@article {pmid42683795,
year = {2026},
author = {Moon, Y and Jeon, HJ and Kim, HJ and Noh, MY and Kim, SH and Han, SH and Kim, H and Moon, WJ},
title = {Education Moderates the Biomarker-Cortical-Thickness Relationship in Females With Cognitive Decline: A Descriptive Study With Sex Comparisons.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {5},
pages = {552-559},
doi = {10.3988/jcn.2025.0686},
pmid = {42683795},
issn = {1738-6586},
support = {/KU/Konkuk University/Korea ; },
abstract = {BACKGROUND AND PURPOSE: Education is a well-established proxy for cognitive reserve and hence may influence the relationship between Alzheimer's disease pathology and brain structure. This is particularly relevant in South Korea, where historical sex disparities in educational level among current elderly populations create unique cohort characteristics. This study examined how educational level moderates the biomarker-cortical-thickness relationship in females with cognitive decline, with descriptive sex comparisons used to contextualize these findings within a cohort reflecting disparities in the history of educational opportunities in South Korea.

METHODS: In 80 patients (58 females, 22 males) with cognitive decline, we assessed plasma amyloid-β 42 (Aβ42), phosphorylated tau 181 (p-tau), and total tau levels, p-tau/Aβ42 ratio, regional cortical thickness, and scores on the Mini-Mental State Examination. Given the substantial confounding between sex and educational level in this cohort, moderated mediation analyses examining the biomarker-cortical-thickness-cognition pathway were restricted to females (n=53 with complete data).

RESULTS: Females had a higher p-tau/Aβ42 ratio (p=0.026) and thicker frontal cortex (p=0.049) despite the absence of a significant difference in age-adjusted cognition. No significant sex× educational level interaction was observed for the biomarkers or cognition. In females, educational level moderated the relationship between the p-tau/Aβ42 ratio and cortical thickness (p<0.05 in all five brain regions), with high-educational level females showing the expected cortical thinning with pathology, while low-educational level females exhibited preserved thickness, which did not mediate the cognitive performance.

CONCLUSIONS: Descriptive sex comparisons revealed a higher biomarker burden yet greater cortical thickness in females. Importantly, educational level significantly moderated the biomarker-cortical thickness relationship specifically in females, with lower-educated individuals showing structural preservation despite the presence of pathology. These findings suggest that measurements of the cortical thickness can underestimate the disease burden in lower-educated females, which highlights the need for educational level-stratified interpretations of structural biomarkers.},
}

@article {pmid42683796,
year = {2026},
author = {Yoon, B and Lee, HJ and Hong, YJ and Park, KH and Kim, S and Wang, MJ and Choi, SH and Kang, S and Jeong, JH and Yang, DW},
title = {Comparative Prognostic Performance of Hippocampal Volume and Plasma Biomarkers in Amyloid-Negative Subjective Cognitive Decline: A Four-Year Follow-up.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {5},
pages = {560-572},
doi = {10.3988/jcn.2025.0659},
pmid = {42683796},
issn = {1738-6586},
support = {P0018061/KIAT/Korea Institute for Advancement of Technology/Korea ; HI18C0530/MOHW/Ministry of Health and Welfare/Korea ; },
abstract = {BACKGROUND AND PURPOSE: Subjective cognitive decline (SCD) may precede mild cognitive impairment (MCI) and dementia. However, the prognosis of patients with amyloid-negative (A-) SCD remains unclear. We investigated whether baseline plasma and imaging biomarkers predict four-year clinical progression in A-SCD.

METHODS: Sixty-five individuals with A-SCD were followed for four years. Baseline plasma biomarkers-phosphorylated tau 181 (pTau181), glial fibrillary acidic protein, neurofilament light chain (NfL), and pTau181/Aβ42 ratio-and MRI markers (hippocampal volume and white matter hyperintensity [WMH] grade) were assessed. Outcomes included MCI conversion and cognitive progression defined as ≥1-point (Prog-1) or ≥2-point (Prog-2) decline in Korean Mini-Mental State Examination. Predictive performance was evaluated using multivariable logistic regression and bootstrap-validated receiver operating characteristic analyses.

RESULTS: Fourteen participants (21.5%) converted to MCI, and 24 (36.9%) were classified as Prog-1. Plasma biomarkers did not show consistent predictive performance across predefined endpoints (all p>0.05), although NfL demonstrated modest discrimination for MCI conversion (area under the curve [AUC] 0.686, p=0.008). Hippocampal volume demonstrated significant discriminative performance for MCI conversion (AUC 0.765, p=0.016) and Prog-1 (AUC 0.933, p<0.001). For Prog-2, hippocampal volume showed high discrimination (AUC 0.952, p<0.001). WMH grade also demonstrated significant discrimination for MCI conversion (AUC 0.835, p<0.001) and Prog-1 (AUC 0.857, p<0.001). Bootstrap analyses (1,000 iterations) tended to show higher AUC estimates for imaging markers compared with plasma biomarkers.

CONCLUSIONS: In this A-SCD cohort, hippocampal atrophy demonstrated more consistent prognostic performance than Alzheimer's disease-focused plasma biomarkers for predicting four-year conversion to MCI and cognitive decline, suggesting a potential role for MRI-based neurodegeneration markers in clinical risk stratification.},
}

@article {pmid42683825,
year = {2026},
author = {El-Shiekh, RA and Mandour, AA and Abdel-Sattar, E and Ali, NB},
title = {Phytochemical profiling of Olea europaea subsp. cuspidata aerial parts using LC-DAD-QToF: cholinesterase inhibition and molecular docking insights into potential Alzheimer's disease targets.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/14786419.2026.2727544},
pmid = {42683825},
issn = {1478-6427},
abstract = {Olea europaea subsp. cuspidata is traditionally used in African medicine, but its phytochemical composition and cholinesterase inhibitory activity have not been comprehensively investigated. This study evaluated the cholinesterase inhibitory activity and phytochemical profile of the methanolic extract of O. europaea aerial parts, integrating in vitro assays with LC-DAD-QToF-MS characterisation and molecular modelling. We used the Ellman assay to measure cholinesterase inhibition and LC-DAD-QToF-MS for metabolite profiling, while molecular docking and dynamics simulations helped us understand how specific metabolites interact with human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extract inhibited AChE (IC50 = 15.99 ± 1.62 μg/mL) to a greater extent than BChE (IC50 = 22.62 ± 2.20 μg/mL). LC-DAD-QToF-MS allowed the tentative identification of 65 metabolites, comprising iridoids, phenylethanoids, flavonoids, phenolic acids, terpenoids, fatty acids, and one alkaloid. Computational predictions support potential interactions only between constituents within the enzyme active sites but do not establish biological activity. These results offer the first detailed phytochemical profile of the aerial parts of O. europaea and confirm its in vitro cholinesterase inhibitory activity. Bioactivity-guided isolation and in vivo studies are required to pinpoint the metabolites responsible for the observed effects and to establish their therapeutic relevance.},
}

@article {pmid42683892,
year = {2026},
author = {Han, P and Dong, P and Zhou, Y and Zhang, L and Mahomed, O},
title = {Stage-Dependent Cognitive Effects of a Multinutrient Intervention in Alzheimer's Disease: A Stage-Stratified Meta-Analysis.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {235},
pages = {},
doi = {10.3791/72385},
pmid = {42683892},
issn = {1940-087X},
mesh = {*Alzheimer Disease/therapy/psychology ; Humans ; Randomized Controlled Trials as Topic ; Cognition ; },
abstract = {A specific multinutrient intervention provides precursors and cofactors for synaptic membrane synthesis. Randomized trials across the Alzheimer's disease (AD) continuum have reported mixed findings. We conducted a systematic review and stage-stratified meta-analysis of randomized, placebo-controlled trials. MEDLINE, Embase, CENTRAL, Web of Science, Scopus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform were searched through February 28, 2026. Disease stage was prespecified as an effect modifier. Standardized mean differences (SMDs; Hedges' g) were synthesized using restricted maximum likelihood random-effects models. Four trials met the inclusion criteria; three contributed to the quantitative synthesis (analyzed n = 906). Souvenir I was retained for qualitative synthesis because its distinct co-primary outcomes and reporting did not permit a compatible SMD for the prespecified pooled analysis. The exploratory pooled cognitive effect was small and not significant (SMD = 0.08; 95% CI, -0.09 to 0.26; p = 0.35; I[2] = 41.8%). For biomarker-confirmed prodromal AD, the 24-month primary neuropsychological test battery (NTB) 5-item composite endpoint showed a small, nonsignificant effect (SMD = 0.16; 95% CI, -0.08 to 0.41; original trial p = 0.166). The primary NTB memory endpoint in mild, drug-naive AD showed a small effect (SMD = 0.21; 95% CI, -0.06 to 0.49; original longitudinal-model p = 0.023), whereas the primary Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) endpoint in treated mild-to-moderate AD showed no benefit (SMD = -0.06; 95% CI, -0.25 to 0.13; p = 0.513). At 36 months, the LipiDiDiet extension reported significant differences in the NTB 5-item composite, clinical dementia rating - sum of boxes (CDR-SB), memory, and brain-volume outcomes. The intervention was well tolerated. The evidence is compatible with a potential early-stage signal, but the small evidence base, lack of replication across stages, and manufacturer sponsorship warrant cautious interpretation.},
}

*Alzheimer Disease/therapy/psychology
Humans
Randomized Controlled Trials as Topic
Cognition

