypical AD phenotypes, including posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), dysexecutive AD (dAD), and corticobasal syndrome because of AD (CBS-AD), is unknown.

METHODS: We conducted a retrospective eligibility analysis of patients with atypical AD evaluated at Mayo Clinic. Theoretical eligibility for AAT was assessed at initial clinical evaluation by applying inclusion and exclusion criteria from landmark clinical trials (Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer's Disease [CLARITY-AD] and the Study of LY3002813 (Donanemab) in Participants With Early Symptomatic Alzheimer's Disease [TRAILBLAZER-ALZ2]) and appropriate use criteria for lecanemab and donanemab. Eligibility percentages and reasons for exclusion were compared across phenotypes.

RESULTS: The cohort included 184 patients (61.4% female) with biomarker-confirmed atypical AD: PCA (n = 98, 53.3%), lvPPA (n = 42, 22.8%), dAD (n = 37, 20.1%), and CBS-AD (n = 7, 3.8%). Age at onset (p = 0.039) and presentation (p < 0.001) differed, with patients with lvPPA oldest (median age at onset, presentation: 63.1, 66.9 years) and patients with dAD youngest (onset, presentation: 55.1, 57.3). Functional impairment differed by phenotype (p = 0.005), with lvPPA more often diagnosed at the mild cognitive impairment/very mild stage (Clinical Dementia Rating [CDR] 0.5; 71.4%), whereas PCA and dAD more frequently presented with mild dementia, although time from symptom onset to diagnosis did not differ (p = 0.634). Mini-Mental State Examination (MMSE) scores differed (p = 0.036), with lower scores in PCA and lvPPA (median 21 and 21, respectively) compared with CBS-AD (median 27). Depending on the eligibility framework applied, 70%-85% of patients would not meet treatment criteria. Bedside cognitive thresholds were the primary drivers of ineligibility (50%-67% of exclusions), despite most patients having early symptomatic disease (global CDR 0.5-1; 82%). Imaging-based exclusions (22%-27%) and severity thresholds (moderate or severe dementia, 19%-23%) were also frequent. Reasons for ineligibility were similar across phenotypes.

DISCUSSION: Most patients with atypical AD would not meet eligibility criteria for AAT, typically because of MMSE-based exclusion rather than measures of cognitive function. Eligibility rates are broadly similar across atypical phenotypes. These findings highlight the need for phenotype-sensitive staging and patient selection for treatment in atypical AD.},
}

Humans
*Alzheimer Disease/drug therapy
Female
Phenotype
Aged
Male
Retrospective Studies
Biomarkers
Aged, 80 and over
*Patient Selection
Middle Aged
*Eligibility Determination

@article {pmid42555976,
year = {2026},
author = {Xu, T and Zhang, C and Yang, Y and Shen, Z and Zhong, Z},
title = {Esketamine alleviates neuroinflammation and cognitive impairment in male 3xTg-AD mice by regulating the TAOK1/IL-17 axis.},
journal = {Canadian journal of physiology and pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1139/cjpp-2025-0340},
pmid = {42555976},
issn = {1205-7541},
abstract = {Beyond its antidepressant effects, esketamine (ESK) has the potential to enhance neuroplasticity, facilitating the reconnection with emotional and cognitive processes, improving social cognition, and promoting resilience. However, not much is known about its role in Alzheimer's disease (AD). This study aims to explore the potential mechanism of ESK in AD treatment. The potential targets of ESK were predicted by bioinformatics analysis, and 3xTg-AD male mice were subjected to adeno-associated virus and ESK treatment. Cognitive ability, neuronal damage, and proinflammatory factors in 3xTg-AD mice were evaluated. An inflammatory model was established by inducing mouse cortical neurons with mouse IL-17A protein. Neuronal viability was assessed after treatment with different concentrations of ESK. TAOK1 knockdown or IL-17RA knockdown was performed on 3xTg-AD mice and neurons. TAOK1 was highly expressed in the cerebral cortex of ESK-treated 3xTg-AD mice. ESK improved IL-17-induced neuronal inflammation and DNA damage in a TAOK1-dependent manner. TAOK1 interacted with IL-17RA. IL-17RA knockdown improved DNA damage and inflammatory responses in cells and alleviated cognitive impairment and neuroinflammation in AD mice. Overall, ESK protects against DNA damage-mediated neuroinflammation by promoting TAOK1 and inhibiting IL-17 signaling, thereby improving cognitive dysfunction in 3xTg-AD mice.},
}

@article {pmid42556030,
year = {2026},
author = {Rodriguez, A and Judge, B and Shelley, N and Mehta, V and Friedrichsen, K and Strain, J and Benzinger, TL and Schindler, SE and Holtzman, DM and Cross, AH and Brier, MR},
title = {Clinical features of older MS patients with and without Alzheimer disease biomarkers.},
journal = {Multiple sclerosis and related disorders},
volume = {114},
number = {},
pages = {107406},
doi = {10.1016/j.msard.2026.107406},
pmid = {42556030},
issn = {2211-0356},
abstract = {Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammatory demyelination and axonal injury. Magnetic resonance imaging (MRI) plays a central role in MS diagnosis. Recent work suggests that biomarkers indicative of Alzheimer's disease (AD) are markedly reduced in people with MS. Whether differences in AD biomarkers are related to different features of MS, including MRI characteristics or treatment history, is unclear. In this study, 100 MS patients from Washington University in St. Louis underwent review of their most recent MRI as well as their prior and present MS disease-modifying treatment (DMT) exposures. We then ascertained the relation of MRI features and DMT to plasma AD biomarker measurements, with only a small subset (N=7) demonstrating APS2+ biomarker evidence of AD. Lesion distribution across MS topographies and total white matter lesion (WML) burden were both similar across MS patients with and without biomarker evidence of AD. Central vein sign (CVS), a recently integrated imaging biomarker of MS, was highly prevalent across the MS cohort and did not differ by AD biomarker status or MS clinical typicality at diagnosis, supporting the MS diagnoses even for people with atypical initial presentations. DMT exposure history showed associations with AD biomarkers: longer exposure to B cell-depleting anti-CD20 monoclonal antibody therapies (BCDT) corresponded to lower levels of amyloid pathology as measured by plasma biomarkers, and longer exposure to interferon-beta corresponded to a less pathological Aβ42/40 ratio. These findings indicate that structural MRI features do not explain differences in AD biomarker profiles in MS, whereas treatment-related immunologic effects may contribute to variation in AD pathology risk in MS patients.},
}

@article {pmid42556278,
year = {2026},
author = {Shi, Z and Cheng, X and Zhang, C and Hu, J and He, X and Chen, S and Wu, H and Tian, M and Yan, C and He, L},
title = {Vorinostat ameliorates cognitive impairment and Tau pathology in an AAV-P301L-Tau-induced tauopathy mouse model: insights into neuroinflammation and PI3K/AKT/GSK3β signaling.},
journal = {International immunopharmacology},
volume = {187},
number = {},
pages = {117216},
doi = {10.1016/j.intimp.2026.117216},
pmid = {42556278},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with significant sex-related differences, exhibiting a higher incidence rate in elderly women. Tau pathology has been implicated in sex-associated differences in AD susceptibility and disease progression, contributing to differential pathological burden between males and females. Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi) used in cancer treatment, has shown potential therapeutic effects in various neurological and psychiatric disorders; however, the mechanisms underlying its regulation of tau-associated pathology remain poorly understood, with limited evidence regarding its effects in tau-related neurodegenerative conditions. In this study, we investigated the effects of SAHA treatment on an AAV-P301L-Tau-induced tauopathy model. In vivo, we observed that SAHA administration significantly improved p-Tau levels in the hippocampus and cortex of mice, reduced microglial activation and neuronal damage, and alleviated tauopathy-associated cognitive impairments. Our findings revealed sex-associated differences in Tau-related pathological alterations, with female mice exhibiting greater pathological changes and differential responses to SAHA treatment in several molecular and histological indicators. Further combined in vivo and in vitro experiments revealed that SAHA was associated with modulation of the PI3K/AKT/GSK3β signaling pathway, suppression of NF-κB activation, and attenuation of neuroinflammatory responses, including reductions in experimentally measured inflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). These molecular alterations may represent important regulatory components contributing to the neuroprotective effects of SAHA, rather than acting as the sole determinants of its therapeutic efficacy. In summary, these results indicate that SAHA can improve Tau-associated pathological alterations in an AAV-P301L-Tau-induced tauopathy model. The potential mechanisms may involve coordinated regulation of multiple pathological processes, including modulation of Tau phosphorylation, neuroinflammatory responses, and aging-associated signaling pathways. The observed sex-dependent responses to SAHA provide additional insights into the potential influence of biological sex on HDACi-based therapeutic strategies, although the molecular mechanisms underlying these differences require further investigation.},
}

@article {pmid42556319,
year = {2026},
author = {Koldamova, R and Fitz, NF and Lefterov, I},
title = {When less is more and when it isn't: Microglial Spi1 and the limits of what we know.},
journal = {Neuron},
volume = {114},
number = {15},
pages = {2669-2671},
doi = {10.1016/j.neuron.2026.06.017},
pmid = {42556319},
issn = {1097-4199},
mesh = {Animals ; *Microglia/metabolism ; Proto-Oncogene Protein Spi-1 ; *Trans-Activators/genetics/metabolism ; *Proto-Oncogene Proteins/metabolism/genetics ; Mice ; *Alzheimer Disease/metabolism/pathology ; Humans ; Amyloid beta-Peptides/metabolism ; },
abstract = {Microglia are key players in Alzheimer's disease, but the transcriptional control of their phagocytic function remains unclear. Kim et al. show that mouse microglial Spi1 deletion worsens amyloid pathology by impairing Aβ clearance through Syk, Lyn, and Fcgr1, providing new insight into PU.1-dependent regulatory networks and microglial functions in neurodegeneration.},
}

Animals
*Microglia/metabolism
Proto-Oncogene Protein Spi-1
*Trans-Activators/genetics/metabolism
*Proto-Oncogene Proteins/metabolism/genetics
Mice
*Alzheimer Disease/metabolism/pathology
Humans
Amyloid beta-Peptides/metabolism

@article {pmid42556344,
year = {2026},
author = {Villareal, JAB and Bathe, T and Rosa, A and Sharma, RV and Hernández Gómez, EO and Ryan, AM and Hawkinson, TR and Tuzzolo, AM and Medina-Parrilla, E and Phillips, JL and Tsering, W and Iturbe, AA and Giasson, BI and Sun, RC and Gentry, MS and Prokop, S},
title = {Corpora amylacea profiling reveals disease stage and brain region-specific alterations in glycogen metabolism in Alzheimer's disease patient brains.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102968},
doi = {10.1016/j.xcrm.2026.102968},
pmid = {42556344},
issn = {2666-3791},
abstract = {Increasing evidence indicates that shifts in brain polysaccharide metabolism can influence the progression of multiple neurodegenerative diseases. Here, we profile corpora amylacea (CA) in 230 postmortem human brains, revealing significantly higher densities in Alzheimer's disease (AD) patients when compared with patients with other or no neurodegenerative diseases and a tight correlation of CA density with neurofibrillary tangle (NFT) pathology. Immunohistochemical profiling using an anti-glycogen antibody confirms the polysaccharide nature of CA and reveals plaque-like glycogen patches (GPs) and densely aggregated intraneuronal glycogen in AD patient brains correlated with the emergence of NFT pathology. matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) orthogonally verifies the polysaccharide identity of these structures and that GPs can be consistently observed at early neuropathological disease stages. GPs are also observed in murine models of AD-like pathology, correlating with tau pathology. The identification of these AD-associated glycogen pathologies in the human brain implies that alterations in glycogen metabolism are tightly associated with AD pathogenesis.},
}

@article {pmid42556454,
year = {2026},
author = {Xue, M and Pan, H and He, Y and Li, H and Zhou, H and Cheng, K and Xiao, C and Zhao, J and Jia, X and Li, Y and Liu, D and Yan, K},
title = {An accessible digital single-molecule sensing platform for plasma P-tau217 quantification in Alzheimer's disease screening.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {593},
number = {},
pages = {121255},
doi = {10.1016/j.cca.2026.121255},
pmid = {42556454},
issn = {1873-3492},
abstract = {BACKGROUND: Early detection of Alzheimer's disease (AD) necessitates affordable and accessible blood biomarkers. Plasma phosphorylated tau 217 (P-tau217) is promising, but low-cost platforms for large-scale screening remain limited.

METHODS: We validated a Digital Single-Molecule Sensing (DiSMS) platform for plasma P-tau217 quantification. A reference interval was established in Cohort I (discovery, n = 325, comprising 143 cognitively unimpaired controls, 80 CE, 34 frontotemporal dementia [FTD], and 68 subcortical ischemic vascular dementia [SIVD] patients). Diagnostic performance was validated in Cohort II (n = 242; 77 CE, 165 controls). Cross-platform concordance was assessed against the Simoa HD-X in 137 paired samples.

RESULTS: The healthy reference interval was 0.09-0.51 pg/mL. In Cohort II, P-tau217 strongly distinguished AD from controls (accuracy 93.4% [95% CI: 90.3%-96.5%], sensitivity 92.2% [95% CI: 83.2%-96.8%], specificity 93.9% [95% CI: 88.8%-96.9%]). A two-cutoff approach (< 0.40, 0.40-0.50, > 0.50 pg/mL) yielded 94.1% accuracy and 95.9% sensitivity, leaving 8.4% of cases in the intermediate zone. DiSMS exhibited strong concordance with the Simoa (concordance rate = 94.9%; Spearman r = 0.94, P < 0.001). Plasma P-tau217 was significantly higher in AD than FTD (median 0.25 pg/mL) and SIVD (median 0.36 pg/mL) (both P < 0.001). Age-adjusted AUC was moderate for AD versus SIVD (0.777) but limited for AD versus FTD (0.665; sensitivity/specificity below 65%).

CONCLUSIONS: The DiSMS platform enables accurate, cost-accessible plasma P-tau217 quantification for AD screening, meeting consensus guidelines (≥90%). The limited P-tau217 performance for differentiating AD from FTD (AUC = 0.665) highlights the need for integration with complementary biomarkers or clinical assessments.},
}

@article {pmid42556482,
year = {2026},
author = {Lu, QX and Guan, W},
title = {A role for apolipoprotein E4 (ApoE4) in the pathogenesis of depressive symptoms and Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118316},
doi = {10.1016/j.bcp.2026.118316},
pmid = {42556482},
issn = {1873-2968},
abstract = {Depression is a chronic mental disorder that is often difficult to diagnose and mostly left untreated. Apolipoprotein E (ApoE) is a lipid transport protein that plays a central role in the metabolism of plasma lipoproteins and the transport of lipids within tissues. Among its three major isoforms, only ApoE4 has a unique structural variant that confers significant neurotoxicity not present in the other two subtypes. ApoE4 not only disrupts lipid metabolism but also interferes with neuroimmune regulation and mitochondrial dynamics, thereby impairing synaptic integrity. It is a major genetic risk factor for Alzheimer's disease (AD) and accelerates its age of onset. Although developing depression in midlife may be a risk factor for AD, the underlying mechanisms by which ApoE4 influences depression or depression-related behaviors associated with AD remain fragmented, and systematic integrative reviews on this topic are scarce. We integrate existing evidence to elucidate the role of ApoE4 in depression or AD-associated prodromal depressive-like behaviors, with a focus on how its dysfunction disrupts cellular lipid homeostasis, impairs synaptic plasticity, and damages mitochondrial function. We also explored specific therapeutic strategies targeting the pathological defects of ApoE4 that enhance synaptic resilience, and utilizing conformational modulating small molecules such as EZ-482 and ALZ-801 to treat depressive symptoms in early AD. Thus, these findings indicate that ApoE4 may influence the progression of depressive phenotypes through multiple pathological pathways, making it a promising therapeutic target for treating depression comorbid with early AD.},
}

@article {pmid42556648,
year = {2026},
author = {Huang, W and Huang, J and Kuang, N and Wu, J and Feng, F and Luo, Y and Huang, N},
title = {Mitochondrial homeostasis dysregulation: Potential mechanisms of Alzheimer's disease mediated by TDP-43.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103290},
doi = {10.1016/j.arr.2026.103290},
pmid = {42556648},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) exhibits substantial clinical and pathological heterogeneity that is not fully explained by amyloid-β and tau pathology alone. TAR DNA-binding protein 43 (TDP-43) is increasingly recognized as a frequent copathology in AD, particularly in limbic regions, where its presence is associated with accelerated cognitive decline. Disruption of mitochondrial homeostasis is also an early and consistent feature of AD and contributes to neuronal vulnerability. In this review, we summarize current evidence linking TDP-43 pathology to impaired mitochondrial homeostasis in AD. We outline key features of mitochondrial homeostasis in neurons, review neuropathological and clinical data supporting the relevance of TDP-43 in AD, and synthesize emerging mechanisms by which TDP-43 may perturb mitochondrial homeostasis, including effects on expression, aggregation and localization, quality control, organelle dynamics, and endoplasmic reticulum-mitochondria communication.},
}

@article {pmid42556890,
year = {2026},
author = {Giuliani, C and Schmidlin, PR and Fakheran, O},
title = {THE ROLE OF PERIODONTITIS IN THE INITIATION AND PROGRESSION OF COGNITIVE DISORDERS: AN UMBRELLA REVIEW.},
journal = {The journal of evidence-based dental practice},
volume = {26},
number = {3},
pages = {102307},
doi = {10.1016/j.jebdp.2026.102307},
pmid = {42556890},
issn = {1532-3390},
mesh = {Humans ; *Periodontitis/complications ; Disease Progression ; *Cognition Disorders/etiology ; Risk Factors ; Alzheimer Disease/etiology ; Systematic Reviews as Topic ; },
abstract = {BACKGROUND: Cognitive disorders are a major cause of morbidity worldwide, and accumulating evidence indicates that chronic systemic inflammation may play a key role in their initiation and progression. Periodontitis, a prevalent chronic inflammatory oral disease, has been increasingly recognized as a potential risk factor for cognitive disorders.

OBJECTIVE: This umbrella review synthesized evidence from systematic reviews and meta-analyses investigating the association between periodontitis and cognitive disorders, including Alzheimer's disease (AD), dementia and cognitive impairment.

METHODS: Following JBI methodological guidance for umbrella reviews, a comprehensive search was conducted across seven databases (Medline, Embase, Cochrane Library, CINAHL, PsycINFO, Web of Science, Scopus) from inception to April 2025 to identify systematic reviews and meta-analyses on the association between periodontitis and cognitive disorders in humans. Two reviewers independently performed study selection, data extraction, and quality appraisal using the JBI Critical Appraisal Tool. Due to heterogeneity, findings were synthesized narratively.

RESULTS: Twenty systematic reviews and meta-analyses comprising 333 primary studies were included. Most reviews reported a significant association between periodontitis and AD or dementia. Meta-analyses consistently found increased risk estimates, with the strongest associations for severe periodontitis. Biological plausibility was supported by shared inflammatory pathways and detection of periodontal pathogens in brain tissue. However, evidence was predominantly observational, with substantial heterogeneity in diagnostic criteria.

CONCLUSION: Evidence suggests a potential link between periodontitis and cognitive disorders, though results are inconsistent and causality remains unproven. Inflammatory and microbial mechanisms are proposed, but well-designed longitudinal and interventional studies with standardized criteria are needed.},
}

Humans
*Periodontitis/complications
Disease Progression
*Cognition Disorders/etiology
Risk Factors
Alzheimer Disease/etiology
Systematic Reviews as Topic

@article {pmid42557116,
year = {2026},
author = {Wei, M and Zhang, J and Shi, J and Li, T and Yao, L and Li, F and Xiao, W and Ni, J and Tian, J},
title = {Temporal order of clinical symptoms in Alzheimer's disease.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100253},
doi = {10.1016/j.inpsyc.2026.100253},
pmid = {42557116},
issn = {1741-203X},
abstract = {BACKGROUND: Understanding the temporal order of clinical symptoms is critical for improving disease progression assessment in biomarker-defined Alzheimer's disease (AD). However, the sequential emergence of cognitive, neuropsychiatric, and functional manifestations remains incompletely characterized. The purpose of this study is to characterize the population-level sequence in which Alzheimer's disease symptoms appear, to help understand how the disease is progressing.

METHODS: We analyzed 932 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 546 amyloid-positive individuals across the AD continuum and 386 amyloid-negative individuals in the comparison group. Longitudinal cumulative incidence was analyzed to estimate the temporal emergence of major clinical symptoms. Any symptom onset was defined using a > 50% cumulative incidence threshold. Cross-sectional relationships between the sequence of clinical symptoms and Mini-Mental State Examination (MMSE) scores were analyzed using locally estimated scatterplot smoothing (LOESS). The concordance between the clinical symptom sequence and PET-derived Braak staging was assessed using weighted kappa statistics.

RESULTS: A reproducible temporal ordering of clinical symptoms was observed across longitudinal and cross-sectional analyses. Memory impairment emerged earliest, affecting 63.75% of participants at baseline, followed by behavioral and affective symptoms. At intermediate stages, executive dysfunction and instrumental activities of daily living (IADL) impairment affected 52.44% and 54.85% of participants, respectively. Language and visuospatial impairments appeared later, affecting 51.25% and 51.54% of participants, respectively, followed by psychotic symptoms and severe functional decline in basic activities of daily living (BADL), which suggests the disease has reached its late stage. The order in which different symptom groups appear-from memory to executive function and instrumental abilities, then language and visuospatial skills, and finally psychotic symptoms and basic abilities-shows moderate consistency respectively with CDR staging (κ = 0.596, 95%CI: 0.524-0.668), and the PET-derived Braak staging (κ = 0.517, 95%CI: 0.436-0.598).

CONCLUSION: Clinical symptoms in AD tend to emerge in a temporal sequence. This finding may help to better characterize disease progression clinically, serving as a symptom-staging framework for symptomatic AD and providing interpretable turning points for clinical assessment and individualized management.},
}

@article {pmid42557118,
year = {2026},
author = {Xu, S and Yang, Z and Zhi, Y and Yu, S and Zhang, T and Jiang, J and Tang, J and He, H and Lu, M and Wang, X and Wu, Q and Zhao, X},
title = {Retraction notice to "The effects of antimony on Alzheimer's disease-like pathological changes in mice brain" [Sci. Total Environ. 760 (2021) 143235].},
journal = {The Science of the total environment},
volume = {},
number = {},
pages = {182162},
doi = {10.1016/j.scitotenv.2026.182162},
pmid = {42557118},
issn = {1879-1026},
}

@article {pmid42557399,
year = {2026},
author = {Zhang, Y},
title = {Exercise-Mediated Modulation of the NLRP3 Inflammasome in Aging and Neurodegenerative Diseases: Mechanisms, Microglial Crosstalk, and Translational Perspectives.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42557399},
issn = {1559-1182},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Microglia/metabolism/pathology ; *Aging/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Humans ; *Inflammasomes/metabolism ; *Exercise/physiology ; },
abstract = {Regular engagement in physical exercise has been recognized as a formidable non-pharmacological intervention aimed at mitigating age-associated neuroinflammation and neurodegenerative phenomena. A fundamental mechanism that underpins these advantageous effects pertains to the modulation of the NLRP3 inflammasome, which serves as a pivotal regulator of innate immune responses within microglial cells. The aging process is marked by a state of chronic low-grade inflammation, commonly referred to as "inflammaging," which is instigated by mitochondrial dysfunction, oxidative stress, and metabolic disturbances; these factors collectively facilitate the activation of NLRP3 and the subsequent secretion of pro-inflammatory cytokines, notably IL-1β. Contemporary research findings suggest that physical exercise diminishes NLRP3 inflammasome activation through various interrelated pathways. These pathways encompass the reduction of reactive oxygen species production, the inhibition of TXNIP-mediated assembly of the inflammasome, and the modulation of metabolites derived from the gut, such as trimethylamine N-oxide. In addition, factors circulating as a result of exercise, which include irisin and meteorin-like protein, play a significant role in promoting systemic and central anti-inflammatory responses, thereby impacting the functional dynamics of microglia. In experimental paradigms investigating the phenomena of aging and neurodegenerative disorders (NDDs), notably Alzheimer's and Parkinson's diseases, physical activity has been shown to diminish amyloid accumulation, tau pathology, and microglial activation, primarily through the attenuation of NLRP3 signaling pathways. Collectively, these observations underscore the role of exercise as a pivotal regulator of neuroimmune equilibrium, thereby providing mechanistic elucidation of its potential therapeutic efficacy in alleviating inflammaging and decelerating the progression of NDDs.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Microglia/metabolism/pathology
*Aging/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
Humans
*Inflammasomes/metabolism
*Exercise/physiology

@article {pmid42557842,
year = {2026},
author = {Rubtsova, K},
title = {Age-Associated B Cells: Origins, Regulation, and Tissue-Specific Pathogenic Contributions in Autoimmune, Metabolic, and Neurological Diseases.},
journal = {Immunological reviews},
volume = {341},
number = {1},
pages = {e70144},
doi = {10.1111/imr.70144},
pmid = {42557842},
issn = {1600-065X},
mesh = {Humans ; Animals ; *Autoimmune Diseases/immunology/metabolism ; *B-Lymphocytes/immunology/metabolism ; *Aging/immunology ; *Nervous System Diseases/immunology/metabolism ; Cell Differentiation ; Organ Specificity ; Autoimmunity ; Signal Transduction ; },
abstract = {Age-associated B cells (ABCs) are a distinct B cell population characterized by coexpression of T-bet and CD11c. First described in aged female mice and autoimmune-prone strains, ABCs are now recognized to be associated with multiple human autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, where their frequency correlates with disease activity. Their differentiation requires toll-like receptor (TLR) signaling, IFN-γ, IL-21, BCR engagement, with ZEB2 emerging as the nonredundant transcriptional master regulator of ABC identity. Here we review requirements for ABC differentiation, their defining phenotypic and functional features, and their tissue-specific distribution and pathogenic contributions in diverse inflammatory settings. A central theme is that ABCs are tissue-homing cells whose contribution extends beyond blood and lymphoid organs. In kidney, inflamed synovium, salivary glands, and adipose tissue, ABCs drive pathology through locally differentiated autoantibody-secreting cells, stromal activation, antigen presentation, and cytokine production. We further discuss roles for ABCs in neurological diseases, including their enrichment in the cerebrospinal fluid in multiple sclerosis (MS) and their contribution to neuroinflammation in Alzheimer's disease, and highlight the EBV-ABC axis as a mechanism linking viral infection to autoimmunity. In summary, ABCs are multi-functional, tissue-adaptable pathogenic effectors whose contributions to human disease extend beyond classical autoimmunity into metabolic dysfunction and neurodegeneration.},
}

Humans
Animals
*Autoimmune Diseases/immunology/metabolism
*B-Lymphocytes/immunology/metabolism
*Aging/immunology
*Nervous System Diseases/immunology/metabolism
Cell Differentiation
Organ Specificity
Autoimmunity
Signal Transduction

@article {pmid42557858,
year = {2026},
author = {Li, X and Yang, F and Jiang, Y and Zhao, F and Liu, F},
title = {HNRNPC Succinylation Influences the Neurodegeneration of Alzheimer's Disease Through YME1L1-Mediated Mitochondrial Metabolism.},
journal = {Aging cell},
volume = {25},
number = {8},
pages = {e70646},
doi = {10.1111/acel.70646},
pmid = {42557858},
issn = {1474-9726},
support = {Z2023168//National Key Clinical Specialty Scientific Research Project/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *Mitochondria/metabolism ; Mice ; Mice, Transgenic ; Sirtuins/metabolism ; Humans ; Disease Models, Animal ; *Mitochondrial Proteins/metabolism ; Metalloendopeptidases ; },
abstract = {Mitochondrial dysfunction and abnormal energy metabolism are important pathological features of Alzheimer's disease (AD). This study investigates how mitochondrial protease YME1L1 affects mitochondrial function and its upstream regulation in the pathogenesis of AD. The AD model was established by using APP/PS1 transgenic mice, primary neurons treated with Aβ1-42, and HT22 cells. The silencing of YME1L1 was achieved to evaluate its effects on mitochondrial function and OPA1 protein hydrolysis. RIP-qPCR and RNA pull-down test were used to evaluate the interaction between HNRNPC and YME1L1 mRNA. The protein succinylation level was detected by proteomic analysis of succinylation, and co-immunoprecipitation (Co-IP) was used to verify the succinylation of HNRNPC. Cognitive ability was tested by behavioral tests, including the Morris water maze, Y-maze, object recognition test, and olfactory test. Finally, the therapeutic potential of SIRT5 was studied by an overexpression experiment in an AD model. YME1L1 was significantly upregulated in the AD model, which promoted mitochondrial dysfunction and neuronal damage through OPA1 hydrolysis. HNRNPC enhances the stability of YME1L1 mRNA through an m6A-dependent mechanism, while its own K50 succinylation enhances the stability of HNRNPC by competitively inhibiting TRIM25-mediated ubiquitination, further amplifying the expression of YME1L1. SIRT5 downregulation in AD elevated HNRNPC succinylation levels. SIRT5 overexpression promoted HNRNPC desuccinylation, reduced YME1L1 expression, restored mitochondrial function, and ameliorated Aβ deposition and cognitive deficits in AD mice. The SIRT5-HNRNPC-YME1L1 axis contributes to AD pathogenesis by disrupting OPA1 proteolysis and mitochondrial dynamics. Targeting HNRNPC succinylation represents a promising therapeutic strategy for AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
*Mitochondria/metabolism
Mice
Mice, Transgenic
Sirtuins/metabolism
Humans
Disease Models, Animal
*Mitochondrial Proteins/metabolism
Metalloendopeptidases

@article {pmid42557872,
year = {2026},
author = {Vaughan, DP and Jensen, MT and Real, R and Fumi, RG and Wu, L and Lux, D and Hodgson, M and Jones, PS and Holland, N and Scotton, WJ and Serrano-Assensio, O and Quattrone, A and Heslegrave, AJ and Veleva, E and Swann, O and Zetterberg, H and Lynch, T and Mir, P and Stamelou, M and Seppi, K and Vandenberghe, R and Warner, TT and Lees, A and Bhatia, KP and Church, A and Kobylecki, C and Leigh, PN and Hu, MT and Taba, P and Matsalu, T and Pavese, N and Ghosh, BCP and Picillo, M and Wallin, J and Svenningson, P and Sánchez-Gómez, A and Fernández, M and Cámara, A and Planellas, L and Compta, Y and , and Quaegebeur, A and Jaunmuktane, Z and Revesz, T and Jabbari, E and Rohrer, JD and Rowe, JB and Morris, HR},
title = {Defining the underlying pathology of corticobasal syndrome using clinical features and biomarkers.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag257},
pmid = {42557872},
issn = {1460-2156},
abstract = {Corticobasal degeneration (CBD) is a late onset progressive neurodegenerative condition of the 4-repeat-tauopathy-type, classically presenting with asymmetrical rigidity, dystonia and myoclonus. In the most recent diagnostic criteria, Armstrong and colleagues (2013) described four clinical phenotypes associated with this pathology, including corticobasal syndrome (CBS), through a large retrospective analysis of published cases and confirmed brain bank cases of CBD. However, predicting CBD pathology remains challenging. With the advent of disease-modifying therapies, it has become particularly important to distinguish Alzheimer's disease pathology from other underlying pathologies. We therefore combined two prospectively recruited cohorts of patients with CBS and analysed their key demographic, clinical and biomarker features. We included a separate cohort from UK brain banks who were diagnosed with CBS in life. We divided patients into three groups: CBS-Alzheimer's (CBS-AD), CBS-non-Alzheimer's (CBS-non-AD) and CBS-indeterminate (CBS-IDT) based on biomarkers and pathology, comparing clinical features, regional volumetric MRI measures and Nucleic Acid-Linked Immuno-Sandwich Assay with detection by next generation sequencing (NULISAseq) blood protein levels between groups. We performed additional analyses of pathologically verified cases. We included 397 participants, of which 57.7% were female. The mean age at symptom onset was 65.9 years. AD biomarkers and pathology permitted classifying 47 (11.8%) of the cases as CBS-AD, 134 (33.8%) as CBS-non-AD and 216 (54.4%) as CBS-IDT. Patients with CBS-AD had a younger age at onset (61.8 years vs 66.1 years, P < 0.01 and less severe motor deficits (non-significantly lower scores on MDS-UPDRS and PSPRS) and more severe cognitive impairment (non-significantly lower scores on MoCA). Patients with CBS-AD had higher rates of cortical sensory impairment (P = 0.087) and lower rates of limb dystonia (P < 0.01) and falls (P < 0.01) compared to the CBS-non-AD group. Volumetric MRI analysis revealed smaller parietal lobe volumes in CBS-AD (P = 0.01). The most common pathological diagnoses were PSP, CBD and AD. Limb dystonia was more common in people with CBD and PSP pathology (P = 0.077). Falls, impaired verbal fluency and impaired vertical saccades were confirmed as more common in PSP (P = 0.046, P = 0.040, P = 0.012, respectively). In summary, younger onset, less parkinsonism and more cognitive and cortical sensory impairment, along with reduced MRI parietal volumes point to CBS-AD, while limb dystonia, falls and worse verbal fluency relate to CBS-non-AD. Clinical, imaging and blood-biomarkers in can augment the Armstrong criteria in predicting the underlying pathology of corticobasal syndromes.},
}

@article {pmid42557882,
year = {2026},
author = {Pini, L and Imbimbo, BP and Corbetta, M},
title = {Reply: The disconnectome as target in Alzheimer disease: a promising framework or a premature end-point?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag263},
pmid = {42557882},
issn = {1460-2156},
}

@article {pmid42557932,
year = {2026},
author = {Wu, H and Chen, Q and Fang, M and Tang, H and Liu, H and Liu, J and Zhang, J and Chi, L and Liu, S and Xin, J and Leng, L and Wang, P and Chi, S and Li, Y and Chen, J and Zhang, L and Zhang, J and Ma, Q and Wang, X and Meng, X and Nao, J and Li, X and Lv, Y and Jia, Y and Zhao, Q and Liu, C and Gan, J and Zhu, J and Song, Y and Li, H and Fei, M and Guo, X and Liu, J and Peng, G and Chen, X and Ji, Y},
title = {Lecanemab use in Chinese patients with Alzheimer's disease: a 12-month multicenter real-world study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71702},
doi = {10.1002/alz.71702},
pmid = {42557932},
issn = {1552-5279},
support = {TJYXZDXK-3-014B//Tianjin Key Medical Discipline Construction Project/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/diagnostic imaging ; Female ; Biomarkers/blood ; Male ; Aged ; China ; Treatment Outcome ; Aged, 80 and over ; Amyloid beta-Peptides ; East Asian People ; },
abstract = {INTRODUCTION: We evaluated lecanemab's safety and cognitive outcomes in Chinese patients with Alzheimer's disease (AD) and the utility of blood-based biomarkers (BBMs) for treatment guidance.

METHODS: A multicenter, real-world cohort enrolled 1042 patients receiving lecanemab, with 453, 359, 97 patients followed up at 3, 6, 12 months, respectively. Safety outcomes included amyloid-related imaging abnormalities (ARIA) and infusion-related reactions (IRRs), and the main clinical outcome was Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score change.

RESULTS: Of 1,042 patients, ARIA occurred in 7.87%, and IRRs in 16.12%. Discontinuation was 16.51%, mainly due to financial burden. CDR-SB did not change at 12 months overall or in any subgroup. High-accuracy BBMs were the sole AD biomarker assay in 5.28%, with comparable outcomes.

DISCUSSION: Lecanemab exhibited favorable 12-month safety, with no clear evidence of cognitive decline, and BBMs hold potential for treatment guidance. Further studies using a control group are now warranted.},
}

Humans
*Alzheimer Disease/drug therapy/blood/diagnostic imaging
Female
Biomarkers/blood
Male
Aged
China
Treatment Outcome
Aged, 80 and over
Amyloid beta-Peptides
East Asian People

@article {pmid42557952,
year = {2026},
author = {Acharya, A and Thurman, M and Sutar, D and Olasunkanmi, OI and Malik, JR and Dyavar, SR and Végvári, Á and Byrareddy, SN},
title = {In-Vitro Evaluation of HIV/SARS-CoV-2 Co-Infection Mediated Proteomic Changes in Astrocytes and Pericytes Reveals Altered Signaling Pathways Associated With Neurodegenerative Disorders.},
journal = {Journal of medical virology},
volume = {98},
number = {8},
pages = {e71086},
doi = {10.1002/jmv.71086},
pmid = {42557952},
issn = {1096-9071},
support = {R01DA05284/NH/NIH HHS/United States ; R01DA061678/NH/NIH HHS/United States ; },
mesh = {*Pericytes/virology/metabolism ; *Astrocytes/virology/metabolism ; Humans ; *Signal Transduction ; *HIV Infections/metabolism/complications/virology ; *SARS-CoV-2/physiology ; *Coinfection/virology/metabolism ; *Neurodegenerative Diseases/metabolism/virology ; *COVID-19/metabolism/complications/virology ; Proteomics ; Microglia/virology/metabolism ; Post-Acute COVID-19 Syndrome ; Virus Replication ; Proteome ; },
abstract = {Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system (CNS), known as neuro-PASC. Notably, people with HIV (PWH), who suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction, collectively known as neuro-HIV, are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuro-HIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study, using an in-vitro cell culture model, we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes, and pericytes. Our results demonstrated that majority of brain cell types support SARS-CoV-2 replication, in the presence and absence of HIV infection. Furthermore, in both mono- and co-infected cells, there were varying degree of up- and downregulation of SARS-CoV-2 host cell entry factors, such as ACE2, TMPRSS2, NRP1, and TRIM28, and inflammatory cytokines including IL-6, TNF-α, and IL-1β. Moreover, conditioned media collected from HIV, SARS-CoV-2, and HIV/SARS-CoV-2 co-infected astrocytes and pericytes were shown to be neurotoxic. Additionally, proteomic analysis has revealed a unique set of proteins significantly up/down regulated in HIV/SARS-CoV-2 co-infected astrocytes and pericytes. The gene set enrichment analysis of these proteins indicates dysregulation of lipid, energy, and immune metabolism pathways linked to neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis. These in-vitro findings indicate that astrocytes and pericytes from HIV/SARS-CoV-2 co-infection exhibit altered protein expression profiles, implicating dysregulated signaling pathways associated with neurodegenerative dysfunction.},
}

*Pericytes/virology/metabolism
*Astrocytes/virology/metabolism
Humans
*Signal Transduction
*HIV Infections/metabolism/complications/virology
*SARS-CoV-2/physiology
*Coinfection/virology/metabolism
*Neurodegenerative Diseases/metabolism/virology
*COVID-19/metabolism/complications/virology
Proteomics
Microglia/virology/metabolism
Post-Acute COVID-19 Syndrome
Virus Replication
Proteome

@article {pmid42557955,
year = {2026},
author = {Trudel, L and Therriault, J and Macedo, AC and Aumont, E and Hosseini, SA and Benedet, AL and Hazrati, LN and Gauthier, S and Zetterberg, H and Vitali, P and Ashton, NJ and Rosa-Neto, P and , },
title = {Predicting continuous amyloid PET levels with CSF and plasma brain-derived p-tau217.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71723},
doi = {10.1002/alz.71723},
pmid = {42557955},
issn = {1552-5279},
support = {//Weston Brain Institute/ ; MOP-11-51-31//Canadian Institutes of Health Research (CIHR)/ ; RFN 152985 159815 162303//Canadian Institutes of Health Research (CIHR)/ ; MOP-11-51-31 -team 1//Canadian Consortium of Neurodegeneration and Aging (CCNA)/ ; NIRG-12-92090 NIRP-12-259245//the Alzheimer's Association/ ; 34874//the Alzheimer's Association/ ; 33397//the Alzheimer's Association/ ; 2020-VICO-279314//the Fonds de Recherche du Québec - Santé (FRQS); Chercheur Boursier/ ; 2024-VICO-356138//the Fonds de Recherche du Québec - Santé (FRQS); Chercheur Boursier/ ; //the Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; U01 AG024904//Alzheimer's Disease Neuroimaging Initiative (ADNI); National Institutes of Health/ ; //the Fonds de Recherche du Québec - Santé/ ; //Fondation Brain Canada/ ; /ALZ/Alzheimer's Association/United States ; //Consortium canadien en neurodégénérescence associée au vieillissement/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/blood/metabolism ; *Positron-Emission Tomography ; Biomarkers/cerebrospinal fluid/blood ; Female ; *Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/blood ; *Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; *Brain/metabolism/diagnostic imaging ; Male ; Aged ; Phosphorylation ; },
abstract = {BACKGROUND: Staging amyloid beta (Aβ) burden along a continuous spectrum provides clinically relevant information. Conventional phosphorylated tau (p-tau)217 reliably identifies amyloid positron emission tomography (PET) positivity, but its ability to capture the full Aβ continuum is limited. Recently developed brain-derived (BD) p-tau217 assays enrich for central nervous system tau species and may improve specificity.

METHODS: We tested how closely BD p-tau217 reflected continuous Aβ and how accurately it could classify participants as Aβ positive or negative across different Centiloid (CL) thresholds in 924 participants from the Alzheimer's Disease Neuroimaging Initiative. Conventional and BD cerebrospinal fluid (CSF) and plasma p-tau217 biomarkers were quantified using the Alamar NULISAseq panel.

RESULTS: Across the full cohort, plasma BD p-tau217 demonstrated the strongest continuous association with PET CL (R[2] = 0.63), and the best prediction across the CL spectrum (root mean square error = = 24.5). Prediction was precise in cognitively unimpaired participants at low CL and reasonably accurate in cognitively impaired participants across intermediate-to-high CL.

CONCLUSIONS: Plasma BD p-tau217 best captured the amyloid PET continuum, with BD processing improving discrimination in plasma but not CSF.},
}

Humans
*tau Proteins/cerebrospinal fluid/blood/metabolism
*Positron-Emission Tomography
Biomarkers/cerebrospinal fluid/blood
Female
*Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/blood
*Amyloid beta-Peptides/metabolism/cerebrospinal fluid
*Brain/metabolism/diagnostic imaging
Male
Aged
Phosphorylation

@article {pmid42557961,
year = {2026},
author = {Carrigan, M and Birkenbihl, C and Klinger, HM and Langford, O and Coughlan, GT and Seto, M and Brown, JA and Li, A and Cuppels, M and Properzi, M and Chhatwal, J and Price, J and Schultz, A and Rentz, D and Amariglio, R and Krugers, HJ and Ossenkoppele, R and Johnson, K and Sperling, R and Hohman, TJ and Donohue, M and Buckley, RF},
title = {Sex specificity of resistance to caTAUstrophe.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71716},
doi = {10.1002/alz.71716},
pmid = {42557961},
issn = {1552-5279},
support = {WE.08-2024-06//Alzheimer Nederland/ ; WE.03-2021-03//Alzheimer Nederland/ ; K99 AG083063/AG/NIA NIH HHS/United States ; R01AG079142/AG/NIA NIH HHS/United States ; DP2AG082342/AG/NIA NIH HHS/United States ; R01AG073439/AG/NIA NIH HHS/United States ; 949570/ERC_/European Research Council/International ; U24AG074855/AG/NIA NIH HHS/United States ; U01AG082350/AG/NIA NIH HHS/United States ; },
mesh = {Female ; Humans ; *Amyloid beta-Peptides/metabolism ; *tau Proteins/metabolism ; Male ; Aged ; *Sex Characteristics ; *Alzheimer Disease/metabolism/pathology ; Aged, 80 and over ; Magnetic Resonance Imaging ; },
abstract = {INTRODUCTION: As amyloid beta (Aβ) accumulates, tau pathology spreads beyond medial temporal lobe (MTL) into neocortical (NEO) regions, though some older adults resist this progression, or what we call here "caTAUstrophe." Given previous evidence of higher tau levels in women, we tested how tau resistance presented in men and women separately.