@article {pmid42683894,
year = {2026},
author = {Agnello, L and Pilotto, A and Gaetani, L and Bellomo, G and Bessi, V and Bozzali, M and Cagnin, A and Labate, A and Massa, F and Moda, F and Monastero, R and Musso, G and Piccoli, T and Sancesario, G and Parnetti, L and Padovani, A and Ciaccio, M},
title = {Toward harmonized reporting of Alzheimer's disease biomarkers in clinical practice.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42683894},
issn = {1437-4331},
abstract = {Cerebrospinal fluid biomarkers, and more recently blood-based biomarkers, are playing a pivotal role in reshaping the clinical management of neurodegenerative diseases, supporting early detection, biological diagnosis, patient stratification, prognostic assessment, therapeutic decision-making, and longitudinal disease monitoring. To effectively support clinical decision-making, biomarker measurements must be communicated in a standardized, transparent, and clinically interpretable manner. Despite international quality standards, considerable heterogeneity persists in reporting practices, including differences in terminology, units of measurement, analytical descriptions, reference frameworks, and interpretative comments, limiting comparability across laboratories and potentially affecting clinical decision-making. In this article, we discuss the principles of harmonized reporting for Alzheimer's disease biomarkers and propose a structured framework for standardized clinical neurochemistry reports. We describe the essential components of a harmonized report, including report identification, analytical information, specification of analytical method and platform, standardized units of measurement, appropriate use of reference intervals and clinical decision thresholds, documentation of pre-analytical and quality-related factors, and evidence-based interpretative comments. We further discuss the importance of structured multimarker interpretation and the need to contextualize biomarker findings within the clinical scenario. Finally, we examine the role of harmonized reporting in promoting interoperability across healthcare systems, facilitating longitudinal patient monitoring, supporting electronic health records and standardized terminologies, and enabling artificial intelligence-driven clinical decision support. As neurodegenerative disease diagnostics continue to evolve and novel biomarkers and technologies emerge, harmonized reporting should be regarded as a critical component of laboratory quality, ensuring that analytical advances translate into consistent, clinically meaningful, and interoperable information that ultimately improves patient care.},
}

@article {pmid42683906,
year = {2026},
author = {Luca, A and Luca, M and Olgiati, P and Ferri, R and Perry, G and Serretti, A},
title = {Neuropsychiatric characteristics of capgras syndrome in Alzheimer's disease in the CATIE-AD.},
journal = {International journal of psychiatry in clinical practice},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/13651501.2026.2724972},
pmid = {42683906},
issn = {1471-1788},
abstract = {INTRODUCTION: Capgras syndrome (CS) is a recurrent and transient delusional misidentification disorder in which an individual is firmly convinced that a familiar person has been replaced by an identical impostor. The aim of the study was to evaluate neuropsychiatric characteristics of CS in a cohort of patients with Alzheimer's disease (AD).

METHODS: 150 participants [84 (56.0%) women, mean age 77.4 ± 7.5 years)] were collected within the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer disease (CATIE-AD). According to the Neuropsychiatric Inventory, patients were classified into Capgras[+] and Capgras[-].

RESULTS: Fifty-five (36.7%) AD patients were Capgras[+]. CS was strongly associated with other misidentification syndromes including phantom boarder (p < 0.001) and misidentification of places (p < 0.001). Moreover, Capgras[+] were presented more frequently with agitation (p = 0.036), depressive (p = 0.018) and anxious (p = 0.004) symptoms, and aberrant motor behaviours (p = 0.020).

CONCLUSIONS: According to our findings, CS was not an 'isolated' phenomenon but rather a complex neuropsychiatric syndrome frequently associated with other misidentification syndromes and specific behavioural disturbances.},
}

@article {pmid42684699,
year = {2026},
author = {Aaronson, A and Nosek, SB and Abdolmohammadi, B and Hadley, J and Labonte, J and Uretsky, M and Mosaheb, S and Nowinski, CJ and Altaras, C and Asken, BM and Banks, SJ and Barr, WB and Dams-O'Connor, K and Hromas, G and Ly, MT and Wethe, JV and Martin, BM and Palmisano, JN and Stern, RA and Tripodis, Y and Stein, TD and McKee, AC and Mez, J and Alosco, ML},
title = {Neuropsychological Profile of Autopsy-Confirmed Chronic Traumatic Encephalopathy.},
journal = {JAMA network open},
volume = {9},
number = {9},
pages = {e2631754},
pmid = {42684699},
issn = {2574-3805},
mesh = {Humans ; *Chronic Traumatic Encephalopathy/diagnosis/pathology/psychology/physiopathology ; Male ; Retrospective Studies ; *Neuropsychological Tests ; Autopsy ; Middle Aged ; Aged ; *Football/injuries ; Female ; Brain/pathology ; tau Proteins/metabolism ; },
abstract = {IMPORTANCE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact exposure. CTE can only be diagnosed post mortem, and the antemortem neuropsychological profile is poorly understood, hindering accurate diagnosis before death.

OBJECTIVE: To characterize antemortem neuropsychological test performance of former National Football League (NFL) players with autopsy-confirmed CTE.

This retrospective case series included former NFL players who completed an antemortem neuropsychological evaluation and had autopsy-confirmed CTE. Data were collected between January 1, 2017, and April 30, 2025. Statistical analysis was performed from September 2025 to June 2026.

EXPOSURE: CTE neuropathology, defined by the National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus panel.

MAIN OUTCOMES AND MEASURES: Neuropsychological test performance, neuropathologic diagnoses, and semiquantitative phosphorylated tau (p-tau) pathology across 11 brain regions were examined. Raw scores were converted to z scores using age, sex, and/or education level-based normative data. Test results with z scores of -1.5 or less were categorized as impaired; domains with 2 or more impaired test results were considered impaired.

RESULTS: The primary analytic sample included 33 men (mean [SD] age at death, 65.4 [13.3] years; mean [SD] time between testing and death, 2.4 [1.6] years), 25 with high- and 8 with low-stage CTE. Learning and memory was most impaired (17 of 27 [63.0%]), followed by executive function (15 of 29 [51.7%]) and language (12 of 29 [41.4%]). High-stage CTE participants generally had worse scores than low-stage CTE participants. Greater global p-tau burden was associated with worse learning and memory performance (B = -0.40; 95% CI, -0.70 to -0.09; P = .01). Findings were similar after excluding 9 participants with co-occurring Alzheimer disease or frontotemporal lobar degeneration tau.

CONCLUSIONS AND RELEVANCE: In this retrospective case series of NFL players with autopsy-confirmed CTE, memory, executive function, and language impairments were common, and p-tau burden was associated with worse memory performance. Findings provide insight into the expected CTE neuropsychological profile and may help advance diagnosis before death.},
}

Humans
*Chronic Traumatic Encephalopathy/diagnosis/pathology/psychology/physiopathology
Male
Retrospective Studies
*Neuropsychological Tests
Autopsy
Middle Aged
Aged
*Football/injuries
Female
Brain/pathology
tau Proteins/metabolism

@article {pmid42684813,
year = {2026},
author = {Unger, RH and Rohatgi, S and Ferraciolli, SF and Kako, B and Omid-Fard, N and Imbett, REM and Dowling, T and Zhu, S and Romero, JM and Ford, JN},
title = {Real-World Challenges in the MRI Detection and Classification of Amyloid-Related Imaging Abnormalities.},
journal = {AJR. American journal of roentgenology},
volume = {},
number = {},
pages = {},
doi = {10.2214/AJR.26.35478},
pmid = {42684813},
issn = {1546-3141},
abstract = {Anti-amyloid monoclonal antibody therapies (AATs) are increasingly used for the treatment of early symptomatic Alzheimer disease. Safe implementation of AATs relies on accurate assessment for exclusionary findings on baseline brain MRI and reliable longitudinal detection of amyloid-related imaging abnormalities (ARIA), including ARIA-H (hemosiderin or hemorrhage) and ARIA-E (edema or effusion). In routine clinical practice, MRI findings encountered during baseline screening and ARIA surveillance sometimes fall into borderline or ambiguous categories that do not clearly conform to trial-defined criteria. For example, subtle or artifactual FLAIR signal abnormality, equivocal microhemorrhage counts, and overlapping features of ARIA-E and ARIA-H can create uncertainty with direct implications for treatment management. Given limited practical guidance addressing these and other gray zones, this imaging-focused review synthesizes common interpretive challenges encountered in a high-volume AAT program and offers practical management-oriented recommendations. Key issues addressed include recognizing technical factors that affect interpretation of susceptibility-weighted and FLAIR images, managing variability in lesion detection across serial examinations, and accurately reporting the temporal evolution of ARIA-related findings. As AAT use expands, recognition of the presented pitfalls can improve diagnostic confidence and help avoid misclassification of findings that may influence therapeutic decisions.},
}

@article {pmid42684942,
year = {2026},
author = {Huang, D and Zhang, Z and Gong, X},
title = {Context-dependent roles of osteopontin in aging-related neurological disorders.},
journal = {The Journal of international medical research},
volume = {54},
number = {9},
pages = {3000605261476190},
pmid = {42684942},
issn = {1473-2300},
mesh = {Humans ; *Osteopontin/metabolism ; *Aging/pathology/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Brain/pathology/metabolism ; Alzheimer Disease ; Microglia/metabolism ; },
abstract = {Osteopontin (encoded by secreted phosphoprotein 1) is a multifunctional matricellular phosphoglycoprotein that has emerged as an important mediator in the aging nervous system. During aging, osteopontin interacts with microglial priming, vascular remodeling, myelin repair, and innate immune responses and is consistently implicated in major late-life neurological disorders. However, its biological effects are highly context dependent. Depending on its cellular source, proteolytic processing, receptor interactions, anatomical distribution, and disease stage, osteopontin may either exacerbate chronic neuroinflammation and tissue injury or promote phagocytic clearance, neuronal survival, remyelination, neuroplasticity, and tissue repair. This review critically synthesizes studies indexed in PubMed and Google Scholar through 3 April 2026 on the role of osteopontin in brain aging, Alzheimer's disease and related dementias, Parkinson's disease and Lewy body disorders, cerebrovascular disease, vascular cognitive impairment, cerebral small vessel disease, and amyotrophic lateral sclerosis. In Alzheimer's disease, cerebrospinal fluid and plasma osteopontin concentrations increase from the prodromal to symptomatic stages, whereas microglial or perivascular secreted phosphoprotein 1 expression correlates with amyloid pathology, synaptic remodeling, and cognitive decline. However, under specific conditions, osteopontin also enhances macrophage-mediated amyloid-beta clearance. In stroke, elevated circulating osteopontin predicts poor clinical outcomes, whereas experimental studies demonstrate that appropriately timed exogenous osteopontin, regulatory T cell-derived osteopontin, and osteopontin-mediated autophagic and reparative pathways promote white-matter repair, peri-infarct plasticity, and blood-brain barrier integrity. Evidence from Parkinson's disease, Lewy body disease, frontotemporal dementia, and amyotrophic lateral sclerosis further supports the role of osteopontin as both a candidate biomarker and a regulator of selective neuronal vulnerability. Rather than being uniformly detrimental or protective, osteopontin should be regarded as a context-dependent regulator of age-related neuroimmune remodeling. This perspective reconciles seemingly conflicting findings and supports the development of therapeutic strategies that are tailored to disease stage, protein fragment, and cell type rather than broadly targeting osteopontin.},
}