METHODS: Employing data from 872 Aβ+ older adults across three cohorts, we trained sex-specific penalized linear regression models in individuals experiencing caTAUstrophe (females: NTrain = 172; males: NTrain = 121) to predict the expected NEO tau levels. We estimate resistance as lower-than-expected NEO tau levels in training-independent individuals (NTest = 579) to assess sex-specific resistance associates.

RESULTS: Relative feature importance in sex-specific expectation models differed in 97.7% of variables (false discovery rate-adjusted p value < 0.001). Age and Aβ burden associated with male resistance, while Clinical Dementia Rating, latent Preclinical Alzheimer's Cognitive Composite, and adjusted hippocampal volume were associates in both sexes.

DISCUSSION: Our study highlights sex-specific biological and clinical factors in the prediction of NEO tau and associates of resistance. Understanding sex-specific resistance pathways informs targeted Alzheimer's interventions.},
}

Female
Humans
*Amyloid beta-Peptides/metabolism
*tau Proteins/metabolism
Male
Aged
*Sex Characteristics
*Alzheimer Disease/metabolism/pathology
Aged, 80 and over
Magnetic Resonance Imaging

@article {pmid42557982,
year = {2026},
author = {Olayinka, O and Farrell, JJ and Zhu, C and Khurshid, Z and , and Martin, ER and Bush, WS and Pericak-Vance, MA and Wang, LS and Schellenberg, GD and Haines, JL and Lunetta, KL and Zhang, X and Farrer, LA},
title = {Stratification by a polygenic risk score of common variation aids in Alzheimer's disease rare variant discovery.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71710},
doi = {10.1002/alz.71710},
pmid = {42557982},
issn = {1552-5279},
support = {U01 AG024904/NH/NIH HHS/United States ; RF1AG054080/NH/NIH HHS/United States ; U01-AG058654/NH/NIH HHS/United States ; U54-AG052427/NH/NIH HHS/United States ; U19-AG068753/NH/NIH HHS/United States ; U01-AG062602/NH/NIH HHS/United States ; U01-AG 081230/NH/NIH HHS/United States ; U01-AG082665/NH/NIH HHS/United States ; P30-AG072978/NH/NIH HHS/United States ; P01AG03991/NH/NIH HHS/United States ; P01AG026276/NH/NIH HHS/United States ; P30AG066462/NH/NIH HHS/United States ; R01AG064614/NH/NIH HHS/United States ; U01AG052410/NH/NIH HHS/United States ; //Alzheimer's Disease Sequencing Project/ ; //Alzheimer's Disease Genetics Consortium/ ; AG033193/AG/NIA NIH HHS/United States ; AG049607/AG/NIA NIH HHS/United States ; AG033040/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; R01AG041797/AG/NIA NIH HHS/United States ; R01AG023629/AG/NIA NIH HHS/United States ; R01AG15928/AG/NIA NIH HHS/United States ; R01AG20098/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; R01 AG059716/AG/NIA NIH HHS/United States ; AI4AD//NIA/ ; //Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)/ ; U01AG057659//Follow Up Study/ ; U01AG062943//Follow Up Study/ ; U54AG052427//Follow Up Study/ ; U01AG058589//Follow Up Study/ ; U01AG058654//Follow Up Study/ ; U01AG058635//Follow Up Study/ ; RF1AG058066//Follow Up Study/ ; RF1AG057519//Follow Up Study/ ; R01AG048927//Follow Up Study/ ; RF1AG054074//Follow Up Study/ ; U01 AG006781//Adult Changes in Thought (ACT)/ ; U19 AG066567//Adult Changes in Thought (ACT)/ ; P30 AG062429//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066468//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062421//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066509//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066514//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066530//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066507//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066444//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066518//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066512//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066462//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072979//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072972//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072976//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072975//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072978//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072977//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066519//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062677//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG079280//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062422//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066511//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072946//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG062715//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072973//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066506//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066508//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066515//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072947//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072931//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG066546//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068024//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068053//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068077//Alzheimer's Disease Research Centers (ADRC)/ ; P20 AG068082//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072958//Alzheimer's Disease Research Centers (ADRC)/ ; P30 AG072959//Alzheimer's Disease Research Centers (ADRC)/ ; R01 AG11101//Alzheimer's Disease Research Centers (ADRC)/ ; RC4 AG039085//Alzheimer's Disease Research Centers (ADRC)/ ; K23 AG030944//Alzheimer's Disease Research Centers (ADRC)/ ; R01 AG019771//Indiana Memory and Aging Study (IMAS)/ ; R01 AG009956//Indiana Memory and Aging Study (IMAS)/ ; P30 AG010133//Indiana Memory and Aging Study (IMAS)/ ; R01 AG032990//Mayo Clinic (MAYO)/ ; U01 AG046139//Mayo Clinic (MAYO)/ ; R01 NS080820//Mayo Clinic (MAYO)/ ; RF1 AG051504//Mayo Clinic (MAYO)/ ; P50 AG016574//Mayo Clinic (MAYO)/ ; NS039764//Mayo Clinic (MAYO)/ ; NS071674//Mayo Clinic (MAYO)/ ; 5RC2HG005605//Mayo Clinic (MAYO)/ ; R01 AG027944//Mayo Clinic (MAYO)/ ; R01 AG028786//Mayo Clinic (MAYO)/ ; R01 AG019085//Mayo Clinic (MAYO)/ ; IIRG09133827//Mayo Clinic (MAYO)/ ; A2011048//Mayo Clinic (MAYO)/ ; R01 AG09029//Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE)/ ; R01 AG025259//Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE)/ ; U24 AG021886//National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)/ ; U24 AG056270//National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA- LOAD)/ ; //Texas Alzheimer's Research and Care Consortium (TARCC)/ ; //Darrell K Royal Texas Alzheimer's Initiative/ ; R01 AG019757//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; R01 AG021547//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; R01 AG027944//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; R01 AG028786//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; P01 NS026630//Vanderbilt University/Case Western Reserve University (VAN/CWRU)/ ; /ALZ/Alzheimer's Association/United States ; RF1 AG054023//Washington Heights-Inwood Columbia Aging Project (WHICAP)/ ; //University of Washington Families/ ; RF1 AG015473//Columbia University Hispanic Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA)/ ; //University of Toronto (UT)/ ; /WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; /CAPMC/CIHR/Canada ; R01 AG007584//Genetic Differences (GD)/ ; HL105756//National Heart, Lung, and Blood Institute (NHLBI)/ ; RC2HL102419//National Heart, Lung, and Blood Institute (NHLBI)/ ; //CHARGE/ ; //Austrian Stroke Prevention Study (ASPS)/ ; //Prospective Dementia Registry-Austria (ASPS/PRODEM-Aus)/ ; //Atherosclerosis Risk in Communities (ARIC)/ ; //Cardiovascular Health Study (CHS)/ ; //Erasmus Rucphen Family Study (ERF)/ ; //Framingham Heart Study (FHS)/ ; //Rotterdam Study (RS)/ ; //ASPS/ ; P20545-P05//Austrian Science Fond (FWF)/ ; P13180//Austrian Science Fond (FWF)/ ; //Medical University of Graz/ ; //ASPS-Fam/ ; //Austrian Science Fund (FWF)/ ; //Joint Programme - Neurodegenerative Disease Research (JPND)/ ; //BRIDGET/ ; //Austrian Research Promotion agency (FFG)/ ; //Austrian National Bank/ ; N01-HC-25195/HL/NHLBI NIH HHS/United States ; HHSN268201100006C/HL/NHLBI NIH HHS/United States ; HHSN268201100007C/HL/NHLBI NIH HHS/United States ; HHSN268201100008C/HL/NHLBI NIH HHS/United States ; HHSN268201100009C/HL/NHLBI NIH HHS/United States ; HHSN268201100010C/HL/NHLBI NIH HHS/United States ; HHSN268201100011C/HL/NHLBI NIH HHS/United States ; HHSN268201100012C/HL/NHLBI NIH HHS/United States ; U01 2U01HL096812//ARIC/ ; 2U01HL096814//ARIC/ ; 2U01HL096899//ARIC/ ; 2U01HL096902//ARIC/ ; 2U01HL096917//ARIC/ ; R01-HL70825//MRI/ ; HHSN268201200036C//CHS/ ; HHSN268200800007C//CHS/ ; N01HC55222//CHS/ ; N01HC85079//CHS/ ; N01HC85080//CHS/ ; N01HC85081//CHS/ ; N01HC85082//CHS/ ; N01HC85083//CHS/ ; N01HC85086//CHS/ ; U01HL080295//CHS/ ; U01HL130114//CHS/ ; 018947//EUROSPAN (European Special Populations Research Network)/ ; LSHG-CT-2006-01947//EUROSPAN (European Special Populations Research Network)/ ; //European Community's Seventh Framework Programme/ ; //European Commission under the programme/ ; //Erasmus Medical Center and Erasmus University/ ; //Rotterdam, the Netherlands Organization for Health Research and Development/ ; //Research Institute for Diseases in the Elderly (RIDE)/ ; //Ministry of Education, Culture and Science/ ; //Ministry for Health/ ; //Welfare and Sports/ ; //European Commission (DG XII)/ ; //Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO)/ ; //Netherlands Consortium for Healthy Aging (NCHA)/ ; R01AG11380//Cache County Study/ ; R01AG031272//Cache County Study/ ; R01AG21136//Cache County Study/ ; RF1AG054052//Cache County Study/ ; P50AG008012//Case Western Reserve University Brain Bank (CWRUBB)/ ; RF1AG058267//Case Western Reserve University Rapid Decline (CWRURD)/ ; NU38CK000480//Case Western Reserve University Rapid Decline (CWRURD)/ ; 3U01AG052410//Cuban American Alzheimer's Disease Initiative (CuAADI)/ ; 5R37AG015473//Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)/ ; RF1AG015473//Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)/ ; R56AG051876//Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA)/ ; 2R01AG09029//Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions)/ ; R01AG025259//Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions)/ ; 2R01AG048927//Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans Study (GenerAAtions)/ ; U01AG062602//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; 2014-A-004-NET//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; R01AG032289//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; R01AG048234//Gwangju Alzheimer and Related Dementias Study (GARD)/ ; R01AG027944//Hussman Institute for Human Genomics Brain Bank (HIHGBB)/ ; 5R01AG009956//Ibadan Study of Aging (IBADAN)/ ; //Longevity Genes Project (LGP)/ ; R01AG042188//LonGenity/ ; R01AG044829//LonGenity/ ; R01AG046949//LonGenity/ ; R01AG057909//LonGenity/ ; R01AG061155//LonGenity/ ; P30AG038072//LonGenity/ ; R01AG018016//Mexican Health and Aging Study (MHAS)/ ; 2R01AG09029//Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE)/ ; R01AG025259//Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE)/ ; 2R01AG048927//Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE)/ ; R01NS29993//Northern Manhattan Study (NOMAS)/ ; RF1AG054074//Peru Alzheimer's Disease Initiative (PeADI)/ ; GR066133/GR080002//Peru Alzheimer's Disease Initiative (PeADI)/ ; 340755/ERC_/European Research Council/International ; RF1AG054074//Puerto Rican Alzheimer Disease Initiative (PRADI)/ ; U01NS041588//Reasons for Geographic and Racial Differences in Stroke (REGARDS)/ ; U01AG052410//Research in African American Alzheimer Disease Initiative (REAAADI)/ ; P30 AG10161//Religious Orders Study (ROS)/ ; R01 AG15819//Religious Orders Study (ROS)/ ; P30 AG72975//Religious Orders Study (ROS)/ ; R01 AG42210//Religious Orders Study (ROS)/ ; R01 AG017917//RUSH Memory and Aging Project (MAP)/ ; R01 AG060747//RUSH Memory and Aging Project (MAP)/ ; //Miami Brain Endowment Bank (MBB)/ ; U01AG052410//University of Miami/Case Western/North Carolina A&T African American (UM/CASE/NCAT)/ ; R01AG028786//University of Miami/Case Western/North Carolina A&T African American (UM/CASE/NCAT)/ ; R01AG027161//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; R01AG054047//Wisconsin Registry for Alzheimer's Prevention (WRAP)/ ; R01AG069013//Mexico-Southern California Autosomal Dominant Alzheimer's Disease Consortium/ ; R01AG047649//Center for Cognitive Neuroscience and Aging/ ; R01AG063689//A4 Study/ ; U19AG010483//A4 Study/ ; U24AG057437//A4 Study/ ; //LSACs/ ; U54 HG003273//Human Genome Sequencing Center at the Baylor College of Medicine/ ; U54HG003067//Broad Institute Genome Center/ ; U01AG057659//American Genome Center at the Uniformed Services University of the Health Sciences/ ; U54HG003079//Washington University Genome Institute/ ; //ADSP FUS/ ; //Hussman Institute for Human Genomics (HIHG)/ ; //Center for Genome Technology (CGT)/ ; //National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site/ ; U24AG041689//NIAGADS/ ; /LM/NLM NIH HHS/United States ; //Phenotype Harmonization Consortium/ ; U19AG024904//Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; RF1AG058066//Alzheimer's Disease Neuroimaging Initiative (ADNI)/ ; W81XWH-12-2-0012//Department of Defense/ ; //AbbVie/ ; //Araclon Biotech/ ; //BioClinica, Inc./ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; //CereSpir/ ; //Cogstate/ ; //Eisai Inc./ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun/ ; //F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc./ ; //NIH/ ; U24AG072122//NACC/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Genetic Risk Score ; Genome-Wide Association Study ; *Genetic Predisposition to Disease/genetics ; *Genetic Variation/genetics ; *Multifactorial Inheritance/genetics ; Polymorphism, Single Nucleotide ; Female ; European People ; White People/genetics ; Male ; },
abstract = {INTRODUCTION: We utilized an Alzheimer's disease (AD) polygenic risk score (PRS) to discover associations with novel rare variants (RVs).

METHODS: PRSs for European ancestry (EA) participants of the Alzheimer's Disease Sequencing Project were calculated using summary statistics from a large genome-wide association study. Participants were classified into high (n = 5738) and low (n = 5324) PRS groups based on the median PRS and on the lower and upper 35% of the PRS distribution.

RESULTS: Risk variants were disproportionately enriched in the low-PRS group, while protective ones were disproportionately enriched in the high-PRS group. Genome-wide significant (GWS) associations for increased AD risk were identified with RVs spanning a 3.5-Mb region on chromosome 14. GWS protective variants in ALDH9A1, BICC1, and PAN3 were identified in the upper 35% PRS group.

CONCLUSION: Our findings provide unique opportunities to study RVs whose effects are opposite to the risk conferred by the genetic background.},
}

Humans
*Alzheimer Disease/genetics
Genetic Risk Score
Genome-Wide Association Study
*Genetic Predisposition to Disease/genetics
*Genetic Variation/genetics
*Multifactorial Inheritance/genetics
Polymorphism, Single Nucleotide
Female
European People
White People/genetics
Male

@article {pmid42558527,
year = {2026},
author = {Li, S and Cao, T and Zhang, Q},
title = {Oxidative stress as a driver of organelle cascade damage in neurological diseases.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1892923},
pmid = {42558527},
issn = {1663-4365},
abstract = {As a core driver in the pathological progression of neurological diseases, oxidative stress contributes to the onset and development of multiple disorders, including traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), by inducing interconnected and bidirectional damage among mitochondria, endoplasmic reticulum, lysosomes, and the nucleus. This review systematically summarizes the oxidative stress-mediated inter-organelle crosstalk network: Mitochondria act as one of the earliest and central hubs, and their dysfunction (e.g., reactive oxygen species burst, calcium overload, and respiratory chain impairment) induces endoplasmic reticulum stress via ROS diffusion and calcium signaling disturbance. The disruption of endoplasmic reticulum calcium homeostasis further exacerbates mitochondrial damage, forming a vicious cycle. Lysosomes exhibit reduced membrane stability and impaired autophagic flux under oxidative stress, failing to clear damaged organelles and aggravating oxidative stress accumulation. Ultimately, oxidative stress signals are transmitted to the nucleus, resulting in DNA damage, aberrant epigenetic modifications, and activation of pro-inflammatory/pro-apoptotic genes, thereby accelerating disease progression. Notably, this organelle injury transmission is not a rigid unidirectional linear cascade; primary lysosomal or MAM defects can independently initiate the full organelle damage loop without preceding mitochondrial dysfunction. This review integrates current studies, clarifies context-dependent and disease-specific characteristics of organelle interactions, and discusses potential therapeutic strategies with critical consideration of translational challenges and limitations, providing a theoretical foundation for mechanistic research and clinical intervention of neurological diseases.},
}

@article {pmid42558626,
year = {2026},
author = {Chen, J and Zhang, Z},
title = {Advancements in non-pharmaceutical interventions for Alzheimer's disease management: an update review.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1855269},
pmid = {42558626},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a chronic, progressive neurodegenerative condition that is characterized by an increasing incidence rate due to global population aging, resulting in a significant social and economic burden. Current pharmacological interventions offer only limited relief and are unable to halt neuronal loss and cognitive decline. Therefore, safe and effective non-pharmacological interventions (NPIs) are needed for the management of AD. This review systematically synthesizes literature from the PubMed and Web of Science databases (2020-2025) to evaluate the comparative efficacy of physical activity, dietary interventions, and cognitive stimulation therapy (CST), aiming to establish an evidence-based framework for optimized clinical implementation. Specifically, physical activity (e.g. aerobic exercise and strength training) has been shown to improve cognitive and physical function. Dietary interventions (e.g. the Mediterranean diet, Dietary Approaches to Stop Hypertension and The Mediterranean-DASH diet intervention for neurodegenerative delay diet) have been demonstrated to delay cognitive decline by modulating inflammation, but evidence regarding supplements is weak. Furthermore, CST has been evidenced to enhance patients' cognitive abilities and quality of life. The present review not only summarizes existing literature on the subject, but also explores future research directions, including mechanisms and personalized approaches of these interventions to improve the prognosis of AD patients.},
}

@article {pmid42558652,
year = {2026},
author = {Del Giudice, L and Guida, M and Aletta, MR and Pontieri, P},
title = {Targeting mitochondrial ribosomal proteins: a functional and translational framework for neurodegenerative disease research.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1882474},
pmid = {42558652},
issn = {1664-2295},
abstract = {Mitochondrial dysfunction is a central feature of neurodegenerative diseases, yet the molecular mechanisms governing mitochondrial protein synthesis remain insufficiently understood. Mitochondrial ribosomal proteins (MRPs), essential for the translation of mitochondrial-encoded components of the oxidative phosphorylation system, are emerging as critical regulators of neuronal homeostasis and survival. In this mini-review, we examine current knowledge on mitochondrial ribosomes with a focused analysis of three mitochondrial ribosomal proteins-MRPL44, NAM9, and GEP3-highlighting their structural and functional roles in maintaining mitochondrial integrity. We discuss evidence linking alterations in these proteins to key pathogenic processes relevant to neurodegeneration, including impaired oxidative phosphorylation, increased oxidative stress, and defective mitochondrial quality control. Importantly, we propose an integrative research perspective that positions these MRPs as potential modulators of tissue-specific vulnerability in neurodegenerative disorders. By synthesizing available data and identifying critical knowledge gaps, we outline future directions aimed at elucidating their contribution to neuronal dysfunction and disease progression. This work underscores mitochondrial ribosomal proteins as underexplored determinants of neurodegenerative pathology and suggests that their systematic investigation may reveal novel mechanistic insights and therapeutic opportunities.},
}

@article {pmid42558846,
year = {2026},
author = {Bhattacharya, A and Manjithaya, R and Chickabasaviah, Y and Alladi, PA},
title = {Locus Coeruleus as a Master Regulator of Diverse Functions in the Central Nervous System: Its Relevance in Ageing and Neurodegenerative Disorders.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531261462296},
pmid = {42558846},
issn = {0972-7531},
abstract = {BACKGROUND: The brainstem nucleus locus coeruleus (LC) is a rod-shaped, cylindrical, deeply pigmented neuromelanin (NM)-rich cluster of noradrenergic cells placed bilaterally in the dorsolateral tegmentum of the pons. The main neurotransmitter synthesised by these neurons is norepinephrine (NE), which polymerises to NM. Collectively, it regulates a plethora of activities, including vigilance, synaptic plasticity, memory processing, pain, stress responses, selective attention, cognition, sleep, emotion, capillary wall permeability and cerebral blood flow, thereby holding a 'master key' to several processes. Despite being small in dimensions, it is of enormous significance in diverse functions. Degeneration of the LC occurs early and progressively in both Alzheimer's disease (AD) and Parkinson's disease (PD), with diverse impacts, and is linked to neuropsychiatric entities such as depression, anxiety, cognitive impairment, schizophrenia and rapid eye movement sleep disorders, thereby raising considerable interest in normal physiology as well as in disease.

SUMMARY: This review is to better understand the neuroanatomical connections of human LC (master regulator of the central nervous system), pigmentation, cellular types, neurotransmitters/co-transmitters, and its role in ageing and neurodegenerative diseases. Recent and relevant classical research and review articles were referred to from PubMed to prepare a short review of the structure of LC, its projections, NM pigment and neuroprotection. We further examined the details of its cell types, neurotransmitters, co-transmitter functions and its effects in ageing, AD and PD, with emphasis on human studies.

KEY MESSAGE: LC is a vital region that offers neuroprotection, assists in the maintenance of cognitive reserve and enhances resilience and neuronal survival, despite the presence of AD and PD pathology for several decades. Further, it synthesises NE and co-transmitters that regulate attention, sleep-wake cycle, mood, cognition and so on. Maintaining its integrity and function promises potential scope to promote its health with normal ageing and improve clinical strategies in patients with neurodegeneration.},
}

@article {pmid42558896,
year = {2026},
author = {Neal, V and Faria, AV and Zhang, W and Hillis, AE and Stockbridge, MD},
title = {Right hemisphere atrophy rate associates with naming recovery after left hemisphere ischaemic stroke.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag291},
pmid = {42558896},
issn = {2632-1297},
abstract = {Numerous large-scale epidemiological studies investigating the trajectory of brain function after ischaemic stroke have presented data suggesting, on average, a persistent, accelerated decline in cognitive domains, including language, after accounting for the immediate impact of the stroke. We sought to further examine this trend, speculating that the average persistent decline may be a reflection of two subgroups with vastly different prognoses: (i) a minority experiencing decline secondary to neurodegenerative processes such as vascular dementia and Alzheimer's disease and (ii) a majority without marked progressive brain atrophy who typically see improvement. Our team thus investigated atrophy's association with language recovery, hypothesizing that declining naming performance in the year after left hemisphere ischaemic stroke would be correlated to atrophy of the contralesional hemisphere. We postulated that volume loss within the lesioned hemisphere would be less informative due to separate confounding processes related to the stroke itself, such as Wallerian degeneration and encephalomalacia. Participants [n = 72; M (SD) age = 60 (11)] in a longitudinal cohort study of language following left hemisphere ischaemic stroke were included if they completed an MRI both acutely and chronically (either 6 or 12 months post-stroke). Naming performance was assessed using the Boston Naming Test; stroke volumes were extracted from acute imaging; and atrophy was measured as the monthly per cent change in hemispheric volume from baseline to chronic scan for each individual. Pearson's correlations were calculated to determine the relationship between lesion volume and atrophy along with atrophy and change in Boston Naming Test score. Lesion volume negatively correlated with the monthly per cent change in volume of the left (ipsilesional) hemisphere (r = -0.48; P < 0.0001) but did not correlate with rate of right (contralesional) hemisphere volume loss. While there was no clear relationship between atrophy of the left hemisphere and language recovery, we found that volume changes of greater negative magnitude within the right hemisphere (increased atrophy) were associated with worse functional recovery of language (r = 0.38; P = 0.0025). By showing that atrophy of the right hemisphere was not significantly impacted by left hemisphere lesion size, we suggest that accelerated volume loss in the non-lesioned hemisphere after stroke may be indicative of a separate pathology. We then support this claim with behavioural data showing that greater rates of volume loss within the non-lesioned hemisphere were associated with poorer naming recovery. Together, these findings imply that contralesional atrophy after stroke may have negative implications for recovery and could serve as a useful imaging signature for separate neurodegenerative processes.},
}

@article {pmid42558962,
year = {2026},
author = {Corley, DA and Alavi, M and Fireman, BH and Finch, T and Prausnitz, S and Rouillard, S and Lee, K and Hamilton, L and Ansari, M},
title = {Associations of multiple evidence-based care strategies with disease mortality, life expectancy, and disparities in the United States.},
journal = {Health affairs scholar},
volume = {4},
number = {8},
pages = {qxag184},
pmid = {42558962},
issn = {2976-5390},
abstract = {INTRODUCTION: Limited data exist regarding the potential cumulative effects of multiple, integrated, system-level strategies on population-level outcomes and disparities.

METHODS: We evaluated associations between membership within a multi-disease, integrated population health management model with disease-specific mortality, life expectancy, and demographic disparities and relevant comparators. Bias was minimized through use of a large, representative, multicenter community-based setting, multiple comparators (including similar insured status, same-state, comparable comorbidity distributions, and national), demographic adjustments, and causality criteria.

RESULTS: Among 3 944 173 persons demographics-adjusted mortality was significantly lower for 9 of 10 leading causes of death, including the 5 leading preventable conditions (age-, sex-, race-adjusted risk ratios and 95% CIs Kaiser Permanente, Northern California vs United States [US, all])-cancer (0.85; 0.83-0.88), heart disease (0.69; 0.67-0.71), stroke (0.86; 0.82, 0.91), injury (majority overdoses and falls; 0.45; 0.42-0.48), and respiratory disease (0.59; 0.55-0.63)-but not unmodifiable causes (eg, Alzheimer's disease (1.58; 1.51-1.66). Most life-years gained occurred during ages most impacted by disease-management programs: 50-72 years (>0.075 life-year/year). Life expectancy exceeded comparators and was 4.9 years higher than the US average (83.3 vs 78.4 years, 2023). Findings were robust to index years, multiple other comparator populations, and adjusted analyses. Demographic disparities were smaller across major benchmarks.

CONCLUSION: These findings suggest that high uptake of multiple, existing, evidence-based population health strategies may be cumulatively associated with substantially reduced disease-specific mortality, decreased disparities, and increased life expectancy, comparable to values in comparator countries.},
}

@article {pmid42559122,
year = {2026},
author = {, and Boquet-Pujadas, A and Anagnostakis, F and Yang, Z and Tian, YE and Duggan, MR and Erus, G and Srinivasan, D and Joynes, CM and Bai, W and Patel, PJ and Walker, KA and Zalesky, A and Davatzikos, C and Wen, J},
title = {Multi-organ AI endophenotypes chart the heterogeneity of brain, eye and heart pan-disease.},
journal = {Nature. Mental health},
volume = {4},
number = {2},
pages = {203-230},
pmid = {42559122},
issn = {2731-6076},
abstract = {Disease heterogeneity and commonality pose significant challenges to precision medicine, as traditional approaches frequently focus on single disease entities and overlook shared mechanisms across conditions. Inspired by pan-cancer and multi-organ research, we introduce the concept of "pan-disease" to investigate the heterogeneity and shared etiology in brain, eye, and heart diseases. Leveraging individual-level data from 129,340 participants, as well as summary-level data, curated from the MULTI consortium, we applied a weakly-supervised deep learning model (Surreal-GAN) to multi-organ imaging, genetic, proteomic, and RNA-seq data, identifying 11 AI-derived biomarkers, called Multi-organ AI Endophenotypes (MAEs), for the brain (Brain 1-6), eye (Eye 1-3), and heart (Heart 1-2), respectively. We found Brain 3 to be a risk factor for Alzheimer's disease (AD) progression and mortality, whereas Brain 5 was protective against AD progression. Crucially, in data from an anti-amyloid AD drug (solanezumab), heterogeneity in cognitive decline trajectories was observed across treatment groups. At week 240, patients with lower brain 1-3 expression had slower cognitive decline, whereas patients with higher expression had faster cognitive decline. A multi-layer causal pathway pinpointed Brain 1 as a mediational endophenotype linking the FLRT2 protein to migraine, exemplifying novel therapeutic targets and pathways. Additionally, genes associated with Eye 1 and Eye 3 were enriched in cancer drug-related gene sets with causal links to specific cancer types and proteins. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery.},
}

@article {pmid42559376,
year = {2026},
author = {Niu, S and Liu, X and Xu, R and Zhu, A and Zhu, S and Hu, F and Ding, K and Li, S and Zhu, B and Liang, P and Zhang, S and Xiao, A and Fan, K and Zhang, Z},
title = {Multifunctional nanozyme platforms in central nervous system therapies: from rational design to translational medicine.},
journal = {Theranostics},
volume = {16},
number = {14},
pages = {8385-8426},
pmid = {42559376},
issn = {1838-7640},
mesh = {Humans ; *Central Nervous System Diseases/drug therapy/therapy ; Animals ; *Nanostructures/chemistry/therapeutic use ; Translational Research, Biomedical/methods ; Drug Delivery Systems/methods ; Neuroprotective Agents ; *Enzymes ; },
abstract = {Central nervous system (CNS) disorders-including ischemic stroke, traumatic brain/spinal cord injury, Parkinson's disease, and Alzheimer's disease-have long faced limitations in achieving functional recovery and disease-modifying therapies because of their complex pathophysiological mechanisms. Traditional therapies are often constrained by poor penetration across CNS barriers, limited participation in multiple pathological cascades, and insufficient persistence of therapeutic effects. Nanozymes are a class of nanomaterials with enzyme-like catalytic activity and tunable physicochemical properties. Not only do these nanozymes continuously scavenge reactive oxygen and nitrogen species in pathological environments through stable multi-enzyme synergistic effects by leveraging their abundant active sites, but also serve as multimodal therapeutic delivery platforms to achieve efficient drug delivery, opening up new avenues for neuroprotection and regenerative medicine. This review systematically examines the fundamental characteristics, classification systems, and functional design approaches of nanozymes, along with their potential for combined therapeutic strategies, including synergistic applications with drugs, hydrogels, genes, or cells. Additionally, it summarizes the latest advancements in neuroprotection and repair associated with CNS disorders. The review further analyzes current limitations and challenges related to clinical translation and offers insights into future research directions to enhance scientific knowledge and clinical applications in this significant field.},
}

Humans
*Central Nervous System Diseases/drug therapy/therapy
Animals
*Nanostructures/chemistry/therapeutic use
Translational Research, Biomedical/methods
Drug Delivery Systems/methods
Neuroprotective Agents
*Enzymes

@article {pmid42559503,
year = {2026},
author = {Acevedo-Nieto, J and Martínez, K and Amaya, C},
title = {The Role of Slow Gait Speed in Cognitive Decline among Aging Women: A Systematic Review.},
journal = {HSOA journal of gerontology & geriatric medicine},
volume = {12},
number = {1},
pages = {},
pmid = {42559503},
issn = {2381-8662},
abstract = {UNLABELLED: The prevalence of Alzheimer's disease and related dementias are increasing at an alarming rate, with projections estimating that by 2060, approximately 13.8 million adults aged 65 years and older in the U.S. will be affected by one or both. Among the many symptoms associated with cognitive decline, gait impairment is one that significantly affects functional independence and mobility.

METHODS: A systematic review was conducted to analyze 49 peer-reviewed studies using the Covidence systematic review software and adhering to PRISMA guidelines. The selected articles examined variables related to gait speed, and cognition. Participants were assessed through validated neurocognitive and mobility measures, including the MoCA and Dynamic Gait Index.

RESULTS: A significant negative correlation was identified between usual walking speed and age. This trend was particularly pronounced in women, in whom a significant negative association between MoCA scores and age (P = -0.019) was observed, suggesting an increased susceptibility to cognitive deterioration with advancing age.

CONCLUSION: These findings underline the sex-specific nature of the relationship between gait speed and cognitive function, highlighting increased vulnerability in aging women. The decline in mobility and cognition observed in this population underscores the urgency of developing targeted interventions that integrate physical and cognitive rehabilitation strategies.},
}

@article {pmid42559518,
year = {2026},
author = {Uppalapati, A and Vishnubhotla, A and Pahan, K},
title = {Prospect of Muscle-Building Supplement HMB in Alzheimer's Disease.},
journal = {Journal of clinical & experimental immunology},
volume = {11},
number = {3},
pages = {},
pmid = {42559518},
abstract = {Alzheimer's disease (AD) is the most common progressive and irreversible neurodegenerative disorder in humans that affects memory, thinking and behavior. Impairment in synaptic plasticity is one of the hallmarks in AD, with most of the impairment occurring in the hippocampal region, a key part of the brain for memory and learning. Therefore, the upregulation of hippocampal plasticity is critical to remediate the progression of AD and preserve memory formation and cognitive functions. Recent studies have described β-hydroxy-β-methylbutyrate (HMB), a body building supplement commonly used by athletes, as a candidate molecule for improving hippocampal plasticity. Clinically, AD is characterized by the abnormal accumulation of beta amyloid (Aβ) plaques, coupled with intracellular aggregates of hyperphosphorylated tau protein. In addition to enhancing hippocampal plasticity, HMB has been also demonstrated to lower amyloid plaques in a mouse model of AD. Although liver is rich in peroxisome proliferator-activated receptor alpha (PPARα), recent findings have established the presence of PPARα in hippocampus and other parts of the brain. Interestingly, HMB has been shown to utilize PPARα for lowering plaques and increasing hippocampal plasticity. Here, we discuss these newly described features of HMB with possible implications for the use of HMB supplement in patients with dementia and AD.},
}

@article {pmid42559821,
year = {2026},
author = {Moradi, K and Hadidchi, R and Majbri, A and Hughes, TM and Lu, H and Zhu, Y and Mohammadi, S and Momtazmanesh, S and Mukherjee, P and Abdullah, M and Simonsick, E and Schrack, JA and Goncalves, MD and Coresh, J and Albert, M and Demehri, S},
title = {Temporalis muscle biomarkers from routine brain MRI and risk of dementia in two independent cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71622},
doi = {10.1002/alz.71622},
pmid = {42559821},
issn = {1552-5279},
support = {//National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/ ; R01AR079620//National Institutes of Health (NIH)/ ; W81XWH-12-2-0012//DOD ADNI/ ; U01HL096812//ARIC Neurocognitive Study/ ; U01HL096814//ARIC Neurocognitive Study/ ; U01HL096899//ARIC Neurocognitive Study/ ; U01HL096902//ARIC Neurocognitive Study/ ; U01HL096917//ARIC Neurocognitive Study/ ; U01AG024904/AG/NIA NIH HHS/United States ; R01AR079620/AR/NIAMS NIH HHS/United States ; },
mesh = {Humans ; *Magnetic Resonance Imaging ; Female ; *Dementia/diagnostic imaging ; Male ; *Brain/diagnostic imaging ; Biomarkers ; Aged ; Cohort Studies ; *Muscle, Skeletal/diagnostic imaging/pathology ; Neuroimaging ; Alzheimer Disease/diagnostic imaging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Skeletal muscle loss is associated with cognitive decline, but whether neuroimaging-derived muscle characteristics predict incident dementia remains unclear.

METHODS: We evaluated associations of deep learning-derived temporalis muscle (TM) cross-sectional area (CSA) and radiomic texture features from baseline T1-weighted magnetic resonance imaging (MRI) with incident dementia in dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 750) and the Atherosclerosis Risk in Communities (ARIC) study (n = 532). TM was segmented using a convolutional neural network trained in ADNI and externally validated in ARIC. Radiomic features were reduced using least absolute shrinkage and selection operator-penalized Cox models to generate a composite score. Multivariable Cox regression adjusted for demographics, apolipoprotein E ε4, baseline cognition, body mass index, and physical performance.

RESULTS: Higher TM radiomic scores were associated with increased dementia risk in ADNI (hazard ratio per SD, 1.32) and ARIC (1.64). Smaller TM CSA predicted dementia in ADNI but not ARIC.

DISCUSSION: TM texture patterns from routine brain MRI are associated with dementia risk, supporting TM phenotyping as a scalable marker of systemic biological vulnerability.},
}

Humans
*Magnetic Resonance Imaging
Female
*Dementia/diagnostic imaging
Male
*Brain/diagnostic imaging
Biomarkers
Aged
Cohort Studies
*Muscle, Skeletal/diagnostic imaging/pathology
Neuroimaging
Alzheimer Disease/diagnostic imaging
Aged, 80 and over

@article {pmid42560011,
year = {2026},
author = {Abrar, F and Martin, DDO},
title = {Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/15548627.2026.2711593},
pmid = {42560011},
issn = {1554-8635},
abstract = {SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review will discuss the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy.Abbreviations: ABHD = α/β-hydrolase domain; AD = Alzheimer Disease; ALS = amyotrophic lateral sclerosis; ATG = autophagy related ; CSNK2/CK2 = casein kinase 2; HD = Huntington Disease; HDAC/KDAC = histone deacetylase/lysine deacetylase; HTT = huntingtin; KAT = lysine acetyltransferase; KEAP1 = kelch like ECH associated protein 1; KIR = KEAP1-interacting region; LIR = LC3-interacting region; LYPLA/APT = lysophospholipase/acyl-protein thioesterase; MAP1LC3/LC3 = microtubule associated protein 1 light chain 3; MEF = mouse embryonic fibroblast; mHTT = mutant huntingtin; MTORC1 = MTOR complex 1; NBR1 = NBR1 autophagy cargo receptor; NEDD4 = NEDD4 E3 ubiquitin protein ligase ; NO = nitric oxide; NFE2L2/Nrf2 = nuclear factor erythroid 2-factor 2; PAT = palmitoyl acyltransferase; PB1 = Phox-BEM1 domain; PE = phosphatidylethanolamine; PLEKHM1 = pleckstrin homology and RUN domain containing M1; PLK2 = polo like kinase 2; PRKA/PKA = protein kinase cAMP-activated; PPT1 = palmitoyl-protein thioesterase 1; RB1CC1 = RB1 inducible coiled-coil 1; SNCA/α-synuclein = synuclein alpha; SNO = S-nitrosothiol; SOD1 = superoxide dismutase 1; SQSTM1 = sequestosome 1; TARDBP/TDP-43 = TAR DNA binding protein ; TBK1 = TANK binding kinase 1; TAX1BP1 = Tax1 binding protein 1; TRIM = tripartite motif containing ; UBA = ubiquitin-associated domain; UBE = ubiquitin-conjugating enzyme; ULK1 = unc-51 like autophagy activating kinase 1; UPS =ubiquitin-proteasome system; USP8 = ubiquitin specific peptidase 8; ZDHHC = zDHHC palmitoyltransferase.},
}

@article {pmid42560015,
year = {2026},
author = {Mandal, T and Sinharoy, U and Biswas, K and Sarkar, P and Biswas, A},
title = {Association of Serum Homocysteine and Vitamin B12 with Different Grades of Cognitive Impairment in Alzheimer's Disease Patients.},
journal = {Annals of African medicine},
volume = {},
number = {},
pages = {},
doi = {10.4103/aam.aam_592_26},
pmid = {42560015},
issn = {0975-5764},
abstract = {BACKGROUND: Studies have shown a relation between Vitamin B12 (B12) and cognitive impairment in Alzheimer's disease (AD). However, B12 levels do not indicate the severity of the disease. High homocysteine-induced neuroinflammation has been related to the pathogenesis of AD.

AIM: This study aimed to determine the correlation of Vitamin B12 and serum homocysteine with the cognitive status of AD patients.

MATERIALS AND METHODS: AD patients (n = 25) and healthy controls (n = 25) were recruited for this study. The revised criteria for diagnosis and staging of AD were used for the diagnosis of AD. Clinical history, laboratory investigations (B12, homocysteine, lipid profile, C-reactive protein, and serum creatinine), and Mini-Mental Status Examination (MMSE) were done. Based on MMSE score, AD patients were subdivided into four groups. All statistical analyses were done on IBM SPSSv26.

RESULTS: In AD patients, B12 was lower (221.3 ± 54.5 vs. 396.6 ± 88.4 pg/ml, P = 0.00), serum homocysteine was higher (15.2 ± 4.6 vs. 11.7 ± 2.3 µmol/L, P = 0.00), and C-reactive protein was higher (0.95 ± ± 0.39 vs. 0.69 ± 0.12 mg/dl, P = 0.00). Among the four AD groups, we observed a gradual increase in the serum homocysteine levels with a decline in the cognitive status (lower MMSE score) (F = 13.32, P = 0.00). MMSE score had a statistically significant correlation with homocysteine (ρ = -0.85, P = 0.00), unlike B12 (ρ =0.33, P = 0.11).