Humans
*Osteopontin/metabolism
*Aging/pathology/metabolism
Animals
*Nervous System Diseases/metabolism/pathology
Brain/pathology/metabolism
Alzheimer Disease
Microglia/metabolism

@article {pmid42684969,
year = {2026},
author = {Chen, L and Xiao, L and Li, Y},
title = {Multi-trajectories of activity participation and risk of mild cognitive impairment in China: A national longitudinal cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483186},
doi = {10.1177/13872877261483186},
pmid = {42684969},
issn = {1875-8908},
abstract = {BackgroundEngagement in physical, social, and intellectual activities is associated with cognitive health in later life, but how their long-term combinations relate to mild cognitive impairment (MCI), a key preclinical stage of Alzheimer's disease, remains unclear.ObjectiveTo identify multi-activity trajectories and examine their associations with MCI.MethodsData were from the China Health and Retirement Longitudinal Study (CHARLS), a nationally representative biennial survey collecting demographic, socioeconomic, health, cognitive, and activity-related information. We included 1884 participants aged ≥60 years in 2020. Group-based multi-trajectory modeling identified physical, social, and intellectual activity patterns using the 2011, 2013, 2015, and 2018 waves. Multivariable logistic regression examined associations with MCI in 2020, with subgroup analyses by sex, baseline age, education, and residence.ResultsFour distinct trajectory groups were identified: Moderate PA-low SI (social and intellectual activity), High PA-low SI, Moderate PA-higher SI, and High PA-moderate SI. The Moderate PA-higher SI group had the lowest MCI prevalence (9.47%) and served as the reference. In the fully adjusted model, MCI odds were highest in the High PA-low SI group (OR = 2.05, 95% CI: 1.34-3.15), followed by the Moderate PA-low SI group (OR = 1.57, 95% CI: 1.08-2.30). The High PA-moderate SI group was not significantly associated with MCI (OR = 1.38, 95% CI: 0.72-2.58).ConclusionsModerate physical activity combined with higher social and intellectual engagement was associated with more favorable cognitive outcomes, supporting integrated, pattern-based lifestyle strategies for early prevention of MCI and Alzheimer's disease.},
}

@article {pmid42684971,
year = {2026},
author = {Freitag, JM and Konen, FF and Heck, J and Jahn, K and Groba, S and Klietz, M and Skripuletz, T and Wegner, F and Schulze Westhoff, M and Schröder, S},
title = {Memory, social cognition, and beyond: Neuropsychological markers differentiating Alzheimer's disease and frontotemporal dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480113},
doi = {10.1177/13872877261480113},
pmid = {42684971},
issn = {1875-8908},
abstract = {BackgroundDistinguishing Alzheimer's disease (AD) from frontotemporal dementia (FTD) remains a major clinical challenge, particularly in early disease stages due to overlapping symptoms. Although neuropsychological assessment is central to diagnosis, brief cognitive screening instruments often emphasize episodic memory, whereas comprehensive neuropsychological assessment encompasses multiple cognitive domains. Nevertheless, social cognition and other relevant functions may remain underrepresented in routine clinical assessment.ObjectiveTo identify neuropsychological domains and test procedures that reliably differentiate AD from FTD and support differential diagnosis.MethodsA systematic PubMed literature search was conducted using predefined inclusion and exclusion criteria. Original studies directly comparing neuropsychological performance in patients with AD and FTD were included. Owing to methodological heterogeneity, findings were synthesized narratively.ResultsA total of 322 records were identified, of which 80 studies met the inclusion criteria. A clear domain-specific pattern emerged. Episodic memory impairment, particularly delayed recall deficits, consistently distinguished AD from FTD, with poorer performance in AD. In contrast, deficits in social cognition, including theory of mind and emotion recognition, were more pronounced in FTD and were often detectable early in the disease course. Executive functions and language showed heterogeneous findings, with discriminative value depending on specific subdomains and FTD subtypes. Visuospatial functions and attention provided supportive but less consistent differentiation, while global screening instruments showed limited diagnostic specificity.ConclusionsDifferentiation between AD and FTD should not rely on single cognitive domains. The most clinically meaningful distinction is achieved through a multidimensional assessment integrating episodic memory, social cognition, and selected executive and behavioral measures.},
}

@article {pmid42684984,
year = {2026},
author = {Singh, RK and Bekena, S and Walker, AIB and Taylor, K and Zhu, Y and Pal, S and Mohamed, EA and Trani, JF and Kaplan, I and Babulal, GM},
title = {Exploratory factor and network analysis of 43 inflammatory plasma biomarkers and cognitive performance in Black adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261481701},
doi = {10.1177/13872877261481701},
pmid = {42684984},
issn = {1875-8908},
abstract = {BackgroundSystemic inflammation has been implicated in cognitive aging and neurodegeneration; however, inflammatory biomarkers are expressed in coordinated patterns rather than as isolated markers.ObjectiveTo identify latent inflammatory biomarker groupings and evaluate their associations with cognitive performance among midlife and older adults.MethodsThis cross-sectional study included 334 participants from the Aging Research Characterizing Health Exposome via Social Drivers (ARCHES) study. Cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma inflammatory biomarkers were quantified using the NuLISA™ multiplex immunoassay platform. Exploratory factor analysis (EFA) (minimum residual extraction, oblimin rotation) identified latent inflammatory factors, retaining biomarkers with loadings ≥0.40. Factor scores were evaluated in multivariable linear regression models adjusted for age, sex, education, and genotype status; sensitivity analyses adjusted for socioeconomic context, medication use, BMI, lifestyle factors, and clinical diagnoses. Age-stratified and nonlinear spline analyses were conducted.Results27 of 43 biomarkers formed an eight-factor structure explaining 43% of variance. Two factors were significantly associated with cognitive performance after FDR correction. Factor 4 (CCL4, CXCL1, S100A12) and Factor 5 (IL2, IL5, IL13, IL10, CSF2) were inversely associated with PACC scores. These associations remained consistent across sensitivity analyses. Age-stratified analyses showed that several inflammatory factors were associated with cognitive performance among participants aged 45-<65 years, whereas no factors remained significant among participants aged ≥65 years after FDR correction. Nonlinear modeling indicated a non-linear age-cognitive performance relationship.ConclusionsEFA identified clusters of correlated inflammatory biomarkers associated with cognitive performance in this cohort of midlife and older adults.},
}

@article {pmid42685496,
year = {2026},
author = {Basir, HS and Rashno, M and Gholipour, P and Faraji, N and Tork, YJ and Naseri, E and Komaki, A and Ghaderi, S},
title = {L-carnitine attenuates Aβ1-42-induced spatial cognitive deficits and hippocampal dysfunction in a rat model of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {203},
number = {},
pages = {119884},
doi = {10.1016/j.biopha.2026.119884},
pmid = {42685496},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction and impaired synaptic plasticity. This study evaluated whether chronic L-carnitine (LC) attenuates amyloid-beta 1-42 (Aβ1-42)-induced spatial learning and memory deficits following intracerebroventricular (ICV) Aβ1-42 infusion. Forty adult male Wistar rats were randomly assigned to four groups (n = 10/group): Sham + Vehicle, Sham + LC, AD + Vehicle, and AD + LC. Following ICV Aβ1-42 infusion, LC (100 mg/kg/day, i.p.) or vehicle was administered for 28 days. Spatial learning and memory, hippocampal long-term potentiation (LTP), oxidative stress markers, Aβ plaque density, and neuronal integrity were evaluated. Compared with the AD + Vehicle-treated rats, LC attenuated Aβ1-42-induced impairments in spatial learning and memory, as indicated by reduced escape latency on training days 3-4 (both p < 0.01) and increased time spent in the target quadrant (p < 0.01). LC also improved hippocampal LTP, as reflected by a 58.4% increase in population spike (PS) amplitude potentiation (p < 0.01). Additionally, LC increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities by 40.3%, 34.4%, and 37.4%, respectively, while reducing malondialdehyde (MDA) levels by 22.0% (all p < 0.01). LC also decreased Aβ plaque density by 36.6% and increased intact pyramidal neurons by 58.3% (both p < 0.01). These findings indicate that LC mitigates Aβ1-42-induced spatial learning and memory deficits and is associated with improved hippocampal LTP, enhanced antioxidant enzyme activities, reduced lipid peroxidation and Aβ plaque density, and preserved neuronal integrity.},
}

@article {pmid42685603,
year = {2026},
author = {Aurore, MD and Sarah, M and Perrine, S and Agnès, D and Lionel, T and Amandine, G and Coline, C and Nathalie, F and Stéphanie, D and Anaëlle, M and Maxime, B and Mélanie, J and Jérémie, P and Lola, D and Thibaud, L and Mai, TT},
title = {Progression of language profiles in primary progressive aphasia: A bicentric longitudinal study.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {204},
number = {},
pages = {271-287},
doi = {10.1016/j.cortex.2026.08.004},
pmid = {42685603},
issn = {1973-8102},
abstract = {BACKGROUND: Primary progressive aphasias (PPA) are syndromes characterised by a progressive loss of language functions. To date, four main variants have been identified: semantic (svPPA), non-fluent/agrammatic (nfvPPA), logopenic (lvPPA) and Primary Progressive Apraxia of Speech (PPAoS). Currently, little is known about their clinical course, especially in French-speaking populations, though such data could aid prognosis and guide therapy.