CONCLUSION: Serum homocysteine is a better diagnostic indicator of cognitive impairment than B12. In resource-limited settings, screening with the Mini-Cog test and timely supplementation with B complex vitamins (B6, B12, and folic acid) can slow the progress of dementia in AD patients.},
}

@article {pmid42560134,
year = {2026},
author = {Papelian, S},
title = {Mechanisms, Biomarkers and Therapeutic Implications of Neuroinflammation in Alzheimer's Disease.},
journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience},
volume = {86},
number = {5},
pages = {e70168},
pmid = {42560134},
issn = {1873-474X},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/therapy/complications/immunology ; *Biomarkers/metabolism ; *Neuroinflammatory Diseases/metabolism/therapy/pathology ; Animals ; Blood-Brain Barrier/metabolism ; Microglia/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide, affecting millions of individuals and imposing substantial socioeconomic burdens. While traditional research has focused on amyloid-β (Aβ) plaques and neurofibrillary tangles as primary pathological hallmarks, mounting evidence implicates neuroinflammation as a critical third pillar in AD pathogenesis. This review critically evaluates current understanding of neuroinflammatory mechanisms in AD, examining the complex interplay between cellular mediators, molecular pathways and environmental triggers across a temporal disease-stage framework. We explore the dual and stage-dependent roles of microglia and astrocytes, expand discussion of blood-brain barrier (BBB) dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors, and integrate emerging evidence linking neuroinflammation specifically to tau pathology and its stereotyped propagation through the brain. Diagnostic biomarkers, including translocator protein-positron emission tomography (TSPO-PET) and plasma glial fibrillary acidic protein (GFAP), are evaluated with explicit attention to clinical utility, technical limitations, and their relationship to established AD biomarkers. Therapeutic strategies are critically assessed with careful distinction between preclinical proof-of-concept data and available clinical evidence, and key translational challenges are highlighted throughout. The review emphasizes the need for stage-appropriate intervention windows, patient stratification by neuroinflammatory endotype, and biologically rational combination strategies. Understanding neuroinflammation's temporal and spatial dynamics offers promising but as yet insufficiently realized avenues for early intervention and disease modification in AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology/therapy/complications/immunology
*Biomarkers/metabolism
*Neuroinflammatory Diseases/metabolism/therapy/pathology
Animals
Blood-Brain Barrier/metabolism
Microglia/metabolism/pathology

@article {pmid37259937,
year = {2024},
author = {De, SK},
title = {Novel Pyrimidin-4-yl-3-amino-pyrrolo[3,4-c]pyrazoles as Protein Kinase C Inhibitors for Treating Diseases.},
journal = {Current medicinal chemistry},
volume = {31},
number = {8},
pages = {1036-1039},
doi = {10.2174/0929867330666230531164754},
pmid = {37259937},
issn = {1875-533X},
mesh = {Humans ; *Protein Kinase Inhibitors/chemistry/therapeutic use/pharmacology ; *Pyrazoles/chemistry/therapeutic use/pharmacology ; *Protein Kinase C/antagonists & inhibitors/metabolism ; Animals ; Neoplasms/drug therapy ; Cardiovascular Diseases/drug therapy ; *Pyrimidines/chemistry/therapeutic use/pharmacology ; Central Nervous System Diseases/drug therapy ; Inflammation/drug therapy ; },
abstract = {This patent describes the series of compounds and their pharmaceutically acceptable salts, such as compound K7 (as a representative potent compound). These protein kinase C selective inhibitors are useful for treating diabetes mellitus and its complications, cancer, ischemia, inflammation, central nervous system disorders, cardiovascular disease, Alzheimer's disease, dermatological disease, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ.},
}

Humans
*Protein Kinase Inhibitors/chemistry/therapeutic use/pharmacology
*Pyrazoles/chemistry/therapeutic use/pharmacology
*Protein Kinase C/antagonists & inhibitors/metabolism
Animals
Neoplasms/drug therapy
Cardiovascular Diseases/drug therapy
*Pyrimidines/chemistry/therapeutic use/pharmacology
Central Nervous System Diseases/drug therapy
Inflammation/drug therapy

@article {pmid42551683,
year = {2026},
author = {Gao, J and Xu, Y and Jiang, W and Wang, Z and Wang, L and Zhang, H},
title = {Adenosine monophosphate-activated protein kinase: A golden mediator of exercise in metabolic dysfunction-associated diseases (review).},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153885},
doi = {10.1016/j.ijbiomac.2026.153885},
pmid = {42551683},
issn = {1879-0003},
abstract = {Metabolic diseases represent a major threat to human health and are largely associated with excessive energy intake and insufficient energy expenditure. Increasing evidence indicates that obesity, diabetes, metabolic dysfunction-associated fatty liver disease, sarcopenia, Alzheimer's disease, and cancer are closely associated with metabolic dysfunction. Extensive clinical studies and therapeutic strategies have been developed for the prevention and treatment of these disorders. Among these approaches, targeted regulation of cellular energy homeostasis has emerged as a widely recognized strategy, with adenosine monophosphate-activated protein kinase (AMPK) identified as an important therapeutic target for metabolic disease intervention. With the growing development of sports medicine, exercise has become a preferred non-pharmacological approach for the prevention and management of metabolic dysfunction-related diseases, with its beneficial effects largely mediated through AMPK activation. However, the mechanisms by which exercise modulates AMPK and its subtypes in different tissues and diseases remain incompletely understood. Therefore, this narrative review retrieved English-language literature published up to May 2026 from the PubMed, Web of Science, and Scopus databases. A search strategy was constructed using the terms "AMPK", "exercise", "obesity", "diabetes", "NAFLD/MASLD", "sarcopenia", and "Alzheimer's disease" and the corresponding tissues associated with these metabolic diseases. A comprehensive analysis was conducted focusing on AMPK and its subtypes. In this narrative review, we synthesize current research on how exercise modulates AMPK in different tissues and subtype-specific functions, summarizing and analyzing existing evidence that may provide a theoretical basis for subtype-targeted therapeutic strategies (including exercise therapy and pharmacological therapy) for metabolic dysfunction-related diseases.},
}

@article {pmid42551762,
year = {2026},
author = {Lin, S and Xue, M and Xu, C and Sheng, C and Wang, T and Sun, J and Chen, Y and Lian, J and Zhang, T and Wang, W},
title = {White and gray matter microstructural alterations in subjective cognitive decline: an exploratory study using TBSS and GBSS.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112070},
doi = {10.1016/j.brainresbull.2026.112070},
pmid = {42551762},
issn = {1873-2747},
abstract = {OBJECTIVE: Subjective cognitive decline (SCD), which may represent the preclinical stage of Alzheimer's disease (AD) in a subset of individuals, lacks objective biomarkers, thus hindering the implementation of early intervention for AD. This study tentatively explored the potential value of neurite orientation dispersion and density imaging (NODDI) in assessing the microstructural integrity of gray matter (GM) and white matter (WM) in SCD.

METHODS: We enrolled 47 SCD subjects and 30 healthy controls (HCs). Through the TBSS and GBSS analysis based on NODDI, the neurite density index (NDI) and orientation dispersion index (ODI) were used to evaluate the microstructural integrity of GM and WM. NODDI parameters were extracted from multiple brain regions to assess their diagnostic utility in distinguishing SCD from HCs.

RESULTS: In WM microstructure, NDI of the genu of corpus callosum was decreased, and the ODI of the left posterior thalamic radiation and posterior corona radiata were decreased. In GM microstructure, the NDI of the left hippocampus, amygdala and parahippocampal gyrus were decreased, whereas the ODI of the rolandic operculum, opercular part of inferior frontal gyrus, and precentral gyrus were increased. Logistic regression analysis results showed that the NDI value of GM, the ODI value of GM and the ODI value of WM were independent predictors and the combination of the three parameters had the best classification effect.

CONCLUSION: This exploratory study suggests that NODDI may detect microstructural differences in GM and WM associated with SCD. These preliminary findings provide hypothesis-generating clues for future research into potential imaging markers for identifying SCD individuals. Additional studies are necessary to confirm these preliminary results.},
}

@article {pmid42551772,
year = {2026},
author = {Muedano-Sosa, A and Trujillo-Pineda, M and Ruiz-Pérez, S and Cervera, A and González-Barrios, R and Arias, C and Flores-León, M},
title = {In silico analysis of transcriptomic datasets reveals nonlinear gene expression trajectories in aging microglia and Alzheimer's disease.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113263},
doi = {10.1016/j.exger.2026.113263},
pmid = {42551772},
issn = {1873-6815},
abstract = {BACKGROUND: Neuroinflammation, a key factor in aging and neurodegeneration, is characterized by the increased activation of microglia, the brain's resident immune cells. Microglia play a central role in maintaining brain homeostasis, and their dysregulation during aging is increasingly implicated in the onset and progression of Alzheimer's disease (AD). However, the molecular mechanisms underlying microglial state transitions across physiological and pathological aging remain poorly understood.

METHODS: To address this gap, we conducted an in silico comparative transcriptomic study using publicly available datasets from two murine bulk RNA-seq including wild-type (WT) and APP/PS1 transgenic (Tg) mice at multiple ages, one human scRNA-seq dataset with multiple ages, and data obtained from SCAD-Brain.

RESULT: Our analyses revealed that physiological microglial aging is characterized by dynamic, non-linear gene expression trajectories, whereby genes involved in mitochondrial function, lysosomal degradation, and immune response follow a mirror-like pattern across aging. This mirror-like behavior was conserved in human microglial data across ages. In contrast, this adaptive pattern was disrupted at late-stage pathological aging in Tg mice, where sustained alterations in inflammatory, mitochondrial, and lysosomal pathways became more pronounced. Consistent with these findings, genes dysregulated in Tg mice showed similar expression trends in AD patients in the SCAD-Brain database.

CONCLUSION: These results suggest that middle age may represent a critical transition stage preceding neuroinflammation and neurodegeneration, making it an attractive window to identify preventive or therapeutic targets in early AD. Collectively, this study identifies candidate pathways and genes that warrant further experimental validation in the context of AD and age-related neurodegeneration.},
}

@article {pmid42551778,
year = {2026},
author = {Jaiswal, V and Deb, N and Latif, F and Shrestha, AB and Garimella, V and Shama, N and Jitta, SR and Naz, S and Kumar, T and Khan, S and Perone, F and Mattumpuram, J and Ang, SP},
title = {Association between PCSK9 targeted therapy and the risk of stroke and dementia: A Meta-Analysis of Randomized Controlled Trials.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2026.06.034},
pmid = {42551778},
issn = {1555-7162},
abstract = {BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeted therapies have been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels and circulating PCSK9. However, its effect on cerebrovascular outcomes, especially stroke and dementia, has not been well established to date.

METHODS: We conducted a systematic literature search of electronic databases for relevant randomized controlled trials (RCTs) from inception through January 2025. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effect model, and a p-value of <0.05 was considered statistically significant.

RESULTS: A total of 22 RCTs with 64,116 patients were included in the study. Pooled analysis showed that PCSK9-targeted therapy significantly reduced the risk of all-cause stroke (OR, 0.78 (95% CI: 0.68-0.90), P < 0.001) and ischemic stroke (OR, 0.77 (95% CI: 0.63-0.94), P=0.01). However, no significant association was observed for the risk of hemorrhagic stroke (OR, 1.16 (95%CI: 0.70-1.93), P=0.56), transient ischemic attack (OR, 0.98 (95%CI: 0.48-2.06), P= 0.95), dementia (OR, 0.77 (95%CI: 0.14-4.28), P=0.76), dementia of Alzheimer's type (OR, 0.81 (95%CI: 0.14-4.70), P=0.82), and Parkinson's disease (OR, 0.82 (95%CI: 0.11-6.37), P=0.85).

CONCLUSION: PCSK9 targeted therapies appear to reduce the risk of stroke; however, no significant association was observed for the risk of dementia and Parkinson's disease.},
}

@article {pmid42551844,
year = {2026},
author = {Xie, Q and Zhang, J and Wang, Y and Huang, J and Lin, F and Weng, RL and He, H and Chen, Q and Xu, H},
title = {CiteSure: retrieval-augmented large language models for faithful biomedical citation recommendation.},
journal = {Journal of the American Medical Informatics Association : JAMIA},
volume = {},
number = {},
pages = {},
doi = {10.1093/jamia/ocag122},
pmid = {42551844},
issn = {1527-974X},
support = {R01AG073435/NH/NIH HHS/United States ; R01LM013519/NH/NIH HHS/United States ; R01AG080429/NH/NIH HHS/United States ; 1K99LM01402/NH/NIH HHS/United States ; 1K99LM014614-01/NH/NIH HHS/United States ; },
abstract = {OBJECTIVES: Accurate citation of relevant publications is essential for scientific integrity in biomedical research. Large language models (LLMs) excel at text generation but often hallucinate fabricated or inaccurate citations. Retrieval-augmented generation (RAG) can mitigate these errors, yet current approaches lack semantic precision in evidence retrieval. This study aims to develop a domain-specific RAG system for reliable, context-specific biomedical citation recommendations.

MATERIALS AND METHODS: We introduce CiteSure, a sentence-level citation recommendation tool designed to deliver reliable, evidence-based, and context-specific references using LLMs. CiteSure utilizes a 2-stage retrieval-augmented generation (RAG) framework, combining a domain-specific dense retriever (BioLLM2Vec) and reranker (BioRankLLaMA), adapted from LLaMA3-8B-Instruct using biomedical-specific training data. CiteSure leverages the complementary strengths of retrieval and generative LLM models, ensuring factual precision and contextual alignment. We evaluated CiteSure on a curated Alzheimer's disease dataset, comparing it to standalone LLMs and traditional retrieval-based methods.

RESULTS: CiteSure achieved 100% factual accuracy and the highest relevance score of 77.50%, outperforming all baselines. BioLLM2Vec retrieved relevant articles with over 80% accuracy in the top 100 candidates. BioRankLLaMA consistently outperformed baseline rerankers across MAP, MRR, and Precision@5 metrics, confirming the benefit of domain-specific adaptation and contrastive fine-tuning.

DISCUSSION AND CONCLUSION: Our results demonstrate that CiteSure, built on a 2-stage retrieval-augmented generation framework, effectively integrates domain-specific retrieval with LLM-based generation to achieve substantial improvements over baseline approaches. Our work underscores the importance of domain-specific adaptation in biomedical citation recommendation and provides publicly available datasets, models, and code for support future research.},
}

@article {pmid42552038,
year = {2026},
author = {Peter L, IR and Chatterjee, D and Chrishone, AF and Francis, D},
title = {Metabolic therapeutic targets in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {1-32},
doi = {10.1016/bs.irn.2026.05.010},
pmid = {42552038},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Energy Metabolism/physiology/drug effects ; *Brain/metabolism ; *Mitochondria/metabolism ; Glucose/metabolism ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder marked not only by amyloid-β and tau pathology, but also by profound disturbances in brain energy metabolism that arise early in disease progression. Accumulating evidence indicates that impairments in glucose utilization, insulin signaling, and mitochondrial function precede neurodegeneration and contribute directly to synaptic failure and cognitive decline. This chapter presents a comprehensive overview of Alzheimer's disease through the lens of metabolic dysfunction, highlighting disrupted neuronal bioenergetics as a central and unifying feature of pathogenesis. We examine key metabolic pathways implicated in AD, including cerebral glucose hypometabolism, brain insulin resistance, impaired glycolysis, mitochondrial oxidative phosphorylation deficits, oxidative stress, and altered mitochondrial dynamics. The chapter further discusses therapeutic strategies aimed at restoring metabolic homeostasis, such as insulin sensitization, enhancement of glucose transport, activation of mitochondrial biogenesis, modulation of the electron transport chain, and the use of mitochondria-targeted antioxidants. In parallel, alternative energy approaches-including ketone metabolism, fatty acid oxidation, and pentose phosphate pathway activation-are explored as promising avenues to bypass glucose-dependent energy deficits and reinforce neuronal resilience. Emerging directions in metabolic therapeutics are also highlighted, including combination treatment strategies, NAD[+]-sirtuin and AMPK signaling, and the expanding role of the gut microbiome-brain metabolism axis. By integrating insights from experimental models, neuroimaging studies, and clinical trials, this chapter underscores the potential of metabolic interventions to enable early, disease-modifying strategies for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
Animals
*Energy Metabolism/physiology/drug effects
*Brain/metabolism
*Mitochondria/metabolism
Glucose/metabolism

@article {pmid42552040,
year = {2026},
author = {Chaurasia, V and Das Modak, S and Singh, GK and Modi, G},
title = {A comprehensive review on therapeutics and diagnostic agents targeting acetyl and butyryl cholinesterases for AD.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {145-198},
doi = {10.1016/bs.irn.2026.05.017},
pmid = {42552040},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/enzymology/metabolism ; *Butyrylcholinesterase/metabolism/drug effects ; *Cholinesterase Inhibitors/pharmacology/therapeutic use ; Animals ; *Acetylcholinesterase/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive, irreversible, and multifaceted neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairment, posing a major global health challenge. Its multifactorial pathology includes cholinergic dysfunction, amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Among these, impairment of the cholinergic system, characterized by reduced acetylcholine levels, plays a crucial role in cognitive deficits. The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which hydrolyze acetylcholine, are closely involved in disease progression and serve as important therapeutic and diagnostic targets in AD. This book chapter provides a comprehensive overview of therapeutic and diagnostic agents targeting AChE and BChE in AD, and discusses small-molecule inhibitors, multifunctional ligands, and emerging strategies to modulate cholinesterase activity and restore cholinergic neurotransmission, alleviating disease symptoms. In addition, the chapter highlights advances in diagnostic approaches using fluorescent probes, particularly near-infrared (NIR) probes, for selective detection and imaging of AChE and BChE, including their molecular design, photophysical properties, enzyme selectivity, and mechanisms of action, all of which are critically examined. Targeting AChE and BChE offers a dual advantage in AD by enabling both symptomatic treatment and early-stage diagnosis. This chapter aims to present a clear and comprehensive overview of recent advances in therapeutic and diagnostic approaches, offering meaningful insights for researchers in developing effective strategies for the treatment and monitoring of AD.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/enzymology/metabolism
*Butyrylcholinesterase/metabolism/drug effects
*Cholinesterase Inhibitors/pharmacology/therapeutic use
Animals
*Acetylcholinesterase/metabolism/drug effects

@article {pmid42552041,
year = {2026},
author = {Khodve, G and Raval, S and Banerjee, S},
title = {Intestinal microbiota in neurodegeneration and ageing: Mechanisms, pathways, and therapeutic interventions.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {199-229},
doi = {10.1016/bs.irn.2026.05.015},
pmid = {42552041},
issn = {2162-5514},
mesh = {Humans ; *Neurodegenerative Diseases/microbiology/metabolism/immunology/diet therapy/therapy ; *Aging/metabolism/immunology ; *Gastrointestinal Microbiome/physiology ; Animals ; *Dysbiosis/metabolism/immunology ; *Brain-Gut Axis/physiology ; Probiotics ; Brain/metabolism ; },
abstract = {The human gut microbiota represents a complex ecosystem of trillions of microorganisms with profound implications for neurological health. Emerging evidence demonstrates that dysbiosis, an imbalance in microbial composition and function, plays a crucial role in the pathogenesis of neurodegenerative diseases and age-related cognitive decline. This chapter summarizes current knowledge of the microbiota-gut-brain axis (MGBA) and elucidates how intestinal microbes and their metabolites communicate with the central nervous system via neural, immune, endocrine, and metabolic pathways. We examine the mechanistic links between gut dysbiosis and specific neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Multiple sclerosis (MS). Furthermore, we explore age-related changes in the microbiota and their contributions to neuroinflammation, immunosenescence, and cognitive decline. Finally, we evaluate therapeutic interventions targeting the microbiota, including probiotics, prebiotics, synbiotics, and dietary modulation as promising strategies to prevent and ameliorate neurodegenerative pathology. The chapter provides a comprehensive summary of how microbiota-targeted approaches may delay ageing and neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/microbiology/metabolism/immunology/diet therapy/therapy
*Aging/metabolism/immunology
*Gastrointestinal Microbiome/physiology
Animals
*Dysbiosis/metabolism/immunology
*Brain-Gut Axis/physiology
Probiotics
Brain/metabolism

@article {pmid42552042,
year = {2026},
author = {Milmile, M and Singh, S and Pandey, A and Pawar, G and Petkar, P and Chander, Y and Mishra, R and Chawla, R},
title = {Brain energy crisis in Alzheimer's and Parkinson's disease: Nanotechnology as a therapeutic strategy.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {231-271},
doi = {10.1016/bs.irn.2026.05.016},
pmid = {42552042},
issn = {2162-5514},
mesh = {Humans ; *Parkinson Disease/metabolism/drug therapy/therapy ; *Energy Metabolism/physiology/drug effects ; *Alzheimer Disease/metabolism/drug therapy/therapy ; Animals ; *Brain/metabolism/drug effects ; *Nanotechnology/methods ; Mitochondria/metabolism ; Nanoparticles ; Oxidative Stress ; Drug Delivery Systems/methods ; },
abstract = {Alzheimer's disease and Parkinson's disease are increasingly recognized as disorders marked not only by protein aggregation but by a sustained failure of brain energy metabolism. Years before overt cognitive or motor symptoms emerge, neurons begin to experience impaired glucose utilization, mitochondrial dysfunction, and declining ATP production. Because the brain is highly energy-dependent, even subtle metabolic disturbances can disrupt synaptic function, impair neuronal signaling, and trigger oxidative stress. As mitochondrial efficiency declines, reactive oxygen species accumulate, inflammatory pathways become chronically activated, and damaged cellular components are insufficiently cleared, creating a vicious cycle that accelerates neurodegeneration. Conventional metabolic therapies, including antioxidants and mitochondrial cofactors, have produced limited clinical success, largely due to poor penetration across the blood-brain barrier and lack of specificity for vulnerable neuronal populations and intracellular targets such as mitochondria. Nanotechnology introduces a more precise therapeutic strategy by enabling targeted delivery of metabolic modulators directly to the brain. Engineered nanocarriers can be designed to cross biological barriers, enhance drug stability, and release therapeutic agents in a controlled or stimuli-responsive manner within diseased regions. Advanced systems including polymeric nanoparticles, lipid-based carriers, intranasal nano formulations, biomimetic vesicles, and catalytic nanozymes offer the ability to simultaneously modulate oxidative stress, restore mitochondrial function, and regulate neuroinflammation. By integrating delivery precision with metabolic intervention, neuro-nanomedicine shifts the therapeutic focus from symptomatic management toward addressing the underlying bioenergetic crisis. Although challenges remain in safety validation, scalability, and clinical translation, targeted nanotherapeutic strategies hold significant promise for transforming the treatment landscape of these debilitating neurodegenerative disorders.},
}

Humans
*Parkinson Disease/metabolism/drug therapy/therapy
*Energy Metabolism/physiology/drug effects
*Alzheimer Disease/metabolism/drug therapy/therapy
Animals
*Brain/metabolism/drug effects
*Nanotechnology/methods
Mitochondria/metabolism
Nanoparticles
Oxidative Stress
Drug Delivery Systems/methods

@article {pmid42552043,
year = {2026},
author = {Jain, V and Bharti, S},
title = {The potential of HDAC inhibitors for Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {273-298},
doi = {10.1016/bs.irn.2026.01.005},
pmid = {42552043},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Animals ; *Histone Deacetylases/metabolism ; Epigenesis, Genetic/drug effects ; *Neuroprotective Agents/pharmacology ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative condition characterized by cognitive deterioration, memory loss, and persistent neuroinflammation. Notwithstanding considerable scientific advancements, current therapy strategies predominantly address symptoms and are ineffective in arresting illness progression. Recent studies have demonstrated the crucial role of epigenetic changes, especially histone modifications, in the pathophysiology of Alzheimer's disease. Removal of the acetyl group from histones and non-histone proteins by histone deacetylases (HDACs) plays a pivotal role in the regulation of gene expression, synaptic plasticity, and neuronal survival. Such changes lead to dysregulated HDAC activity, which is further associated with significant clinical characteristics of Alzheimer's disease, including amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. In Alzheimer's disease and other neurodegenerative diseases, the histone acetylation equilibrium is markedly disrupted, resulting in a shift towards hypoacetylation, which further inhibits the production of neuroprotective genes. Pharmacological inhibition of HDACs can reinstate hyperacetylation, therefore facilitating neuroprotective effects. This chapter explores the therapeutic potential of HDAC inhibitors in relation to Alzheimer's disease. This chapter also focuses on various HDAC isoforms associated with disease progression and explores the detailed mechanism by which HDAC inhibitors affect the epigenetic regulation and neuronal function. Preclinical investigations focusing on the role of HDAC inhibitors in mitigating neuroinflammation and Alzheimer's diseases, with a special focus on HDAC inhibitors in clinical trials, present intriguing opportunities for therapeutic advancement. The chapter further explores various challenges such as off-target effects, restricted isoform specificity, and inadequate blood-brain barrier permeability. To address these constraints, various strategies such as isoform-selective inhibitors, targeted delivery methods, and combination treatments are also explored. Thus, the chapter provides in-depth information on the role of HDAC inhibitors, which hold significant potential as disease-modifying agents in the treatment of Alzheimer's disease.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Histone Deacetylase Inhibitors/pharmacology/therapeutic use
Animals
*Histone Deacetylases/metabolism
Epigenesis, Genetic/drug effects
*Neuroprotective Agents/pharmacology

@article {pmid42552044,
year = {2026},
author = {Singh, AK and M R, S and P S, A and Krishnamoorthi, S and Iyaswamy, A and Durairajan, SSK},
title = {The Tau-mitochondria connection and its impact on cellular energy metabolism in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {299-361},
doi = {10.1016/bs.irn.2026.06.002},
pmid = {42552044},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Energy Metabolism/physiology ; *Mitochondria/metabolism ; *tau Proteins/metabolism ; Animals ; },
abstract = {Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease process resulting in progressive cognitive deterioration and synaptic dysfunction. The primary research approach in AD has traditionally focused on amyloid- pathology however an increasingly evidence suggests that tau protein is a key mediator of neuronal damage via a direct action on mitochondrial bioenergetics. In this chapter we look at the nature of the tau-mitochondrial interface, and propose a paradigm of tau-induced energy failure in AD. Physiologically tau provides stability to the microtubules and is involved in transport mechanisms within cells. In AD, tau is excessively post-translationally modified hyperphosphorylated and truncated tau species form toxic oligomers that incorrectly translocate to mitochondria, interacting pathologically with critical proteins such as voltage-dependent anion channel 1 (VDAC1) and adenine nucleotide translocase (ANT), impeding the mitochondrial ATP/ADP exchange and reducing oxidative phosphorylation efficiency. Tau also further damages mitochondria by excessive fission, inhibition of axonal transport and Inhibition of mitophagy by interrupting PINK1-Parkin signaling. In turn, the build-up of dysfunctional mitochondria leads to ROS production, mtDNA damage and calcium imbalance creating a vicious cycle toward oxidative stress and tau pathology. At the cellular level they cause an energy depletion of the synapse and at the systems level cause glucose hypometabolism and activation of neuroinflammation. The chapter additionally discusses novel therapeutic approaches that target both tau and mitochondrial abnormalities, namely antisense oligonucleotides (ASO), mitochondria targeted compounds and mitophagy modifiers, stressing that it would be more effective to utilize a cocktail of these inhibitors. As a whole, in the context of decreased bioenergetics, the tau-mitochondria axis is an important factor to consider in the successful treatment of AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Energy Metabolism/physiology
*Mitochondria/metabolism
*tau Proteins/metabolism
Animals

@article {pmid42552045,
year = {2026},
author = {Khodadadi, S and Rezaeimanesh, N and Ariyae Motahar, A and Yousefi, F and Avateffazeli, M and Montazeri-Shatouri, R and Hosseini, E and Sahab Negah, S and Naser Moghadasi, A},
title = {Brain energy metabolism changes and neuropsychological impairment in Parkinson disease vs Alzheimer disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {33-66},
doi = {10.1016/bs.irn.2026.06.001},
pmid = {42552045},
issn = {2162-5514},
mesh = {Humans ; *Parkinson Disease/metabolism/complications ; *Energy Metabolism/physiology ; *Alzheimer Disease/metabolism/complications ; *Brain/metabolism ; Animals ; *Cognitive Dysfunction/metabolism/etiology ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders, posing a significant public health risk. Although they are separate diseases, they have similar neuropsychological characteristics. Despite making up only a small portion of total body mass, the brain requires a disproportionately large amount of energy to maintain neuronal activity, synapse function, and cellular homeostasis. Disruption of energy metabolism is thus a major contributor to neurodegeneration. Energy metabolism has a wide-ranging impact on brain function, including cognitive and psychological processes, and gets increasingly compromised in neurodegenerative disorders. This chapter aims to offer a thorough overview of the link between altered brain energy metabolism and neuropsychological impairment in AD and PD.},
}

Humans
*Parkinson Disease/metabolism/complications
*Energy Metabolism/physiology
*Alzheimer Disease/metabolism/complications
*Brain/metabolism
Animals
*Cognitive Dysfunction/metabolism/etiology

@article {pmid42552046,
year = {2026},
author = {Yadav, N and Banerjee, J and Tiwari, M and Dixit, A},
title = {Brain lipid dysregulation as a driver of energy metabolism failure in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {363-396},
doi = {10.1016/bs.irn.2026.02.004},
pmid = {42552046},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Energy Metabolism/physiology ; Animals ; *Lipid Metabolism/physiology ; *Brain/metabolism ; Mitochondria/metabolism ; },
abstract = {Alzheimer's Disease (AD) is becoming more widely recognized as a condition of brain energy metabolism, wherein lipid dysregulation plays a crucial, although unrecognized, role. In addition to functioning as structural elements of neuronal membranes, lipids such as phospholipids, sphingolipids, and cholesterol play a crucial role in regulating mitochondrial bioenergetics, synaptic activity, and membrane-associated signaling pathways. In AD, modifications in lipid composition, distribution, and turnover compromise membrane fluidity, disturb mitochondrial dynamics, and obstruct lipid-mediated transport of energy substrates. These alterations intensify oxidative stress, impair glucose and ketone utilization, and stimulate neuroinflammatory pathways that further diminish metabolic capacity. Progress in lipidomics has uncovered disease-specific lipid signatures, providing a fresh understanding of the relationship between lipid homeostasis and neuronal energy loss. Despite extensive focus on amyloid and tau, lipid-mediated bioenergetic failure remains underrepresented in integrative AD models; this chapter addresses this gap and consolidates existing information connecting lipid modifications to metabolic dysfunction in AD, emphasizing molecular pathways and prospective treatment strategies aimed at lipid metabolism to re-establish bioenergetic equilibrium.},
}

Humans
*Alzheimer Disease/metabolism
*Energy Metabolism/physiology
Animals
*Lipid Metabolism/physiology
*Brain/metabolism
Mitochondria/metabolism

@article {pmid42552047,
year = {2026},
author = {Mittal, R and Priya, and Banerjee, J and Dixit, A},
title = {Metabolic dysregulation in Alzheimer's disease: Mechanisms, markers, and therapeutic prospects.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {397-434},
doi = {10.1016/bs.irn.2026.05.011},
pmid = {42552047},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/therapy ; Biomarkers/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Glucose/metabolism ; *Brain/metabolism ; },
abstract = {Metabolic dysregulation has emerged as a crucial pathogenic factor that contributes in progression of Alzheimer's disease (AD), and is often found to precede classical AD's pathologies, the amyloid-β accumulation and hyperphosphorylated tau proteinopathies. The key metabolic underpinnings associated with Alzheimer's disease (AD) includes cerebral glucose hypometabolism, insulin resistance, mitochondrial dysfunction, altered lipid metabolism, vascular and systemic metabolic impairments, disrupted amino acid and nitrogen metabolism driving secondary metabolic disturbances. The chapter outlines the current evidences on dysregulated metabolic processes, and highlights emerging metabolic biomarkers that are identified through advanced neuroimaging modalities, plasma/cerebrospinal fluid (CSF) profiles, lipidomic signatures and markers of mitochondrial impairment, underscoring their diagnostic and prognostic potential. Furthermore, the chapter discusses about the therapeutic prospects targeting metabolic pathways, addressing current challenges in development of therapeutic strategies, reinforcing the need for integrative and precision-based interventions for early diagnosis and disease modifying therapeutic strategies in AD.},
}

Humans
*Alzheimer Disease/metabolism/therapy
Biomarkers/metabolism
Animals
Amyloid beta-Peptides/metabolism
Glucose/metabolism
*Brain/metabolism

@article {pmid42552048,
year = {2026},
author = {Baskar, G and Kandasamy, M},
title = {Energetic crisis, mitochondrial vulnerability and disruption of lactate shuttle in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {188},
number = {},
pages = {67-89},
doi = {10.1016/bs.irn.2026.05.012},
pmid = {42552048},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism ; Animals ; *Energy Metabolism/physiology ; *Mitochondria/metabolism/pathology ; *Lactic Acid/metabolism ; *Neurons/metabolism ; Astrocytes/metabolism ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) has traditionally been characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Emerging evidence reveals that metabolic dysfunction represents a key pathological feature central to disease progression. Mitochondrial dysfunction in AD leads to impaired electron transport chain activity and reduced level of adenosine triphosphate (ATP) synthesis, preceding neurodegeneration and structural abnormalities in cognitive centres of the brain. Early glucose hypometabolism and lactate deprivation or interference with their utilization represent a primary bioenergetic failure driving mitochondrial dysfunction and neuroinflammation prior to the clinical manifestation of AD. While the brain relies on lactate as a prominent energy substrate, astrocytic metabolic defects lead to impaired neuronal energy homeostasis, thereby promoting neurodegeneration. In turn, this metabolic uncoupling could also be associated with defects in regenerative mechanisms by impairing adult neurogenesis in the hippocampus due to energy deprivation, accounting for memory deficits. This chapter discusses the evidence for the energetic crisis in AD, focusing on the disruption of the astrocyte-neuron lactate shuttle (ANLS), hypometabolism of glucose, and mitochondrial vulnerability, as interconnected pathogenic mechanisms. We emphasise cerebral bioenergetic metabolic failure as a central driver of cognitive decline, arising from irreversible reactive gliosis and neuroblastosis mechanisms and highlight various therapeutic options, including restoration of ANLS to mitigate the pathogenesis and memory loss in AD.},
}

Humans
*Alzheimer Disease/metabolism
Animals
*Energy Metabolism/physiology
*Mitochondria/metabolism/pathology
*Lactic Acid/metabolism
*Neurons/metabolism
Astrocytes/metabolism
*Brain/metabolism

@article {pmid42552066,
year = {2025},
author = {Liu, Y and Poon, CH and Tse, LSR and Roy, J and So, CT and Tong, BC and Yao, KM and Tipoe, GL and Steinbusch, H and Aquili, L and Kalueff, A and Cheung, KH and Fung, ML and Lim, LW},
title = {Homeostatic DNMT3a Activity Is Required to Restore Cognition and Hippocampal DNA Methylation in the 5xFAD Model of Alzheimer's Disease.},
journal = {Aging and disease},
volume = {17},
number = {5},
pages = {2710-2739},
doi = {10.14336/AD.2025.0283},
pmid = {42552066},
issn = {2152-5250},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/drug therapy ; DNA Methyltransferase 3A ; *Hippocampus/metabolism ; *DNA Methylation/drug effects ; Disease Models, Animal ; Mice ; *DNA (Cytosine-5-)-Methyltransferases/metabolism/genetics ; *Cognition/drug effects/physiology ; Mice, Transgenic ; Methionine/pharmacology ; Spatial Memory/drug effects ; Homeostasis ; Male ; Neuronal Plasticity/drug effects ; },
abstract = {Dysregulation of DNA methylation has been implicated in Alzheimer's disease (AD), making the manipulation of DNA methylation processes a promising therapeutic strategy. DNA methyltransferase 3a (DNMT3a), one of the two de novo DNMTs, is involved in learning and memory. However, it remains elusive whether and how alterations in DNMT3a expression contributes to AD pathogenesis. In this study, we investigated the consequences of DNA methylation dysregulations in the hippocampus of 5xFAD mouse model of AD and explored the use of L-methionine (MET) supplement to restore DNA methylation dysregulations. The 5xFAD model exhibited spatial memory impairments accompanied by global DNA hypomethylation and dysregulated hippocampal expression of DNA methyltransferases (DNMT) and demethylases. Prolonged treatment with MET rescued memory deficits, reduced amyloid-β load, decreased neuroinflammation, restored the expression of plasticity-regulating genes and proteins, and enhanced serotonergic neurotransmission. DNMT3a knockdown diminished the pro-cognitive effects of MET and independently impaired spatial memory and hippocampal neuroplasticity in both wildtype and 5xFAD mice. Interestingly, DNMT3a overexpression also had detrimental effects on spatial memory and hippocampal neuroplasticity in both genotypes. Our findings demonstrate that methyl supplementation can be a promising therapeutic strategy for AD patients with brain DNA hypomethylation and that maintaining DNMT3a homeostasis is crucial for normal cognitive functions and the pro-cognitive effects of MET.},
}

Animals
*Alzheimer Disease/genetics/metabolism/drug therapy
DNA Methyltransferase 3A
*Hippocampus/metabolism
*DNA Methylation/drug effects
Disease Models, Animal
Mice
*DNA (Cytosine-5-)-Methyltransferases/metabolism/genetics
*Cognition/drug effects/physiology
Mice, Transgenic
Methionine/pharmacology
Spatial Memory/drug effects
Homeostasis
Male
Neuronal Plasticity/drug effects

@article {pmid42552207,
year = {2026},
author = {Chen, R and Pan, C and Mao, X and Zhang, Y and Chen, G and Xu, M and Nivar, J and Tao, Y and Cao, H and JunLi, },
title = {Retraction notice to "Chloride intracellular channel 4 blockade improves cognition in mice with Alzheimer's disease: CLIC4 protein expression and tau protein hyperphosphorylation" [Int. J. Biol. Macromol. 278 (2024) 134972].},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153849},
doi = {10.1016/j.ijbiomac.2026.153849},
pmid = {42552207},
issn = {1879-0003},
}

@article {pmid42552272,
year = {2026},
author = {Turrisi, R and Cammarasana, S and Paccini, M and Patanè, G and , },
title = {Super-Resolution of Through-Plane Undersampled MRIs in Alzheimer's Disease Diagnosis.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02159-9},
pmid = {42552272},
issn = {2948-2933},
support = {ECS00000035//Ministero dell'Università e della Ricerca/ ; 2022WK7NHC//Ministero dell'Università e della Ricerca/ ; },
abstract = {Alzheimer's disease is a complex neurodegenerative disorder and the leading cause of dementia worldwide. Learning-based techniques applied to magnetic resonance imaging (MRI) have recently shown strong potential for automated diagnosis. Accurate classification typically relies on high-resolution (HR) 3D MRI acquired with thin axial slices to reduce partial-volume artefacts, capture fine anatomical details, and improve diagnostic performance. However, acquiring such data is time-consuming, costly, and prone to motion artefacts and patient discomfort. Super-resolution methods offer a promising alternative by reconstructing HR 3D images from lower-resolution scans and enabling shorter acquisition times. In this study, we propose a novel pipeline that applies super-resolution to through-plane undersampled 3D magnetic resonance images and demonstrates that the resulting volumes preserve Alzheimer's disease diagnostic accuracy comparable to that achieved using fully sampled HR scans. We compare different state-of-the-art super-resolution methods from distinct methodological families, with the best-performing method achieving an F1 score of 65.6, close to the HR reference of 65.7 and substantially higher than the low-resolution baseline of 55.9. Furthermore, we investigate whether standard image quality metrics (e.g. pixel-based metrics) are sufficient to assess the contribution of super-resolution to the clinical evaluation of Alzheimer's disease. To this end, we compare them with machine learning-based measures, such as maximum mean discrepancy, and surface-based metrics derived from segmented anatomical structures, highlighting their limitations in clinically oriented evaluations.},
}

@article {pmid42552337,
year = {2026},
author = {Ma, N and Stieler, J and Hilbrich, I and Vogel, T and Hilgeroth, A and Briel, D and Schaefer, M and Holzer, M and Metelmann, M},
title = {NanoBiT screening identifies the azaoxafluorene VT11 as potent tau interaction inhibitor.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42552337},
issn = {2045-2322},
mesh = {*tau Proteins/metabolism/antagonists & inhibitors/chemistry ; Humans ; Protein Binding/drug effects ; Tauopathies/drug therapy/metabolism ; Biosensing Techniques ; },
abstract = {Tauopathies are neurodegenerative disorders characterized by accumulating misfolded, insoluble tau protein aggregates in neurons or glial cells. In this study, we screened the Spectrum Collection and other compound libraries for inhibitors of tau self-interaction using a structural complementation reporter system (NanoLuciferase Binary Technology). Resulting candidates were tested in dose-response assays and evaluated for cell toxicity and microtubule destabilization. Further, a seed-induced tau interaction biosensor assay and a cell-free tau Real-Time Quaking-Induced Conversion assay have been established to study their effects on the kinetics of tau interaction and aggregation, respectively. The substances ritanserin, 3-methoxycatechol, gambogic amide, azaoxafluorenes VT11, and NS 185 and thieno[2,3-d][1.3]oxazine B6/55 showed a concentration-dependent tau self-interaction inhibition without relevant cell toxicity or microtubule destabilization. Ritanserin, VT11, NS 185 and B6/55 blocked tau interaction in the seed-induced tau interaction biosensor assay. Finally, the cell-free tau RT-QuIC assay displayed highest inhibitory potential for VT11. Thus, the azaoxafluorene VT11 seems to be a promising candidate for further investigations as tau interaction inhibitor to address a pivotal pathological process in Alzheimer's disease and other tauopathies.},
}

*tau Proteins/metabolism/antagonists & inhibitors/chemistry
Humans
Protein Binding/drug effects
Tauopathies/drug therapy/metabolism
Biosensing Techniques

@article {pmid42552384,
year = {2026},
author = {Klimmt, J and Cardoso Gonçalves, C and Montgomery, JV and Müller, SA and Bublitz, M and Filser, S and Paeger, L and Nuscher, B and Dannert, A and Roeber, S and Pravata, V and Schifferer, M and Shrouder, JJ and Schulz, N and González-Gallego, J and Cappello, S and Misgeld, T and Plesnila, N and Beltrán, E and Herms, J and De Domenico, E and Beyer, MD and Schultze, JL and Haass, C and Lichtenthaler, SF and Carraro, C and Paquet, D},
title = {A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42552384},
issn = {1546-1726},
support = {ADR AD2019604S//BrightFocus Foundation (BrightFocus)/ ; 16LW047//Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)/ ; },
abstract = {Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer's disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer's disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.},
}

@article {pmid42552390,
year = {2026},
author = {Lucey, BP and Howell, MJ},
title = {Losing sleep over glia: new mechanisms for Alzheimer-related sleep disruption.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42552390},
issn = {1759-4766},
}

@article {pmid42552421,
year = {2026},
author = {Liao, K and Xie, M and Ibáñez, CF},
title = {p75 neurotrophin receptor signaling through the RhoA/ROCK pathway contributes to Tau-mediated neurodegeneration.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42552421},
issn = {1476-5578},
support = {X2026t/77//Royal Swedish Academy of Sciences (Kungl. Vetenskapsakademien)/ ; },
abstract = {Therapeutic development in Alzheimer's Disease (AD) has for the most part been focused on reducing β-amyloid load. Nevertheless, neurofibrillary tangles (NFTs), produced by aggregation of hyper-phosphorylated Tau protein, correlate with neurodegeneration and cognitive impairment significantly better than amyloid accumulation in AD patients. Here we report that P301S mice, a model of Tau-mediated neurodegeneration, carrying mutant variants of the p75 neurotrophin receptor (p75[NTR]) deficient in RhoA/ROCK signaling are protected from neurodegeneration and cognitive impairment. Both p75[∆DD], lacking the death domain, and triple mutant p75[KKEA], unable to interact with RhoGDI, decreased insoluble Tau species, reduced gliosis, neurodegeneration and synapse loss, and improved spatial learning and memory in P301S mice. Intriguingly, p75[C259A], a variant unresponsive to neurotrophins but still competent for RhoA signaling induced by myelin-derived ligands, did not afford any neuroprotection. P301S neurons expressing p75[∆DD] or p75[KKEA], but not p75[C259A], showed reduced phospho-Tau and ROCK and GSK3β activity, the two main kinases responsible for Tau phosphorylation. In line with this, treatment with myelin-associated glycoprotein (MAG) enhanced Tau phosphorylation and ROCK activity in P301S neurons expressing wild type p75[NTR] or p75[C259A], but not p75[∆DD] or p75[KKEA]. Together, these results indicate that p75[NTR] contributes to AD Tauopathy by enhancing the activity of the RhoA-ROCK pathway.},
}