OBJECTIVE: To characterise longitudinal changes in the language profiles in PPA using the GRÉMOTS, a French language assessment tool specifically developed for neurodegenerative disorders.

METHODS: We retrospectively included PPA patients, as well as patients with typical amnesic Alzheimer's disease (AD) and behavioural variant frontotemporal degeneration (bvFTD), from the Lille and Toulouse Memory Centres, who underwent longitudinal assessment ≥6 months with the GRÉMOTS. We performed between-groups comparisons and within-group paired analyses of GRÉMOTS subscores.

RESULTS: Eighty-two patients were included: 20 svPPA, 9 lvPPA, 12 nfvPPA, 9 PPAoS, 20 AD and 12 bvFTD. svPPA patients showed a predominant decline in lexico-semantic domains. nfvPPA patients deteriorated mainly in phonetics and syntactic production. Apraxia remained the prominent symptom in PPAoS patients, although mild agrammatical aphasia emerged at follow-up. lvPPA patients exhibited a significant decline in lexical oral comprehension alongside their core impairments. Language impairments remained modest in AD and bvFTD.

CONCLUSION: Our results highlighted a progression of core language impairments across PPA variants, with lvPPA additionally showing significant decline beyond its defining criteria. These results support the development of tailored speech-language interventions that anticipate the evolving needs of PPA patients in French-speaking settings.},
}

@article {pmid42685677,
year = {2026},
author = {Sassano, ML and De Strooper, B},
title = {Glucose hypometabolism gates tau-dependent necroptosis.},
journal = {Neuron},
volume = {114},
number = {17},
pages = {3130-3132},
doi = {10.1016/j.neuron.2026.07.011},
pmid = {42685677},
issn = {1097-4199},
mesh = {*tau Proteins/metabolism ; *Glucose/metabolism ; Humans ; *Necroptosis/physiology ; Animals ; Phosphorylation ; Neurons/metabolism ; Alzheimer Disease/metabolism/pathology ; },
abstract = {Tau pathology closely tracks neuronal loss in Alzheimer's disease, but how phosphorylated tau becomes lethal has remained unclear. Chen et al. identify a dual-hit mechanism: glucose hypometabolism removes a protective A20-mediated brake on necroptosis while phosphorylated tau scaffolds RIPK1 activation, driving tau-associated neuronal death.[1].},
}

*tau Proteins/metabolism
*Glucose/metabolism
Humans
*Necroptosis/physiology
Animals
Phosphorylation
Neurons/metabolism
Alzheimer Disease/metabolism/pathology

@article {pmid42685684,
year = {2026},
author = {Matallana Rincón, S and Orozco López, F and Galindo, JF},
title = {Computational identification of novel acetylcholinesterase inhibitors as potential treatments for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483260},
doi = {10.1177/13872877261483260},
pmid = {42685684},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease represents a major public health issue that affects millions of people worldwide. Although symptomatic treatments are available, they neither prevent nor halt disease progression; therefore, it is necessary to develop new therapeutic alternatives.ObjectiveTo identify acetylcholinesterase inhibitors with potential biological activity through a computational protocol.MethodsIn this study, a computational approach based on virtual screening, molecular docking, and molecular dynamics simulations was applied to identify new potential acetylcholinesterase inhibitors.ResultsThe results allowed the identification of three compounds with higher binding affinities than donepezil, which was used as a reference. Among them, ligand code 24771824 stood out for establishing hydrophobic and aromatic interactions that maximize dispersive contributions and promote a rigid and stable conformation within the active site. In contrast, ligand codes 151171 and 21081761 were favored by more directional polar contacts, which increased specificity but limited the overall affinity toward the enzyme.ConclusionsAltogether, the free energy, structural fluctuation, hydrogen bond occupancy, and molecular clustering analyses suggest that 24771824 exhibits the most favorable energetic and dynamic behavior, consolidating it as the best candidate for future experimental validation.},
}

@article {pmid42685685,
year = {2026},
author = {Yang, X and Li, X and Wang, C and Duan, A and Zhou, J and Wang, J and Jiang, Z and Li, M},
title = {A dual-branch time-frequency fusion network for EEG-based classification of Alzheimer's disease and frontotemporal dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483197},
doi = {10.1177/13872877261483197},
pmid = {42685685},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) and frontotemporal dementia (FTD) exhibit substantial overlap in clinical manifestations and patterns of brain functional degeneration, which poses significant challenges for automated classification based on electroencephalography (EEG).ObjectiveThis study aims to develop an EEG-based framework capable of simultaneously capturing temporal dynamics and frequency-related characteristics of EEG signals for discrimination among AD, FTD, and cognitively normal (CN) subjects.MethodsA Dual-Branch Time-Frequency Fusion Network (DBTF-Net) based on routine clinical resting-state EEG recordings acquired under eyes-closed conditions is proposed. The model employs parallel temporal and frequency branches to process raw EEG time-series signals and their corresponding time-frequency representations. A global temporal dependency construction mechanism is introduced in the temporal branch to capture both local temporal patterns and long-range temporal dependencies. Feature-level fusion is then performed across the two branches to achieve a collaborative representation of multidimensional brain functional information. The proposed method was systematically evaluated on one three-class classification task (AD versus FTD versus CN) and multiple binary classification tasks.ResultsExperimental results from five-fold cross-validation at the epoch level show the classification accuracies of DBTF-Net as 86.36%±4.28%, 83.01%±6.15%, 92.13%±10.35%, and 88.74%±7.69%% for AD versus FTD versus CN, AD versus CN, FTD versus CN, and AD versus FTD, respectively.ConclusionsThe proposed DBTF-Net leverages temporal and time-frequency information in EEG signals and provides classification of AD and FTD. Visualization analysis further indicates that the model attends to disease-relevant discriminative patterns in time-frequency representations, enhancing the interpretability of its classification decisions.},
}

@article {pmid42685686,
year = {2026},
author = {Sahuquillo, R and García-Pérez, E and Navarro, B and Fernández-Aguilar, L and Martínez-Sáez, MC and Ros, L and Borja, AL and Latorre, JM},
title = {Machine learning classification of mild Alzheimer's disease using EEG during emotional processing.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261483280},
doi = {10.1177/13872877261483280},
pmid = {42685686},
issn = {1875-8908},
abstract = {BackgroundMild Alzheimer's disease (AD) is associated with alterations in brain activity, which can be detected using electroencephalography (EEG). Investigating these changes during emotional processing may help identify neurophysiological patterns that differentiate patients with mild AD from healthy controls (HCs).ObjectiveTo investigate whether EEG responses elicited during emotional processing provide biomarkers capable of discriminating patients with AD from HCs. Additionally, to identify the emotional contexts, brain regions, frequency bands, and machine learning models that maximize this discriminative capacity.MethodsA sample of 39 AD patients and 54 HCs watched brief movie clips designed to elicit tenderness, amusement, anger, fear, and sadness, along with an Alzheimer's-related clip, together with neutral clips used as control, baseline, and recovery conditions, while cortical activity was recorded using EEG. The signals were then classified across emotional contexts using LASSO, Random Forest, SVM-RBF, XGBoost, and CatBoost ML models.ResultsEEG signals allowed for discrimination between AD patients and HCs across different emotional contexts, including individual emotions, grouped by valence or arousal, and the Alzheimer's-related stimulus. LASSO achieved the best performance for positive and neutral conditions in the parietal and posterior gamma bands, whereas CatBoost performed best for high-arousal negative emotions such as anger and fear, particularly in frontal gamma and theta bands, respectively.ConclusionsPatients with mild AD show EEG signal patterns that differ from those of HCs across different emotional contexts. These findings highlight the potential of EEG recorded during emotional processing to support the development of objective biomarkers for mild AD.},
}

@article {pmid42685709,
year = {2026},
author = {Zarhin, D and Bregman, N and Shiner, T and Mirelman, A and Alcalay, RN and Thaler, A},
title = {Cognitive and motor profiles in biologically defined Parkinson's and Alzheimer's disease.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261477521},
pmid = {42685709},
issn = {1877-718X},
abstract = {BackgroundParkinson's disease (PD) patients may harbor coexisting Alzheimer's disease (AD) pathology that accelerates cognitive and motor decline. Defining biomarker-defined AD in PD is important for prognosis, patient counseling, and trial stratification.ObjectiveTo determine the prevalence of AD biomarker positivity in α-synuclein seed amplification assay (αSyn-SAA) positive PD and assess its impact on cognitive and motor progression.MethodsWe analyzed data from the Parkinson's Progression Markers Initiative, a multinational prospective cohort of de novo PD patients. Baseline CSF biomarkers included αSyn-SAA, amyloid-β1-42 (Aβ1-42), and phosphorylated tau181 (p-tau181). AD biomarker positivity was defined by a low Aβ1-42/high p-tau181 profile using the CSF Aβ1-42/p-tau181 ratio (<39.2). αSyn-SAA-positive PD participants with and without AD biomarker positivity were compared. Outcomes included cognition, Montreal Cognitive Assessment (MoCA), neuropsychological testing, and MDS-UPDRS motor scores over follow-up.ResultsAmong 449 αSyn-SAA-positive PD patients, 42 (9.3%) met AD biomarker criteria (PD-AD). Baseline cognition and motor scores did not differ between PD-AD and PD without AD biomarkers (PD-nonAD). Over time, PD-AD patients showed greater cognitive decline, with lower MoCA scores and higher MCI prevalence at 5 years. At 8 years, PD-AD patients also demonstrated worse motor outcomes. MoCA <24 predicted AD biomarker positivity (PPV 15%; OR 6.1). APOE ε4 status was not associated with cognition.ConclusionsBiomarker-defined AD identifies a distinct PD subgroup with accelerated cognitive and motor decline, independent of APOE ε4. A ratio-based CSF Aβ1-42/p-tau181 framework offers a practical approach to detect AD copathology in PD and refine prognostic stratification.},
}