@article {pmid42552687,
year = {2026},
author = {Koychev, I and Rowe, JB and Amin, J and Arsland, D and Archer, H and Barber, R and Burns, A and Coulthard, E and Deasy, C and Dunne, R and Fox, N and Humphrey, SH and Jenkinson, J and Jones, D and Kennelly, S and Khan, F and Krishnan, MSP and Malhotra, P and McFarlane, B and McGuinness, B and Mummery, C and Pennington, C and Perry, JR and Raczek, G and Rasmussen, J and Ritchie, C and Taylor, JP and Underwood, BR and Venkataraman, AV and Raymont, V},
title = {Interpreting evolving evidence in Alzheimer's disease: implications for dementia clinicians.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-2},
doi = {10.1192/bjp.2026.10750},
pmid = {42552687},
issn = {1472-1465},
}

@article {pmid42552722,
year = {2026},
author = {Kotah, JM and Lima, MT and Dragt, EC and Voulgaroglou, A and Brouwer, N and Holtman, IR and Kooistra, SM and Eggen, BJL},
title = {Predicting Relevant Microglia-Associated Cell-Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1.},
journal = {Glia},
volume = {74},
number = {10},
pages = {e70210},
doi = {10.1002/glia.70210},
pmid = {42552722},
issn = {1098-1136},
support = {WE.03-2025-06//Alzheimer Nederland/ ; WE.03-2020-03//Alzheimer Nederland/ ; //Stichting De Cock-Hadders/ ; MODEM 10510032120006/ZONMW_/ZonMw/Netherlands ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; Humans ; *Cell Communication/physiology ; *Brain/metabolism/pathology ; *Osteopontin/metabolism/genetics ; Signal Transduction/physiology ; Male ; Female ; Aged ; Plaque, Amyloid/pathology/metabolism ; Aged, 80 and over ; },
abstract = {Microglia play a key role in the pathophysiology of Alzheimer's Disease (AD) and their increased heterogeneity likely affects disease progression. We previously identified distinct microglial signatures that were enriched in AD donors and associated with amyloid and tau, respectively. Here we generated a snRNAseq dataset from postmortem control and AD cases and analyzed alterations in cell-cell communication pathways that might be relevant to AD pathophysiology. One signaling pathway perturbed in AD cases involved SPP1, and while this pathway was also present in control samples, microglia-microglia SPP1 signaling was restricted to AD donors. Further analyses within microglia-microglia signaling predict AD-specific induction of GAS6-AXL signaling (from inflammatory and ribosomal microglia), and SPP1-ITGAV/ITGB5 signaling (from disease-associated and inflammatory microglia, among others). Together, these findings might in part explain the increased microglia phagocytic profile described in AD. RNAscope confirmed enrichment of SPP1 expressing microglia near amyloid plaques in AD brain tissue samples. These data indicate altered cellular communications between microglia in the AD brain.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
Humans
*Cell Communication/physiology
*Brain/metabolism/pathology
*Osteopontin/metabolism/genetics
Signal Transduction/physiology
Male
Female
Aged
Plaque, Amyloid/pathology/metabolism
Aged, 80 and over

@article {pmid42552749,
year = {2026},
author = {Boustani, M and Klein, EG and Zimmer, JA and Wang, H and Engle, SE and Phipps, A and Japha, M and Schilling, T and Hartry, A and , },
title = {Further data to address the Alzheimer's coverage with evidence development questions.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71724},
doi = {10.1002/alz.71724},
pmid = {42552749},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; United States ; *Medicare ; *Antibodies, Monoclonal, Humanized/therapeutic use ; },
abstract = {INTRODUCTION: Medicare patients currently access amyloid-targeting therapies for Alzheimer's disease through the class-based National Coverage Determination (NCD) with coverage with evidence development (CED) established in 2022. Evidence addressing the stated CED questions was previously published in a 2024 review; however, the original 2022 NCD remains unchanged.

METHODS: Update the previously published review responding to the CED questions by summarizing recently published donanemab and lecanemab extension data and new safety-related data.

RESULTS: New evidence addresses each of the three CED questions. Extension data show that the benefit of amyloid-targeting therapy continues to accrue with no new safety signals observed. Safety analyses identified baseline risk factors for amyloid-related imaging abnormalities (ARIA). Further, a more gradual donanemab titration regimen decreased risk of ARIA-edema/effusions.

DISCUSSION: With CED questions addressed, reconsideration of the class-based NCD is scientifically justified.

CLINICAL TRIAL REGISTRATION: NCT04437511, NCT05738486, NCT03887455.},
}

*Alzheimer Disease/drug therapy
Humans
United States
*Medicare
*Antibodies, Monoclonal, Humanized/therapeutic use

@article {pmid42552750,
year = {2026},
author = {Fernández-Lebrero, A and Jiménez-Balado, J and García-Escobar, G and Contador, J and Estraguès-Gázquez, I and Peraferrer-Montesinos, L and Manero-Borràs, RM and Gramegna, LL and Viles, M and Campello, AR and Ortiz-Romero, P and de Diego, M and Del Campo, M and Torres-Torronteras, J and Jiménez-Moyano, E and Blasco-Forniés, H and Suárez-Calvet, M and Ois, A and Puig-Pijoan, A and Navalpotro-Gómez, I},
title = {Plasma p-tau217 detects Alzheimer's disease co-pathology in cerebral amyloid angiopathy: Comparison to CSF biomarkers in the ANGMAR cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71709},
doi = {10.1002/alz.71709},
pmid = {42552750},
issn = {1552-5279},
support = {PI21/00194//the Fondo de Investigación Sanitaria (FIS)/ ; ERA-CVD_JTC2020-015//the European Research Area Network on Cardiovascular Diseases/ ; AC20/00001//the European Research Area Network on Cardiovascular Diseases/ ; CP25/00015//Miguel Servet program/ ; 948677//the European Research Council (ERC)/ ; PI22/00456//Instituto de Salud Carlos III (ISCIII)/ ; 847648 (LCF/BQ/PR21/11840004)//"la Caixa" Foundation/ ; },
mesh = {Humans ; *tau Proteins/blood/cerebrospinal fluid ; *Cerebral Amyloid Angiopathy/blood/pathology/complications/cerebrospinal fluid/diagnostic imaging ; *Alzheimer Disease/blood/cerebrospinal fluid/pathology/complications/diagnostic imaging/diagnosis ; Female ; Biomarkers/blood/cerebrospinal fluid ; Male ; Aged ; Magnetic Resonance Imaging ; Cohort Studies ; Phosphorylation ; Aged, 80 and over ; Middle Aged ; Brain/pathology ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) frequently co-occurs with Alzheimer's disease (AD), generating mixed vascular-neurodegenerative phenotypes. Plasma phosphorylated tau (p-tau)217 is a robust biomarker of AD, but its performance in CAA remains unclear.

METHODS: We studied 231 participants, including 50 patients with CAA (Boston v2.0), 154 with AD, and 27 cognitively unimpaired controls. Plasma p-tau217 was measured on an automated platform and compared to cerebrospinal fluid (CSF)-defined AD status. Associations with magnetic resonance imaging (MRI) markers of CAA burden were evaluated.

RESULTS: Among CAA participants, 29 met CSF criteria for AD co-pathology. Plasma p-tau217 discriminated CAA patients with and without AD co-pathology (area under the curve = 0.920) and showed no association with MRI markers of CAA burden. Predefined cut-offs (≥ 0.27 pg/mL and ≥ 0.34 pg/mL) yielded high accuracy for identifying AD co-pathology within CAA.

CONCLUSIONS: Plasma p-tau217 shows high diagnostic accuracy for identifying AD co-pathology in CAA and is not associated with MRI markers of CAA burden, supporting its specificity for AD-related pathology.},
}

Humans
*tau Proteins/blood/cerebrospinal fluid
*Cerebral Amyloid Angiopathy/blood/pathology/complications/cerebrospinal fluid/diagnostic imaging
*Alzheimer Disease/blood/cerebrospinal fluid/pathology/complications/diagnostic imaging/diagnosis
Female
Biomarkers/blood/cerebrospinal fluid
Male
Aged
Magnetic Resonance Imaging
Cohort Studies
Phosphorylation
Aged, 80 and over
Middle Aged
Brain/pathology

@article {pmid42552753,
year = {2026},
author = {Hutten, CG and Beck, T and Evans, D and Rajan, KB},
title = {The role of polygenic risk in Alzheimer's disease prediction for African Americans.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71712},
doi = {10.1002/alz.71712},
pmid = {42552753},
issn = {1552-5279},
support = {R01AG073627/AG/NIA NIH HHS/United States ; R01AG058679/AG/NIA NIH HHS/United States ; UH2AG083289/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/ethnology ; *Black or African American/genetics ; Genetic Risk Score ; Female ; Male ; *Genetic Predisposition to Disease ; Aged ; White People/genetics ; *Multifactorial Inheritance/genetics ; Risk Factors ; Aged, 80 and over ; Apolipoprotein E4/genetics ; European People ; },
abstract = {INTRODUCTION: African Americans (AAs) face a higher risk of Alzheimer's disease and related dementias (ADRD) than European Americans (EUs), yet the utility of polygenic risk scores (PRS) in AAs remains underexplored.

METHODS: A standardized dementia PRS was evaluated in the Chicago Health and Aging Project (n = 4336; 61% AA) for associations with ADRD and cognitive trajectories over 8.4 years.

RESULTS: PRS predicted ADRD more strongly in EUs (c-index 0.86) than AAs (0.77); however, it conferred higher risk in AAs (hazard ratio [HR] = 1.36, 95% confidence interval [CI]: 1.04-1.78) compared to EU (HR = 1.13, 95% CI: 0.88-1.44). The PRS remained predictive among AAs after apolipoprotein E (APOE) ε4 adjustment (HR = 1.53, 95% CI: 1.03-2.27). Higher PRS associated with lower baseline cognition and faster decline (p < 0.05).

DISCUSSION: PRS conferred greater ADRD risk in AAs and comparable rates of cognitive decline, despite stronger discrimination in EUs, adding to the limited knowledge of genetic contributions to ADRD risk among AAs beyond APOE ε4 alleles.},
}

Humans
*Alzheimer Disease/genetics/ethnology
*Black or African American/genetics
Genetic Risk Score
Female
Male
*Genetic Predisposition to Disease
Aged
White People/genetics
*Multifactorial Inheritance/genetics
Risk Factors
Aged, 80 and over
Apolipoprotein E4/genetics
European People

@article {pmid42552789,
year = {2026},
author = {Piras, F and Serra, L and Caltagirone, C and Giove, F},
title = {The disconnectome as target in Alzheimer disease: a promising framework or a premature end-point?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag262},
pmid = {42552789},
issn = {1460-2156},
}

@article {pmid42552845,
year = {2026},
author = {Wang, X and Li, Y and Ye, J and Lian, H and Li, T and Wang, J},
title = {Lymphedema and Alzheimer's Disease: Connecting Through the "Peripheral-Central Lymphatic System".},
journal = {Lymphatic research and biology},
volume = {},
number = {},
pages = {15578585261471251},
doi = {10.1177/15578585261471251},
pmid = {42552845},
issn = {1557-8585},
abstract = {The connection between the peripheral lymphatic system (PLS) and the central lymphatic system (CLS) plays a crucial role for the overall circulatory system. Notably, there are several similarities between lymphedema and Alzheimer's disease (AD). Accumulating evidence suggests that lymphedema might be associated with AD, potentially influencing its progression through mechanisms related to the peripheral-central lymphatic circulation. This review summarizes the lymphatic system's structure, function, and drainage pathways, emphasizing how aging and blockage of the CLS can exacerbate the progression of AD. Additionally, we discuss the relationship between lymphedema and AD, highlighting the significance of the PLS-CLS and exploring lymphaticovenous anastomosis as a promising treatment for both lymphedema and AD.},
}

@article {pmid42553105,
year = {2026},
author = {Rubinshtein, R and Obied, B and Salti, T and König, AI and Zahavi, A and Goldenberg-Cohen, N},
title = {Longitudinal assessment of intraocular pressure in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1858031},
pmid = {42553105},
issn = {1664-2295},
abstract = {OBJECTIVES: Glaucoma and Alzheimer's disease (AD) are major neurodegenerative disorders with increasing evidence of shared pathogenic pathways. Glaucoma involves progressive optic nerve degeneration and irreversible vision loss, often associated with elevated intraocular pressure (IOP) but also occurring independently of it. AD, the leading cause of dementia, results in progressive cognitive and functional decline, with vision disturbances including visual field defects. Epidemiological studies report higher co-prevalence of glaucoma and AD in older adults. This study longitudinally assessed IOP in a transgenic AD mouse model to determine whether AD-related amyloid pathology inherently drives alterations in ocular pressure.

METHODS: Ten young (25 weeks old; 9 males, 1 female) and fifteen aged 5xFAD (57-60 weeks old; 5 males and 10 females) transgenic mice, a well-established amyloidogenic model of AD, were examined. Age-matched control groups included ten young wild type (WT) mice (9 males and 1 female) and fourteen aged WT mice (7 males and 7 females). IOP was measured repeatedly without anesthesia using a rebound tonometer (Icare Tonolab) calibrated for mice. Four IOP measurement sessions were performed at days 1, 36, 55, and 77, with all measurements conducted during midday hours (11:00-14:00) to minimize circadian variability.

RESULTS: IOP remained stable across most groups and time points. Aged 5xFAD mice exhibited transient, statistically significant fluctuations, characterized by an initial decrease at day 36 followed by a return to baseline levels. Age-matched WT mice showed no significant longitudinal changes. When comparing between groups, the only significant difference was observed at day 36, where aged 5xFAD mice demonstrated significantly lower IOP than aged WT controls.

CONCLUSIONS: 5xFAD mice did not exhibit sustained IOP elevation compared with WT controls, with aged animals displaying only transient fluctuations that likely reflect physiological or measurement variability. These results suggest that amyloid-driven pathology in this model is not accompanied by chronic ocular hypertension. Consequently, our findings support the hypothesis that visual dysfunction in AD models may occur independently of elevated intraocular pressure, though the specific overlapping mechanisms between AD and glaucoma warrant cautious interpretation and further investigation.},
}

@article {pmid42553297,
year = {2026},
author = {Li, Q and You, M},
title = {Targeting mitochondria for the treatment of neurodegenerative diseases.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1835506},
pmid = {42553297},
issn = {1662-4548},
abstract = {Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.},
}

@article {pmid42553403,
year = {2026},
author = {Fan, JD and Fu, Y and Li, QY and Zhang, ZQ and Zhao, YL and Hao, Q and Tan, L and Tan, MS and , },
title = {Association of cerebrospinal fluid amphiphysin-1 levels with cognition and Alzheimer's disease pathology biomarkers.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1875646},
pmid = {42553403},
issn = {1663-4365},
abstract = {INTRODUCTION: Amphiphysin-1 (AMPH), an accessory component of the clathrin-mediated endocytosis (CME) machinery, plays a critical role in synaptic vesicle recycling and membrane dynamics and has been implicated in Alzheimer's disease (AD) risk. However, its relationship with core AD biomarkers and disease progression remains unclear.

METHODS: In this study, we examined the associations between cerebrospinal fluid (CSF) AMPH and core AD biomarkers (CSF amyloid-β42 [Aβ42], phosphorylated tau [P-tau], and total tau [T-tau]), cognitive performance, neurodegeneration, and clinical progression in 723 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were categorized according to the AT(N) framework into stage 0, stage 1, stage 2, and suspected non-AD pathophysiology (SNAP).

RESULTS: AMPH exhibited stage-dependent alterations across the AD continuum, characterized by lower levels in stage 1, and elevated levels in stage 2 and SNAP. Cross-sectionally, CSF AMPH was positively associated with core CSF biomarkers. Longitudinal analyses showed that, among amyloid-negative individuals, higher baseline AMPH was associated with faster decreases in CSF Aβ42 and increases in P-tau and T-tau. In the overall cohort, higher baseline AMPH was associated with accelerated hippocampal atrophy and cognitive decline, and with an increased risk of clinical progression (HR = 1.21, 95% CI: 1.05-1.37).

DISCUSSION: In ADNI, CSF AMPH was associated with biological changes across the AD continuum, cognitive decline, hippocampal atrophy, and clinical progression. These findings may provide complementary information for understanding disease progression.},
}

@article {pmid42553595,
year = {2026},
author = {Tamvaka, N and Scotton, W and Lilley, MT and Shoai, M and Gavrielatos, M and Heckman, MG and Soto-Beasley, AI and Roemer, SF and Baker, MC and Rademakers, R and Murray, ME and Dickson, DW and Hardy, JA and Cook, CN and Rohrer, JD and Ross, OA and , and , },
title = {Evaluating MAPT p.A152T as a risk factor for the 3R tauopathy Pick's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag266},
pmid = {42553595},
issn = {2632-1297},
abstract = {Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick's disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer's disease and progressive supranuclear palsy, but its role in Pick's disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick's disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick's disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer's disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick's disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.},
}

@article {pmid42553702,
year = {2026},
author = {Morgan, J and Aarons, T and Mukhopadhyay, A and Lace, G},
title = {Distinct brain extracellular vesicle microRNA profiles differ in frontotemporal dementia and Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag277},
pmid = {42553702},
issn = {2632-1297},
abstract = {Dementia is a syndrome caused by various diseases including Alzheimer's disease (AD) and frontotemporal dementia (FTD) with an estimated global prevalence of 60 million individuals. Recently, therapeutic development in the dementia field has accelerated, with the introduction of monoclonal antibody therapeutics such as Lecanemab and Donanemab. However, AD and FTD patients are still either diagnosed too late to benefit from available therapies or are misdiagnosed due to the clinical overlap between dementia subgroups making therapeutic intervention challenging. This highlights a real need to improve early diagnostic tools of neurodegenerative disease (ND) biomarkers. A potential source of such biomarkers come from small extracellular vesicles (sEVs), groups of cell-derived, lipid-bound assemblies with the capability to cross the blood-brain barrier (BBB) and known to carry pathogenic proteins associated with AD and FTD. A known cargo of sEVs is microRNA (miRNA), regulatory molecules that post-transcriptionally silence gene expression including transcripts of autophagic systems, processes which dysfunction in dementia-causing diseases leading to toxic aggregate build-up, causing neurodegeneration. The targeting of functional machineries in macroautophagy (MA) and chaperone-mediated autophagy (CMA) by different miRNA may vary between AD and FTD mutations, leading to potential biomarkers of disease being highlighted. Through isolating sEVs from the frontal cortex of post-mortem brain tissue of AD, FTD-MAPT, FTD-C9orf72, FTD-GRN and no-disease control patients (Manchester Brain Bank), miRNA cargoes were analysed and compared using real-time quantitative PCR (RT-qPCR). Seven autophagy-associated miRNA candidates (MA: miR-124-3p, miR-30a-5p, miR-128-3p; and CMA: miR-224-5p, miR-373-5p, miR-106a-3p and miR-26b-5p) were tested to identify dementia sub-group variations, used alongside small RNA-sequencing to explore broader miRNA variation within sEV populations. Of the miRNA tested miR-224-5p (P = 1.76 × 10[-5]) and miR-106a-3p (P = 0.033) showed significant group differences, and further significant pairwise comparison differences [miR-224-5p: AD fold change (FC) = 4.29, MAPT FC = 7.62; miR-106a-5p: AD FC = 5.59] when compared with no disease controls and other dementia subgroups, potentially showing initial diagnostic and differentiating potential. Small RNA-sequencing results revealed 8 AD, 2 FTD-GRN, 52 FTD-MAPT and 12 FTD-C9orf72 differentially expressed sEV-miRNAs when compared with no disease controls. Further direct comparisons between AD versus FTD mutation-derived sEV cargoes, and even FTD mutation versus FTD mutation-derived sEV cargoes, identified additional miRNA with differentiating capabilities. These findings demonstrate sEV-derived miRNA signatures vary across dementia sub-types and suggest potential roles of sEV cargoes in both disease diagnostics and identifying drivers of ND, such as autophagic impairments and signalling pathways.},
}

@article {pmid42553791,
year = {2026},
author = {Mehdi, MR and Al-Qassab, ZMS and Sabuni, O and Rai, M and Patel, T and Patel, R and Iftikhar, L},
title = {Exploring the Link Between Obstructive Sleep Apnea and Neuropsychiatric Disorders: Role of Neuroinflammatory Mechanisms.},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e112096},
pmid = {42553791},
issn = {2168-8184},
abstract = {Obstructive sleep apnea syndrome (OSAS) is a prevalent sleep-related breathing disorder characterized by recurrent episodes of upper airway obstruction during sleep, resulting in intermittent reductions or complete cessation of airflow. These interruptions reduce oxygen saturation and disrupt normal sleep architecture, frequently resulting in daytime fatigue and adverse health outcomes. Recent research has provided increasing evidence that OSAS may be associated with neuroinflammation, defined as inflammation within the brain and nervous system. Such neuroinflammation may contribute to the development of conditions including depression, anxiety, Alzheimer's disease, and Parkinson's disease. This narrative review examines the association between OSAS and neuroinflammation and outlines the potential biological mechanisms involved. Intermittent hypoxemia and recurrent sleep fragmentation are thought to promote oxidative stress, neuroinflammation, and neuronal injury, ultimately contributing to impaired memory, executive function, emotional regulation, and overall neurological function. Over time, these processes can impair memory, executive function, emotional regulation, and overall neurological function. The review also highlights key risk factors and clinical manifestations and emphasizes the importance of early diagnosis and intervention for OSAS. Evidence from both experimental animal studies and human clinical studies is discussed to highlight current understanding while distinguishing established findings from emerging hypotheses. In summary, this review indicates that neuroinflammation may represent an important mechanistic pathway linking OSAS with depression, anxiety, cognitive impairment, and neurodegenerative disorders. However, much of the available evidence remains associative, and further longitudinal and biomarker-driven studies are required to clarify causal relationships and determine the long-term impact of interventions such as continuous positive airway pressure (CPAP) therapy. Improved understanding of these mechanisms may facilitate earlier diagnosis, risk stratification, and the development of targeted therapeutic strategies for individuals with OSAS.},
}