@article {pmid42686546,
year = {2026},
author = {Shigetomi, E and Koizumi, S},
title = {[Gq-GPCR upregulation in reactive astrocytes: implication for neurological disorders].},
journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica},
volume = {161},
number = {5},
pages = {313-318},
doi = {10.1254/fpj.26045},
pmid = {42686546},
issn = {0015-5691},
mesh = {*Astrocytes/metabolism ; Animals ; *Up-Regulation ; Humans ; *Nervous System Diseases/metabolism/genetics ; *Receptors, Purinergic P2Y1/metabolism/genetics ; Mice ; Insulin-Like Growth Factor Binding Protein 2/metabolism ; *GTP-Binding Protein alpha Subunits, Gq-G11/metabolism ; },
abstract = {Astrocytes are essential glial cells that maintain brain homeostasis. Upon brain injury, they become reactive astrocytes with altered morphology, gene expression, and function, including dysregulated Ca[2+] signaling implicated in disease development and progression. P2Y1 receptor (P2Y1R), one of Gq-GPCRs, is upregulated in reactive astrocytes across multiple brain disorders, including Alzheimer's disease, epilepsy, and stroke; however, how this upregulation contributes to pathology has remained unclear. To address this question, we generated astrocyte-specific P2Y1R-overexpressing transgenic mice. P2Y1R overexpression in astrocytes induced neuronal hyperexcitability, as evidenced by increased hippocampal neuronal firing, abnormal EEG spikes, and heightened susceptibility to pilocarpine-induced seizures. Dual-color Ca[2+] imaging of neurons and astrocytes, electrophysiology, transcriptome analysis of astrocytes, immunohistochemistry, and CRISPR/Cas9-mediated astrocyte-specific knockdown revealed that P2Y1R overexpression amplified both neuron-to-neuron and neuron-to-astrocyte signaling, with astrocytes becoming hypersensitive to neuronal activity-derived ATP. Astrocyte-specific transcriptomic analysis identified insulin-like growth factor binding protein 2 (IGFBP2) as a key downstream effector. IGFBP2, a secreted protein selectively expressed in astrocytes, enhanced glutamatergic synaptic transmission. Furthermore, co-upregulation of P2Y1R and IGFBP2 was confirmed in reactive astrocytes in both kainate-induced epilepsy and middle cerebral artery occlusion stroke models. These findings identify the P2Y1R-IGFBP2 signaling axis as a common pathological feature of reactive astrocytes across brain diseases and establish IGFBP2 as a novel glial-derived factor that could promote neuronal hyperexcitability.},
}

*Astrocytes/metabolism
Animals
*Up-Regulation
Humans
*Nervous System Diseases/metabolism/genetics
*Receptors, Purinergic P2Y1/metabolism/genetics
Mice
Insulin-Like Growth Factor Binding Protein 2/metabolism
*GTP-Binding Protein alpha Subunits, Gq-G11/metabolism

@article {pmid42686563,
year = {2026},
author = {Nishikubo, K and Muramatsu, R},
title = {[Metal homeostasis dysregulation and pharmacological modulation in Alzheimer's disease].},
journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica},
volume = {161},
number = {5},
pages = {410},
doi = {10.1254/fpj.26043},
pmid = {42686563},
issn = {0015-5691},
}

@article {pmid42686621,
year = {2026},
author = {Shirotani, K and Hatta, D and Watanabe, K and Saito, T and Saido, TC and Iwata, N},
title = {Stepwise Upregulation of Microglial Genes through the Slow Progression of Amyloid Pathology in Alzheimer's Disease Model Mice.},
journal = {Biological & pharmaceutical bulletin},
volume = {49},
number = {9},
pages = {1409-1415},
doi = {10.1248/bpb.b26-00310},
pmid = {42686621},
issn = {1347-5215},
mesh = {Animals ; *Microglia/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; Up-Regulation ; Disease Models, Animal ; Brain/metabolism/pathology ; Amyloid beta-Protein Precursor/genetics ; Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Receptors, Immunologic/genetics ; Membrane Glycoproteins/genetics ; Disease Progression ; Mice ; Mice, Inbred C57BL ; },
abstract = {The mechanistic role of microglial activation in Alzheimer's disease pathology is typically investigated using mouse models with aggressive amyloid accumulation, leaving the dynamics of microglial responses under the relatively slow deposition of amyloid-β (Aβ) characteristic of the early stages of the disease poorly understood. In this study, we examined microglial gene expression in the brains of App[NL-F] knock-in mice, which gradually develop Aβ pathology in an aging-dependent manner without amyloid-β precursor protein overexpression. Quantitative PCR (qPCR) analysis revealed that microglial gene expression presents a stepwise activation pattern: early-induced genes increased at 12 months, whereas late-induced genes emerged at 18 months. Notably, neither group showed further induction at 24 months despite continued Aβ accumulation, indicating that microglial activation does not scale proportionally with the amyloid burden. Several canonical components of the disease-associated microglia program were not induced in App[NL-F] mice, whereas a set of previously unrecognized microglial genes (Ly86, Snx20, and Pram1) was upregulated. The induction of these novel genes was preserved in the brains of Trem2 R47H knock-in mice, corroborating that the R47H variant exhibits only mild, if any, phenotype. Immunoblotting of selected proteins confirmed these qPCR-based findings. Together, these results reveal a stepwise mode of microglial gene activation under slow amyloid progression and identify novel genes that may be relevant to the early stages of Alzheimer's disease.},
}

Animals
*Microglia/metabolism
*Alzheimer Disease/genetics/metabolism/pathology
Up-Regulation
Disease Models, Animal
Brain/metabolism/pathology
Amyloid beta-Protein Precursor/genetics
Mice, Transgenic
*Amyloid beta-Peptides/metabolism
Receptors, Immunologic/genetics
Membrane Glycoproteins/genetics
Disease Progression
Mice
Mice, Inbred C57BL

@article {pmid42686898,
year = {2026},
author = {Belk, JA and Zhang, Y and Reilly, EE and Shi, Q and Liu, DD and Womack-Gambrel, N and van der Linde, M and Ma, L and Paul, D and Enciso, AM and Kalluru, R and Weiss, J and Li, R and Eastman, AE and Zhu, C and Chakravarthy, A and Bukhari, S and Bhattacharya, D and Raj, S and Richard, D and Brioschi, S and Chrostek, MR and Nachun, DC and Arends, CM and Gopakumar, J and Tengesdal, IW and Bynum, A and Mitchell, S and Sandor, K and Zhang, W and Vardarajan, BN and Cobos, I and Born, DE and West, RB and Brunet, A and Colonna, M and Bharani, KL and Vogel, H and Montine, TJ and Latimer, CS and Weissman, IL and Matusiak, M and Hooper, JE and Keene, CD and Chang, HY and Jaiswal, S},
title = {Somatic mutations reveal the ontogeny of microglia in human ageing.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {42686898},
issn = {1476-4687},
abstract = {Microglia are the resident macrophages of the central nervous system[1]. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult haematopoiesis[2-4]. The origins of human microglia are less clear, but recent evidence suggests that bone-marrow-derived cells contribute to the human microglial pool in certain individuals[5-9]. Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of accumulated somatic mutations that uniquely labels each clone of cells to track the infiltration of bone-marrow-derived cells into the human brain. Applying this approach to 20 older individuals, we find evidence of an influx of bone-marrow-derived cells into the brain in all examined individuals. Single-cell analysis, including single-cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are similar to microglia and can comprise a large fraction of the microglial pool. Analysis of human cohort data demonstrates a protective association between most types of clonal haematopoiesis and Alzheimer's disease. Together, we identify a widespread influx of myeloid cells into the healthy human brain that contributes to the pool of human microglia and becomes common with ageing.},
}

@article {pmid42686946,
year = {2026},
author = {Trushin, S and Nguyen, TKO and Ostroot, M and Nesbitt, JJ and Kovalenko, T and Galkin, A and Nambara, T and Lu, W and Kanekiyo, T and Johnson, G and Trushina, E},
title = {Discovery and preclinical validation of a translationally optimized mitochondrial complex I modulator for Alzheimer's disease.},
journal = {npj drug discovery},
volume = {3},
number = {1},
pages = {},
pmid = {42686946},
issn = {3005-1452},
support = {23AARF-1027342/ALZ/Alzheimer's Association/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; R01AG 55549//NIH/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive metabolic failure, impaired mitochondrial function, and diminished adaptive stress responses, highlighting the need for disease-modifying therapies that restore cellular resilience rather than target downstream pathology. Here, we report the discovery and preclinical validation of C273, a translationally optimized, brain-penetrant mitochondrial complex I (mtCI) modulator developed through medicinal chemistry optimization of our first-generation compounds. C273 retained nanomolar neuroprotective activity against Aβ-induced toxicity while exhibiting favorable drug-like properties, including high oral bioavailability, efficient brain penetration, microsomal stability, minimal CYP and off-target pharmacology liabilities, and selective mild modulation of mtCI. Mechanistic studies demonstrated that C273 activated AMP-activated protein kinase (AMPK) and coordinated antioxidant, autophagic, anti-inflammatory, and mitochondrial quality-control pathways in cultured cells and mouse brain. These responses were absent in AMPKα1/α2-deficient cells, establishing AMPK as an essential mediator, while rotenone pretreatment abolished C273-mediated neuroprotection, supporting engagement of the mtCI quinone-binding site. Repeated administration to wild-type mice for 30 days produced no detectable cardiac or hepatic toxicity. Importantly, C273 activated the same neuroprotective pathways and reduced Aβ and p-Tau levels in induced pluripotent stem cell-derived cerebral organoids from patients with sporadic AD. Together, these findings establish mild modulation of mtCI as a therapeutic strategy to restore metabolic resilience and identify C273 as a promising disease-modifying candidate for AD treatment.},
}

@article {pmid42686974,
year = {2026},
author = {Sharma, V and Vashisht, K and Choudhary, G and Choudhay, V and Bhatia, V and Ashawat, MS and Baldi, A and Kushawaha, SK},
title = {Acitretin shows promising potential in Alzheimer's disease: retinoid-driven modulation of amyloid processing, neuroinflammation, and translational prospects.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42686974},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by the convergence of amyloid-β (Aβ) accumulation, tau hyperphosphorylation, synaptic failure, and chronic neuroinflammation, for which effective disease-modifying therapies remain elusive. Increasing evidence identifies dysregulated retinoid signaling as a critical yet underexplored contributor to AD pathogenesis. Retinoic acid, acting through retinoic acid receptors (RARs) and retinoid X receptors (RXRs), is essential for maintaining neuronal homeostasis, synaptic plasticity, and neuroimmune equilibrium in the adult central nervous system. In AD, impairment of RAR/RXR signaling shifts amyloid precursor protein (APP) processing toward amyloidogenic pathways, sustains NF-κB-driven inflammatory cascades, and promotes microglial dysfunction, thereby accelerating the progression of neurodegenerative processes. This review integrates mechanistic, preclinical, and translational evidence supporting acitretin, a second-generation synthetic retinoid, as a multi-target therapeutic candidate for AD. Acitretin enhances ADAM10-mediated non-amyloidogenic APP cleavage, increases soluble APP-α production, and reduces Aβ generation in transgenic AD models, while concurrently modulating microglial activation to attenuate pro-inflammatory cytokine signaling, including IL-6 and TNF-α, and preserve synaptic integrity. Importantly, biomarker-based clinical studies demonstrate increased cerebrospinal fluid APP-α following acitretin administration, confirming central target engagement in humans. Although definitive clinical efficacy remains to be established, acitretin's pleiotropic mechanism, established pharmacological profile, and biomarker responsiveness position it as a promising repurposed candidate within biomarker-guided and combination-based therapeutic strategies for AD.},
}

@article {pmid42686992,
year = {2026},
author = {Wang, Y and Smith, GE and Lipori, GP and Sun, RC and Shenkman, EA and Liu, M and Wu, Y and Guo, Y},
title = {Structural requirements for intelligent clinical digital twins in feedback-driven care.},
journal = {npj health systems},
volume = {3},
number = {1},
pages = {},
pmid = {42686992},
issn = {3005-1959},
abstract = {Clinical digital twins are increasingly promoted for decision support, yet most are designed and validated for prediction under observed care rather than decision-support validity. We identify four structural requirements for intelligent clinical digital twins used in bidirectional clinical care. Using Alzheimer's disease and related dementias as an example, we show how routine deployment can induce care-path-dependent epistemic drift despite stable predictive performance.},
}

@article {pmid42686999,
year = {2026},
author = {Akhter, F and Akhter, A and Guo, X and Zhu, X and Zhao, Z and Zhu, D},
title = {Advanced glycation end products drive blood-brain barrier lipid dysregulation via RAGE-ABCA1 signaling to promote neurovascular dysfunction in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42686999},
issn = {1476-5578},
support = {R01HL140562//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01DK129493//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; R01AG064798//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Neurovascular dysfunction is an early and critical contributor to Alzheimer's disease (AD), yet the molecular mechanisms linking vascular pathology to metabolic dysregulation remain incompletely understood. Advanced glycation end products (AGEs), which accumulate during aging and metabolic stress, have been implicated in AD pathology; however, their role in cerebrovascular lipid homeostasis is unclear. Here, we demonstrate that AGE accumulation within cerebral microvessels promotes lipid droplet (LD) formation in endothelial cells through receptor for AGE (RAGE)-dependent disruption of cholesterol efflux pathways. In aged APP transgenic mice and human AD brains, we observe increased AGE deposition concomitant with elevated RAGE, DGAT1, and perilipin expression, alongside reduced ABCA1 levels. In human brain endothelial cells, AGE exposure induces lipid metabolic reprogramming characterized by enhanced LD accumulation, upregulation of lipogenic machinery, and suppression of cholesterol efflux. Mechanistically, RAGE silencing restores ABCA1 expression and attenuates LD formation, identifying RAGE as a key upstream regulator. Pharmacological activation of ABCA1 reverses AGE-induced lipid accumulation and reduces RAGE expression, highlighting a therapeutic axis. Furthermore, AGE exposure disrupts blood-brain barrier (BBB) integrity and impairs amyloid-β transport in an in vitro BBB model. In vivo, aging is associated with progressive microvascular LD accumulation, linking metabolic dysfunction to vascular pathology. Together, our findings establish an AGE-RAGE-ABCA1 signaling axis that drives endothelial lipid dysregulation and BBB impairment, providing a mechanistic framework connecting metabolic stress to neurovascular dysfunction in AD.},
}

@article {pmid42687000,
year = {2026},
author = {Liu, J and Peng, F and Li, P and Yao, C and Jin, S and Wu, G and Zhang, T and Liang, Q and Wang, X and Du, X},
title = {Correction: Mechanistic insights into cannabidiol-mediated TrkB activation via FRS2 interaction in attenuating Alzheimer's disease pathology and cognitive impairment.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41380-026-03864-1},
pmid = {42687000},
issn = {1476-5578},
}

@article {pmid42687124,
year = {2026},
author = {Ghosh, P and Mukhopadhyay, S and Rati, S and Ghosh, SS and Krishnan Iyer, P},
title = {Sustainably Synthesized Small Molecule Therapeutic Aggregates Attenuate Aβ-Induced ROS-Mitochondrial-Apoptotic Cascade in Alzheimer's Disease.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01210},
pmid = {42687124},
issn = {2576-6422},
support = {DST/CRG/2019/002614//Department of Science and Technology, Ministry of Science and Technology, India/ ; 5/3/8/20/2019-ITR//Indian Council of Medical Research/ ; PMRF ID: 1900819//Ministry of Education, India/ ; 5(1)/2022-NANO//Ministry of Electronics and Information technology/ ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation, oxidative stress, mitochondrial dysfunction, and progressive neuronal loss, yet effective disease-modifying therapeutics remain limited. Herein, we report the sustainable synthesis of two triphenylamine-based donor-acceptor (D-A) scaffolds, TPA-IM (triphenylamine-indanonemalononitrile) and TPA-FM (triphenylamine-furanmalononitrile), via a catalyst-free ethanol-mediated Knoevenagel condensation under mild conditions, yielding high yields (>80%). Integrated photophysical, computational, biophysical, and cellular investigations revealed that acceptor engineering critically governs supramolecular assembly, amyloid-binding behavior, and neuroprotective efficacy. Among the two molecules, TPA-IM exhibited superior inhibition of Aβ40 fibrillogenesis and a stronger fibril-binding affinity, as evidenced by ThT kinetics, ITC, docking, and molecular dynamics simulations. Aggregate simulations and FETEM analyses further demonstrated distinct supramolecular assembly behavior associated with enhanced amyloid interactions. Importantly, TPA-IM effectively suppressed intracellular ROS generation, restored mitochondrial membrane potential, and attenuated Aβ-induced apoptosis in neuronal cells. Favorable BBB permeability and ADMET profiles further support its therapeutic potential. Collectively, this work establishes a mechanistic framework linking acceptor-controlled supramolecular organization with amyloid modulation and mitochondrial neuroprotection for AD therapeutics.},
}

@article {pmid42687127,
year = {2026},
author = {Yu, P and Jiang, M and Qiu, Z and Fu, Y and Yu, Y and Luo, Y and Deng, X and Li, J and Chen, X and Zhang, J and Huang, M and Cui, X and Yang, X},
title = {Cerium-Rutin Coordination Polymer Nanoparticles for Scavenging ROS and Inhibiting Amyloid-β Fibrillation in Alzheimer's Disease.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c12785},
pmid = {42687127},
issn = {1944-8252},
support = {2023CXQD049//Central South University/ ; 82403717//National Natural Science Foundation of China/ ; },
abstract = {The abnormal accumulation of amyloid-beta (Aβ) triggers cellular dysfunction and tissue damage through processes including reactive oxygen species (ROS) and neuroinflammation, ultimately leading to the manifestation of AD symptoms. However, existing studies have revealed that the isolated clearance of amyloid-beta (Aβ), reactive oxygen species (ROS), or neuroinflammation confers no significant benefit on cognitive and memory function in AD patients. Thus, given the complex pathogenic mechanisms underlying AD, multitarget synergistic therapy represents a promising therapeutic strategy. Herein, we reported coordination polymer nanoparticles, Ce-Ru@Trf NPs, composed of cerium (Ce), rutin (Ru), and transferrin (Trf), which efficiently scavenge various ROS and anti-neuroinflammation and inhibit Aβ fibrillization. Owing to Trf modification, its accumulation in brain tissues increased significantly. The Ce-Ru@Trf NPs also dampened neuroinflammation by redirecting microglia toward the M2 phenotype and curtailing proinflammatory factor release. In an AD APP/PS1 model, it significantly achieved a neuroprotective effect and improved cognitive function. The findings suggest that biocompatible coordination polymers composed of metals and natural products may offer a viable therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42687401,
year = {2026},
author = {Hooper, C and González, E and Nogueira, L and Delrieu, J and Coley, N and Soto, M and Vellas, B and Guyonnet, S and , },
title = {Cross-sectional associations of loneliness with plasma p-tau217 and neurofilament light chain in dementia-free older adults in the INSPIRE-T baseline cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261482077},
doi = {10.1177/13872877261482077},
pmid = {42687401},
issn = {1875-8908},
abstract = {BackgroundLoneliness is the subjective feeling of social isolation and evidence suggests that it increases the risk for cognitive decline and Alzheimer's disease (AD). However, studies examining the associations between loneliness and AD biomarkers are limited and inconclusive.ObjectiveWe sought to investigate the relationships between loneliness and plasma tau phosphorylated at threonine 217 (p-tau217) and plasma neurofilament light chain (NfL): peripheral biomarkers of central AD pathology.MethodsThis is a cross-sectional analysis of the 'INStitute for Prevention' 'healthy agIng' and 'medicine REjuvenative' 'Translational' (INSPIRE-T) baseline data. Participants were dementia-free (Mini-Mental State Exam score ≥ 24) community-dwellers aged ≥ 65 years (n = 434). Loneliness was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS[®]) Item Bank v2.0, Short Form 8a questionnaire and plasma p-tau217 and plasma NfL were measured using Lumipulse immunoassays. Multiple linear regression was conducted to evaluate the relationships between loneliness (exposure) and plasma biomarkers (outcomes).ResultsLoneliness was not associated with plasma p-tau217 (β = 0.00458 [95% CI: -0.00328, 0.01243], p = 0.253) or plasma NfL (β = 0.00138 [95% CI: -0.00418, 0.00693], p = 0.626) in multiple linear regression models adjusted for age, sex, education, cognitive performance, depressive score, eyesight, hearing, and apolipoprotein ε4 (APOE ε4) status (model 2). There was no significant moderating effect of sex, depression, eyesight, hearing or APOE ε4 on these associations.ConclusionsOur findings suggest that loneliness is not associated with plasma p-tau217 or plasma NfL in dementia-free older adults. Perspective studies are warranted to examine these associations further.},
}