@article {pmid42553843,
year = {2026},
author = {Sharma, S and Sharma, S and Raghuvanshi, V and Kumari, S and Singh, S and Butcher, RJ and Srikrishna, S and Katiyar, D},
title = {Design, synthesis, and evaluation of pyrano[3,2-c]coumarin derivatives for simultaneous targeting of amyloid-β42 and acetylcholinesterase in transgenic AD model of Drosophila.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42553843},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving amyloid-β (Aβ) aggregation, cholinergic dysfunction, oxidative stress, mitochondrial impairment, and progressive neuronal loss. Consequently, the development of multi-target-directed ligands (MTDLs) capable of modulating multiple pathological pathways simultaneously has emerged as a promising therapeutic strategy. In this context, the present study describes the design, synthesis, and biological evaluation of a novel series of pyrano[3,2-c]coumarin derivatives 4a-n as dual Aβ42 and acetylcholinesterase (AChE) targeting anti-AD agents. Compounds 4a-n showed significant protection by inhibiting tissue specific Aβ42 aggregation in a transgenic AD model of Drosophila. In particular, compounds 4g and 4i were identified as potential lead compounds for targeting AD. These compounds inhibited endogenous Aβ42 aggregation and exhibited a significant rescue of eye phenotypes at respective effective concentrations (ECs) (4g, 46% rescue at EC = 250 µM and 4i, 65% rescue at EC = 50 µM). Furthermore, compounds 4g and 4i effectively reduced lipid-peroxidation, which was determined by assessing thiobarbituric acid reactive substances (TBARS) levels, at 25 and 50 µM, respectively, and reactive oxygen species (ROS). Compounds 4g and 4i also exhibited AChE inhibitory activity, with IC50 values of 0.02652 and 0.0268 µM, respectively. In silico molecular docking studies of 4i with Aβ42 (PDB ID: 1IYT) and AChE (PDB ID: 4EY4) also corroborated their anti-AD activity. Therefore, the present study indicated these compounds, especially 4i, could be promising lead candidates for AD drug development.},
}

@article {pmid42554173,
year = {2026},
author = {Yıldırım, N and Güven Aksu, NM and Perk, BÖ and Can Eke, B},
title = {Plasma Concentrations of Amyloid-β Peptides, BACE-1, and Tau Proteins in Alzheimer's Disease.},
journal = {Turkish journal of pharmaceutical sciences},
volume = {},
number = {},
pages = {},
doi = {10.4274/tjps.galenos.2026.68256},
pmid = {42554173},
issn = {2148-6247},
abstract = {OBJECTIVES: The aim of this study was to compare, using ELISA, plasma levels of amyloid beta (Aβ)40, Aβ42, beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), total tau (t-tau), and phosphorylated tau (p-tau), as well as the Aβ42/Aβ40 ratio, between patients with Alzheimer's disease (AD) and healthy controls, and to evaluate their diagnostic performance in relation to demographic and lifestyle factors.

MATERIALS AND METHODS: This study is a single-center, cross-sectional, case-control study. Twenty-four individuals diagnosed with AD and 37 healthy volunteers included in the study. Alongside the analysis of plasma samples obtained from the participants, demographic data were analyzed to assess the potential influence of lifestyle and environmental factors on disease development.

RESULTS: Analysis of the case data showed that increasing age was a risk factor for AD, higher education level was associated with an increased risk of AD, and tea consumption was inversely associated with AD. While age is a well-known risk factor, both the increased risk of AD associated with higher education and the relatively protective effect of tea consumption against AD are supported by the literature. Evaluation of the levels of Aβ40, Aβ42, BACE-1, t-tau, and p-tau and of the Aβ42/Aβ40 ratio revealed no significant differences between the patient and control groups. Additionally, Aβ40, Aβ42, BACE-1 showed correlations in both the control and Alzheimer's groups, whereas t-tau did not.

CONCLUSION: None of the investigated plasma biomarkers (Aβ40, Aβ42, BACE-1, t-tau, p-tau, and the Aβ42/Aβ40 ratio) discriminated Alzheimer's patients from healthy controls, with all receiver operating characteristic area under the curve values below 0.62. These findings indicate that in this cohort, plasma levels of these individual markers did not provide diagnostic value; larger longitudinal studies including cerebrospinal fluid comparisons and multi-marker panels are needed.},
}

@article {pmid42554188,
year = {2026},
author = {Zhang, H and Zhang, Y and Cheng, Y and Liu, Q and Meng, X and Wang, D and Li, M},
title = {Docosahexaenoic acid improves cognitive function and reduces neuronal apoptosis in an Alzheimer's disease mouse model: association with reduced oxidative stress and telomere attrition.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1028415X.2026.2700765},
pmid = {42554188},
issn = {1476-8305},
abstract = {OBJECTIVE: Given the global aging intensification, age-related chronic diseases like Alzheimer's disease (AD) severely harm the elderly's health, with unclear pathogenesis and no effective drugs. Thus, this study intervened in APP/PS1 mice with docosahexaenoic acid (DHA) feeds of different doses to explore DHA's effects on the mice's cognitive function and nerve cell apoptosis, aiming to find the ways to prevent or delay the elderly's cognitive decline.

METHODS: Six-month-old APP/PS1 mice were divided into 4 groups: wild control (WT), model control (Con), low-dose DHA (DHA-L), and high-dose DHA (DHA-H). After intervention, the study evaluated mice's cognitive function, determined brain AD-related protein and free fatty acid levels, assessed neuronal degeneration and apoptosis, measured telomere oxidative damage, telomere length, and brain oxidative stress levels.

RESULTS: (1) DHA shortened water maze escape latency, increased platform crossings and target quadrant residence time, and reduced the expression of AD-related proteins (APP, Aβ, etc.) (P < 0.05); (2) It improved brain neuronal degeneration and apoptosis (P < 0.05); (3) It enhanced brain antioxidant capacity, regulated SOD, LPO, and MDA levels, and reduced DNA and telomere oxidative damage (P < 0.05); (4) It prolonged brain telomere length (P < 0.05).

CONCLUSION: DHA supplementation can improve cognitive decline in AD model mice, and the mechanism may be that DHA supplementation alleviates oxidative stress-mediated telomere wear in brain tissue, thereby inhibiting apoptosis of neuronal cells. These conditions provide a scientific basis for the elderly and people with cognitive impairment to prevent or alleviate cognitive impairment with reasonable intake of DHA.},
}

@article {pmid42554237,
year = {2026},
author = {Maestre, GE and Patel, NK and Pirela, RV and Hilsabeck, RC and Stine, K and Epps, FR and Garcia, N and Santiago-Mejias, S and Reyes, R and Satizabal, CL and Mejia-Arango, S and Sullivan, AC and Oropeza, O and Gireud-Goss, M and Rodriguez, H and Trevino, H and Ramirez, A and Young, VM and Alliey-Rodriguez, N and LaRoche, A and Martinez-Menendez, CJ and Tanner, JA and Otto, L and Garza-Parker, C and Garza, N and Flores, M and Casas, N and Robles, S and Davila, A and Maestre, CA and Shipp, E and Melgarejo, JD and de Erausquin, GA and Williams-Blangero, S and Seshadri, S},
title = {Engagement of understudied populations as community change: The South Texas ADRC model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71695},
doi = {10.1002/alz.71695},
pmid = {42554237},
issn = {1552-5279},
support = {P30AG066546/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Texas ; *Alzheimer Disease ; Hispanic or Latino ; *Patient Selection ; Community-Institutional Relations ; Focus Groups ; Rural Population ; Registries ; },
abstract = {Many populations experiencing the highest burdens of Alzheimer's disease and related dementias remain understudied, in part because traditional recruitment and retention models are insufficient to support sustained engagement. The Outreach, Recruitment, and Engagement Core (OREC) of the South Texas Alzheimer's Disease Research Center reconceptualized participant recruitment as a long-term system change in a Hispanic-majority, urban-rural region. OREC institutionalizes shared power through community advisory governance, aligns research protocols with local lived realities (through patient navigators, community health workers/promotores, and decentralized access points), and employs a data-driven feedback loop for continuous improvement. In 1 year, 46 outreach events touched 10,134 individuals (71% Hispanic) and generated 172 new registry enrollments. Qualitative engagement (focus groups/key-informant interviews) progressed to high-sensitivity topics (e.g., brain donation), signaling maturation of trust. This shift from outreach to reciprocity infrastructure reflects a systems-level change, one that lowers barriers, builds trust, and enables research participation to become routine rather than exceptional.},
}

Humans
Texas
*Alzheimer Disease
Hispanic or Latino
*Patient Selection
Community-Institutional Relations
Focus Groups
Rural Population
Registries

@article {pmid42554250,
year = {2026},
author = {Song, W and Liu, X and Yu, T and Xiang, Y and Fu, P and Wu, M and Yin, X and Zhang, X and Chen, Z},
title = {Early identification of vascular cognitive impairment from a multimodal perspective: a combined diagnosis from targeted cognitive assessments, imaging biomarkers, and molecular fluid biomarkers to ecological behavioral characteristics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71667},
doi = {10.1002/alz.71667},
pmid = {42554250},
issn = {1552-5279},
support = {81960221//National Natural Science Foundation of China/ ; 82260249//National Natural Science Foundation of China/ ; 202311506//Jiangxi Provincial Health Commission Science and Technology Plan project/ ; 2022A322//Jiangxi Provincial Administration of Traditional Chinese Medicine science and technology plan project/ ; 20224BAB216045//Youth Foundation of Natural Science Foundation of Jiangxi Province/ ; JXJG-24-17-20//Research and Reform Project on Education and Teaching in Ordinary Colleges/ ; JXJG-24-17-2//Research and Reform Project on Education and Teaching in Ordinary Colleges/ ; JXYJG-2024-140//Research and Reform Project on Education and Teaching in Ordinary Colleges/ ; },
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Early Diagnosis ; *Cognitive Dysfunction/diagnosis ; Neuroimaging ; Machine Learning ; *Dementia, Vascular/diagnosis ; Neuropsychological Tests ; },
abstract = {Vascular cognitive impairment (VCI), the second leading cause of dementia, is characterized by heterogeneous pathophysiology and a potentially reversible early phase, underscoring the need for timely identification. This review synthesizes advances across four complementary domains - targeted cognitive assessments, imaging biomarkers, molecular fluid biomarkers, and ecological behavioral characteristics - conceptualized as the TIME framework. Emerging markers, including the peak width of skeletonized mean diffusivity (PSMD), oxygen extraction fraction, brain-derived extracellular vesicles, and digital gait metrics, enable the detection of microvascular injury before overt cognitive decline. Given the limitations of single modalities, we advocate for multimodal integration via machine learning to capture the disease continuum from vascular insult to clinical impairment. Establishing a standardized, pathophysiologically anchored classification system, analogous to the AT(N) framework in Alzheimer's disease, is essential to advance precision risk stratification and early intervention in VCI.},
}

Humans
*Biomarkers/cerebrospinal fluid
Early Diagnosis
*Cognitive Dysfunction/diagnosis
Neuroimaging
Machine Learning
*Dementia, Vascular/diagnosis
Neuropsychological Tests

@article {pmid42554263,
year = {2026},
author = {Kim, BH and Lee, H and Kim, J and Seo, SW and Nho, K and , },
title = {Epigenetic aging in Alzheimer's disease: Relation to proteome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71732},
doi = {10.1002/alz.71732},
pmid = {42554263},
issn = {1552-5279},
support = {P30AG010133/NH/NIH HHS/United States ; P30AG072976/NH/NIH HHS/United States ; R01AG081951/NH/NIH HHS/United States ; R01LM012535/NH/NIH HHS/United States ; U01AG06857/NH/NIH HHS/United States ; U01AG24904/NH/NIH HHS/United States ; U01AG072177/NH/NIH HHS/United States ; U19AG074879/NH/NIH HHS/United States ; RS-2020-KH106434//Korea Dementia Research Center (KDRC)/ ; RS-2025-02223212//Korea Health Industry Development Institute (KHIDI)/ ; 2024-ER1003-02//Korea National Institute of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/cerebrospinal fluid ; *Epigenesis, Genetic ; *Aging/genetics ; *Proteome ; DNA Methylation ; Proteomics ; Biomarkers/cerebrospinal fluid ; Female ; Male ; Aged ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) arises from heterogeneous biological processes, and long-term environmental exposures may become biologically embedded, as reflected in epigenetic clocks.

METHODS: We calculated blood DNA methylation-based epigenetic clocks and constructed protein co-abundance networks of cerebrospinal fluid (CSF) proteomics data. We performed association analysis of epigenetic age acceleration with network modules, followed by functional and cell-type enrichment analyses, association analyses of hub proteins with AD endophenotypes, and pseudotime trajectory analysis.

RESULTS: Six network modules were significantly associated with epigenetic age acceleration and were enriched in pathways related to neuronal connectivity, proteostasis, immune activation and remodeling, immune signaling, and immunoepigenetic regulation. Hub proteins demonstrated significant associations with baseline amyloid/tau/neurodegeneration biomarkers and longitudinal cognitive changes. Pseudotime analysis revealed continuous, non-linear variation in epigenetic age acceleration along the inferred trajectory.

DISCUSSION: Our CSF proteomics study identified neuronal, proteostatic, and immune-related molecular signatures associated with epigenetic age acceleration in AD.},
}

Humans
*Alzheimer Disease/genetics/cerebrospinal fluid
*Epigenesis, Genetic
*Aging/genetics
*Proteome
DNA Methylation
Proteomics
Biomarkers/cerebrospinal fluid
Female
Male
Aged

@article {pmid42554285,
year = {2026},
author = {Benussi, A and Bracca, V and Premi, E and Cantoni, V and Palacino, F and Saccavini, A and Cotelli, MS and Binetti, G and Manenti, R and Alberici, A and Gasparotti, R and Ashton, NJ and Zetterberg, H and Blennow, K and Ghidoni, R and Borroni, B},
title = {Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71722},
doi = {10.1002/alz.71722},
pmid = {42554285},
issn = {1552-5279},
support = {//University of Brescia, Italy/ ; //Italian Ministry of Health (Ricerca Corrente)/ ; },
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; Magnetic Resonance Imaging ; *Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/blood ; Aged ; Middle Aged ; Neurofilament Proteins/blood ; Disease Progression ; Glial Fibrillary Acidic Protein/blood ; Atrophy/pathology ; Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Supranuclear Palsy, Progressive/pathology ; },
abstract = {BACKGROUND: The temporal sequence of clinical, imaging, and biological changes in sporadic frontotemporal lobar degeneration (FTLD)-associated syndromes remains poorly characterized, and a comprehensive biomarker cascade model is lacking.

METHODS: We developed a data-driven biomarker cascade model in 489 patients across the FTLD spectrum (211 behaviorial variant frontotemporal dementia [bvFTD], 129 primary progressive aphasia [PPA], 71 corticobasal syndrome [CBS], 66 progressive supranuclear palsy [PSP], and 12 FTD associated with amyotrophic lateral sclerosis [FTD-ALS]; 1904 patient-visit observations). Plasma, magnetic resonance imaging (MRI), and clinical biomarkers were modeled using sigmoid trajectories fitted to covariate-adjusted longitudinal data.

RESULTS: Plasma glial fibrillary acidic protein departed from normality earliest, followed by Trail Making Test Part B (TMT-B), white matter lesion volume, and neurofilament light chain. Insular atrophy showed the steepest transition among MRI measures; clinical dementia rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains sum of boxes declined most steeply overall. TMT-B inflected earliest in bvFTD, whereas insula atrophy dominated in PPA.

CONCLUSIONS: This first data-driven temporal cascade of multimodal biomarkers in sporadic FTLD-associated syndromes offers a framework for disease staging and stage-specific clinical trial design.},
}

Humans
Female
*Biomarkers/blood
Male
Magnetic Resonance Imaging
*Frontotemporal Lobar Degeneration/pathology/diagnostic imaging/blood
Aged
Middle Aged
Neurofilament Proteins/blood
Disease Progression
Glial Fibrillary Acidic Protein/blood
Atrophy/pathology
Brain/pathology/diagnostic imaging
Neuropsychological Tests
Supranuclear Palsy, Progressive/pathology

@article {pmid42554607,
year = {2026},
author = {Wang, J and Xie, W and Yang, L and Wang, Z and Huang, Y and Huang, P and Liu, Y and Hu, J},
title = {Systematic Multi-Level Analyses Decode the Arthritis-Neurodegeneration Axis With In Vivo Validation.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76930},
doi = {10.1002/advs.76930},
pmid = {42554607},
issn = {2198-3844},
support = {82272544//National Natural Science Foundation of China/ ; 81672218//National Natural Science Foundation of China/ ; BK20251945//Natural Science Foundation of Jiangsu Province/ ; },
abstract = {Arthritis may influence neurodegenerative risk, but directionality and mediators remain unclear. This study integrates population survival analysis, Mendelian randomization, transcriptomic mapping, and mouse perturbation to map osteoarthritis (OA)/rheumatoid arthritis (RA) links with five neurodegenerative outcomes and prioritize mediators. In 310 162 European-ancestry UK Biobank participants, Cox models associate OA with higher risks of Alzheimer's disease (AD; hazard ratio: 1.13, 95% confidence interval: 1.04-1.22), Parkinson's disease (PD; 1.10, 1.00-1.21), and disorders of autonomic nervous system (DANS; 1.36, 1.06-1.74), and RA with higher AD risk (1.37, 1.13-1.67) (all p < 0.05), but not incident PD. Mendelian randomization prioritizes a modest protective genetic effect of RA on PD (odds ratio: 0.93, 0.88-0.99; p = 0.015), without reverse causation. Transcriptome-wide association and colocalization analyses identify shared RA-PD genes and prioritize Ring Finger Protein 40 (RNF40). In a collagen-induced arthritis (CIA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, CIA attenuates dopaminergic injury, whereas systemic Rnf40 knockdown alleviates arthritis but exacerbates Parkinsonian pathology. Endogenous RNF40 is induced in arthritic joints but remains stable in midbrain. These cross-layer data define arthritis-neurodegeneration connections and nominate RNF40 as a context-dependent joint-brain candidate linking inflammatory arthritis with dopaminergic vulnerability.},
}

@article {pmid42554796,
year = {2026},
author = {Ray, A and Agarwal, K and Jha, S and Singh, AM and Majumder, S and Lodh, E and Chowdhury, T and , },
title = {miRNA-mRNA Interaction Network Analysis in Alzheimer's Disease for Biomarker Discovery.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42554796},
issn = {1559-1166},
mesh = {*Alzheimer Disease/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; Humans ; *RNA, Messenger/genetics/metabolism ; *Gene Regulatory Networks ; Biomarkers/metabolism ; Transcriptome ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by widespread dysregulation of gene expression and regulatory pathways. MicroRNAs (miRNAs) act as key post-transcriptional regulators by modulating messenger RNAs (mRNAs), and their disruption can influence synaptic function, neuroinflammation, and neuronal survival. In this study, we present a transcriptomic-driven framework in which differentially expressed genes (DEGs) are identified from gene expression data and integrated with curated miRNA-target interaction databases to infer putative AD-associated miRNA-mRNA regulatory signatures and potential candidate biomarkers. Transcriptomic and clinical data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI), and the GEO dataset GSE48552 was used as supplementary support to assess the consistency of observed transcriptomic patterns. Using an exploratory differential expression threshold with Welch's t-test and FDR correction, 123 candidate dysregulated genes (34 up-regulated, 89 down-regulated) were identified between AD and cognitively normal controls. To further assess robustness, threshold-sensitivity and cross-method concordance analyses were conducted, supporting the presence of a reproducible core transcriptional signal within the broader discovery-level DEG set. Experimentally validated and predicted miRNA-target interactions were integrated using miRTarBase, yielding 1,669,089 miRNA-gene interactions involving 3,055 unique miRNAs, with strong enrichment toward down-regulated gene targeting. Functional enrichment analysis revealed convergence of miRNA-regulated genes on synaptic signaling, neuronal communication, intracellular transport, apoptosis, oxidative stress, and PI3K-Akt/MAPK-related pathways. A bipartite putative miRNA-mRNA regulatory network (2,207 nodes connected by 11,437 edges, including 2,104 miRNAs and 103 significant genes) was constructed and analyzed using centrality metrics, prioritizing candidate hub genes, including PBX1 and KREMEN1, which were subsequently interpreted in the context of neuronal transcriptional regulation, Wnt-related signalling, synaptic vulnerability, and AD-associated pathway enrichment. Finally, supervised machine learning models trained on selected molecular features showed discriminative performance in the held-out test set, with Random Forest, Gradient Boosting, and LightGBM achieving the highest ROC-AUC values, indicating strong capability in distinguishing AD from control samples. Overall, the framework provides a biologically interpretable strategy for biomarker discovery, prioritizing AD-associated candidate biomarkers and putative regulatory interactions while highlighting targets for future experimental and clinical validation.},
}

*Alzheimer Disease/genetics/metabolism
*MicroRNAs/genetics/metabolism
Humans
*RNA, Messenger/genetics/metabolism
*Gene Regulatory Networks
Biomarkers/metabolism
Transcriptome