@article {pmid42687894,
year = {2026},
author = {Mitchell, BA and Hausle, I and Smith, S and Thropp, P and Sirota, M and Tosun, D},
title = {Peripheral blood microarray-based transcriptomic and epigenetic analyses identify immune, inflammation, and metabolic dysregulation in Alzheimer's disease.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {74},
pmid = {42687894},
issn = {3005-1940},
abstract = {Leveraging multi-omics to better understand the molecular signatures and pathways underlying Alzheimer's disease (AD) pathogenesis is critical for early diagnosis and disease modifying interventions. We performed peripheral blood transcriptome (N = 669) and epigenome microarray analyses (N = 553) on non-Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify molecular signatures of AD. We identified specific transcripts (e.g., MAPK14, GM2A, CD177) and co-expression networks that were dysregulated in AD, marked by a strong influence of APOE ε4 genotype, and characterized by a consistent pattern of immune activation, inflammation, and metabolic suppression. Further, these peripheral signatures were linked to central AD pathology (amyloid PET, CSF p-tau181) and neurodegeneration (plasma NfL, regional atrophy), with two genes, MXD3 and NR4A1, identified as protective against progression from MCI to AD. Our work emphasizes the importance of APOE genotypes in AD pathophysiology and highlights potential targets for biomarker discovery and personalized therapeutic strategies.},
}

@article {pmid42687896,
year = {2026},
author = {Afifi, T and Collins, N and Rand, K and Stamps, J and Naffziger, E and Truscelli, N and Harris, P and Neumann, T and Mazur, A and Rosen, Y and Salehuddin, A and Gonzales, C and Otmar, C and Wilson, V and Salmon, J and Fujiwara, K and Monin, J and Lou, Y},
title = {The effects of virtual reality and video conferencing on personal and relational well-being among older adults with cognitive impairments and their adult children: The Thrive randomized controlled trial.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10584186/v1},
pmid = {42687896},
issn = {2693-5015},
abstract = {Older adults in senior living communities (SLCs) often face barriers to maintaining emotional well-being and family ties. This stratified, unblinded, parallel-group randomized controlled trial tested a four-week virtual reality (VR) intervention (Thrive) designed to improve well-being for older adults with cognitive impairment and their adult children living at a distance, compared to an active video conferencing (VC) control. A total of 186 dyads - each comprising a parent with mild cognitive impairment (MCI) or mild-to-moderate Alzheimer's disease and related dementias (ADRD) and an adult child - were recruited from 23 SLCs and randomized 1:1 to VR (n=90) or VC (n=96). Primary outcomes - including personal, social, and relational well-being for parents and adult children, and perceived stress and caregiver guilt for adult children - were assessed at baseline, one week post-intervention (primary endpoint), and one and three months post-intervention using intention-to-treat linear mixed models; secondary outcomes captured session engagement via self-report and behavioral coding. Retention was high (89% at post-intervention). Parents with ADRD showed significantly greater improvement in VR than VC for psychological well-being, social connection, and relationship quality, while parents with MCI showed a comparable pattern favoring VC for relationship quality and social connection. Adult children in both conditions reported improved personal, social, and relational well-being, with VR showing more sustained reductions in caregiver guilt through three months. Overall, VR sessions elicited more engagement than VC. These findings indicate that both VR and VC improved well-being and family connection, with VR conferring additional benefits for parents living with dementia and a sustained caregiver-guilt benefit for adult children, suggesting that tailoring technology to cognitive abilities may enhance outcomes in senior care settings.},
}

@article {pmid42687900,
year = {2026},
author = {McClarty, B and Monteiro, R and Dong, H},
title = {Histone Deacetylase Inhibitors Improve Memory Function and Decrease Neuropathology in APP/PS1 Mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10816126/v1},
pmid = {42687900},
issn = {2693-5015},
abstract = {Although histone deacetylase (HDAC) inhibitors have shown therapeutic potential in aging and Alzheimer's disease (AD), direct comparisons of nonselective and selective HDAC inhibitors across aging and AD models are lacking. We compared the effects of the broad-spectrum HDAC inhibitor valproic acid (VPA) and the selective class I HDAC inhibitors entinostat (MS-275) and tacedinaline (CI-994) in 3-, 12-, and 18-month-old wild-type and APP/PS1 mice. Mice received 30 days of treatment, followed by a series of behavioral tests assessing different memory domains. Brain tissue was then analyzed for molecular and pathological changes. Both MS-275 and CI-994 improved recognition memory and short-term working memory in 12- and 18-month-old APP/PS1 mice, whereas only CI-994 restored long-term spatial reference memory. CI-994 increased hippocampal synapse-related gene expression and H3K9 acetylation at their promoters, consistent with improved hippocampus-dependent memory. In contrast, MS-275 enhanced synapse-related gene expression and H3K9 acetylation, in the prefrontal cortex (PFC), corresponding to improvements in recognition and working memory. MS-275 also significantly reduced amyloid plaque burden in the hippocampus and PFC, whereas both MS-275 and CI-994 decreased microglial density in APP/PS1 mice. These findings demonstrate distinct spatial and functional effects of selective HDAC inhibition in AD. CI-994 primarily targets hippocampal synaptic plasticity to improve long-term spatial memory, whereas MS-275 preferentially modulates PFC synaptic function and reduces amyloid pathology, leading to improved recognition and working memory. Together, these results identify region-specific HDAC mechanisms that differentially regulate cognitive function and AD pathology, supporting selective HDAC inhibition as a promising therapeutic strategy for AD.},
}

@article {pmid42687915,
year = {2026},
author = {Javanray, M and Gallego-Rudolf, J and Yakoub, Y and Qiu, T and St-Onge, F and Remz, J and Soucy, JP and Misic, B and Bellec, L and Vogel, J and Group, PR and Villeneuve, S},
title = {Network-level functional connectivity is associated with longitudinal tau accumulation and amyloid-dependent cognitive decline in preclinical Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10282950/v1},
pmid = {42687915},
issn = {2693-5015},
abstract = {Amyloid-β and tau, pathological hallmarks of AD, silently accumulate years before clinical symptoms' onset and are associated with neuronal dysfunction and cognitive impairment. Although functional connectivity has shown promise in tracking AD proteinopathy, how large-scale brain functional connections and their temporal variability relate to longitudinal pathological and cognitive changes during the preclinical stage remains unclear. Here, we examined both static and time-varying functional connectivity across brain networks in cognitively unimpaired older adults with a family history of AD, who underwent resting-state fMRI, longitudinal amyloid- and tau-PET imaging, and decade-long neuropsychological assessments. We found that lower static connectivity across multiple large-scale networks was associated with faster longitudinal tau accumulation and, selectively in individuals with elevated amyloid burden, with accelerated cognitive decline. These associations were not observed for time-varying connectivity. Together, our results demonstrate a role of static functional network organization in early pathological and cognitive progression of AD.},
}

@article {pmid42687927,
year = {2026},
author = {Duche, A and Chandnra, DV and Han, D and Sumbria, RK and Rahman, M},
title = {Hepatic and Brain Spatial Gene Expression Changes in Intragastric Alcohol Fed APP/PS1 Alzheimer's Disease Mouse Model.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10760512/v1},
pmid = {42687927},
issn = {2693-5015},
abstract = {Background Alcohol use is increasingly recognized as a significant modifier of Alzheimer's disease (AD) risk and progression. Two key organs, the liver and the brain, are central to understanding the impact of alcohol intake on AD. This is due to the liver being the primary site of alcohol detoxification and a major target of alcohol-induced injury, while the brain harbors the neuropathological hallmarks of AD. Although growing literature now links liver dysfunction to AD pathogenesis, the molecular mechanisms linking peripheral alcohol-induced liver injury to brain pathology remain poorly defined. To address this gap, we performed what is, to the best of our knowledge, the first integrated, multi-organ spatial transcriptomic analysis of liver and brain tissue from APP/PS1 AD mice subjected to chronic intragastric alcohol feeding. Methods Following five-weeks of either control- or alcohol-diet feeding of APP/PS1 mice, differentially expressed genes (DEGs) were quantified in postmortem tissue across regions of interest (ROIs) spanning periportal and perivenous liver zones, along with Aβ plaque-bearing and Aβ plaque-free regions of the cortex and hippocampus in the brain. Pathway and network analyses were then used to identify candidate hub genes and biological processes altered within and across ROIs, followed by in silico nomination of therapeutic targets and drug repurposing compounds. Results Following alcohol exposure, the most prominent transcriptional changes in the liver occurred in the perivenous zone, followed by the periportal zone. Among brain ROIs, the strongest differential expression occurred in the plaque-bearing hippocampus, with few or no DEGs detected in the remaining ROIs. These findings highlight Aβ pathology-dependent and region-selective tissue vulnerability to alcohol in the brain and liver during AD. Accordingly, cross-tissue comparisons focused on the plaque-bearing hippocampus and liver ROIs. This revealed coordinated molecular perturbations, including shared downregulation of S100a8 and Tmem267 , as well as opposing regulation of Lrp1 , Osgin1 , and Cpsf7 between the plaque-bearing hippocampus and perivenous liver ROIs, respectively. Enrichment analyses indicated convergent dysregulation of cytoplasmic processes, metal ion homeostasis, redox/oxidative stress responses, mitochondrial pathways, and immune signaling. Although no gene-level overlap was observed, identified candidate therapeutic compounds and targets converged on pathways regulating metabolic sensing, kinase and phosphatase balance, proteostasis, inflammation, autophagy, and neurovascular signaling, which are central to aging biology, chronic alcohol exposure, and AD. Conclusion These findings implicate significant liver-brain crosstalk through which chronic alcohol exposure may modulate AD-relevant pathology and reinforce the growing recognition of the liver as a critical organ in AD pathogenesis. Furthermore, these results reveal key alcohol-driven hepatic and brain gene perturbations and dysregulated pathways relevant to AD along with actionable therapeutic targets for future investigation.},
}

@article {pmid42687952,
year = {2026},
author = {Illán-Gala, I and Vera, E and Selma-González, J and Rodríguez-Baz, Í and Abdelnour, C and Rodriguez-Porcel, F and Wyman-Chick, K and Toledo, J and Ferreira, D and Habich, A and Sala-Matevera, I and Peris-Subiza, J and García-Castro, J and Rubio-Guerra, S and Dols-Icardo, O and Belbin, O and Fortea, J and Lleó, A and Alcolea, D},
title = {Pre-dementia clinical trajectories associated with neuronal α-synuclein neuropathologic change: a retrospective cohort study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10788306/v1},
pmid = {42687952},
issn = {2693-5015},
abstract = {Biological definitions of neuronal α-synuclein disease are advancing diagnosis beyond traditional clinical syndromes, but the trajectories preceding dementia and the influence of concomitant Alzheimer pathology remain uncertain. We analyzed longitudinal data from 1,543 participants without dementia at baseline who underwent repeated cognitive, functional, neuropsychiatric, and motor assessments and had neuropathological characterization at autopsy. Participants were classified as having neuronal α-synuclein neuropathologic change (NSNC), Alzheimer's disease neuropathologic change (ADNC), or both. NSNC without intermediate or high ADNC was associated with the greatest motor burden. Among participants without mild cognitive impairment at baseline, concomitant ADNC was associated with earlier cognitive impairment and faster cognitive decline; mixed NSNC/ADNC also showed faster functional worsening than NSNC alone. Across participants with NSNC, baseline mild cognitive impairment, neuropsychiatric manifestations and concomitant ADNC predicted progression to dementia, whereas prespecified motor signs did not. These findings reveal heterogeneous pre-dementia trajectories and support combining α-synuclein detection with Alzheimer biomarkers, cognitive staging and multidomain clinical measures to improve prognosis and trial design.},
}

@article {pmid42687965,
year = {2026},
author = {Zeidan, HM and Shah, GH and Zeidan, IH and Samawi, HM and Jones, JA},
title = {Association between Internet Use for Health Information and Self-reported Alzheimer's Disease Diagnosis among Older Adults in the United States: Racial and Gender Disparities.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10570409/v1},
pmid = {42687965},
issn = {2693-5015},
abstract = {UNLABELLED: Background Alzheimer's disease (AD) disproportionately affects racial and ethnic minority populations, reflecting broader inequities in access to diagnosis, treatment, and long-term care. As digital health technologies become increasingly widespread, understanding whether internet use for health information is associated with Alzheimer's disease diagnosis may inform strategies to address disparities in aging populations.

AIM: This study examined the association between internet use for health or medical information and AD diagnosis among older adults in the United States and assessed whether this association varied by race/ethnicity, gender, and socioeconomic status.

SUBJECT AND METHODS: Data were drawn from Round 13 (2024) of the National Health and Aging Trends Study, a nationally representative survey of adults aged 65 years and older. Internet use for health information was assessed via self-report, binary and multivariable logistic regression models estimated adjusted odds ratios for AD diagnosis, controlling for sociodemographic characteristics.

RESULTS: Internet use for health information was significantly associated with Alzheimer's disease diagnosis. Stratified analyses by race/ethnicity and gender showed consistent patterns, although no statistically significant interaction effects were observed.

CONCLUSION: These findings suggest that digital health engagement is associated with Alzheimer's disease diagnosis among older adults and underscore the importance of equitable and culturally responsive access to digital health resources to address persistent disparities in cognitive aging.},
}

@article {pmid42687999,
year = {2026},
author = {Hai, H and Li, M and Hu, X and Peng, J and He, Z},
title = {Targeting cellular senescence with Traditional Chinese Medicine: advances in neurodegenerative disorder treatment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1875385},
pmid = {42687999},
issn = {1664-2295},
mesh = {Humans ; *Cellular Senescence/drug effects/physiology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Medicine, Chinese Traditional/methods ; Animals ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Signal Transduction/drug effects ; },
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), represent formidable health challenges, particularly within aging populations. Cellular senescence, marked by irreversible cell cycle arrest and the secretion of pro-inflammatory cytokines, has emerged as a crucial factor in the pathogenesis of these disorders. The accumulation of senescent cells in the nervous system exacerbates neuroinflammation, impairs neuronal function, and accelerates tissue degeneration, all of which are key features of NDDs. In this context, bioactive components derived from Traditional Chinese Medicine (TCM) have attracted significant attention for their potential to modulate cellular senescence and alleviate neurodegeneration. This review examines the shared molecular signaling pathways linking cellular senescence to NDDs, explores the mechanisms by which TCM-derived compounds-such as ginsenosides, ginkgo biloba extract, and curcumin-intervene in senescence-related processes, and discusses the translational potential of these natural compounds for clinical application.},
}

Humans
*Cellular Senescence/drug effects/physiology
*Neurodegenerative Diseases/drug therapy/metabolism
*Medicine, Chinese Traditional/methods
Animals
*Drugs, Chinese Herbal/therapeutic use/pharmacology
Signal Transduction/drug effects

@article {pmid42688049,
year = {2026},
author = {Hu, M and Sun, Z and Mao, D and Tian, X and Shang, Q},
title = {Temporal trends in the prevalence of Alzheimer's disease, 1980-2024: a systematic review and meta-analysis.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1884058},
pmid = {42688049},
issn = {2296-2565},
mesh = {*Alzheimer Disease/epidemiology ; Humans ; Prevalence ; Female ; Male ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the primary cause of dementia and represents a significant public health concern in aging populations. Existing evidence indicates geographic and sex-related differences in AD prevalence; however, comparability across time periods and diagnostic criteria is limited, and data from lower-resource regions remain scarce. This study synthesized evidence on reported AD prevalence from 1980 to 2024 and examined temporal, geographic, demographic, and methodological variation.

METHODS: PubMed, Web of Science, and Embase were systematically searched from inception to December 31, 2024, for observational studies reporting AD prevalence in general or community-based populations. Eligible studies reported prevalence estimates with 95% confidence intervals or provided sufficient data for calculation. Studies with sample sizes below 100 and non-original reports were excluded. Two reviewers independently screened studies and extracted data; disagreements were resolved by a third reviewer. Pooled reported prevalence was estimated using a random-effects model. The review was prospectively registered in PROSPERO (CRD420251111597).

RESULTS: Fifty-two studies from 19 countries met the inclusion criteria. The pooled reported prevalence of AD was 4.43 per 100 population (95% CI 3.47-5.50). Prevalence was higher among females (4.65 per 100, 95% CI 3.37-6.13) than males (2.30 per 100, 95% CI 1.71-2.97). By survey period, reported prevalence was 3.52 per 100 for 1980-1989, 4.21 for 1990-1999, 4.12 for 2000-2009, and 6.78 for 2010-2024. Adjusted meta-regression did not identify a significant association between survey year and reported prevalence. Estimates also varied by WHO region, Human Development Index (HDI) level, sample size, and study design.

CONCLUSIONS: Reported AD prevalence was substantial and varied by demographic, geographic, and methodological factors. Although prevalence was highest in the most recent survey period, meta-regression did not indicate a consistent global increase over time. Given the extremely high between-study heterogeneity, these findings should be interpreted with caution. More standardized, age-comparable, and geographically representative studies are needed, particularly in underrepresented and lower-resource settings.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251111597, identifier CRD420251111597.},
}

*Alzheimer Disease/epidemiology
Humans
Prevalence
Female
Male

@article {pmid42688072,
year = {2026},
author = {Chen, J and Chen, X and Yu, W and Chen, T and Liu, Z and Hu, J},
title = {Multi-omics integration identifies a gut-microbiota-associated plasma metabolite signature for alzheimer disease diagnosis and metabolic pathway targeting.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1933454},
pmid = {42688072},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia, with early diagnosis remaining constrained by the invasiveness and limited accessibility of current biomarkers. The gut-brain axis has emerged as a critical communication network linking intestinal homeostasis with central nervous system function, yet the diagnostic utility of gut-microbiota-associated circulating metabolites in AD remains largely unexplored.

METHODS: In this case-control study, 85 participants (37 AD patients and 48 cognitively normal controls) were enrolled. Targeted plasma metabolomics using four complementary UPLC-MS/MS assays covering 375 endogenous metabolites was integrated with fecal metagenomic sequencing in 72 participants with paired samples. Differential metabolites were screened using the Mann-Whitney U test, orthogonal partial least squares discriminant analysis, and fold-change thresholds. Gut-microbiota-associated plasma metabolites were defined through Spearman correlation with linear discriminant analysis effect size-identified differential bacterial species. A diagnostic panel was constructed using least absolute shrinkage and selection operator logistic regression with stability selection, and its performance was evaluated by support vector machine with repeated cross-validation, with age and sex evaluated as covariates.

METHODS: We identified 27 differential plasma metabolites enriched in tricarboxylic acid cycle and amino acid metabolic pathways. Correlation analysis identified 10 gut-microbiota-associated plasma metabolites significantly associated with gut microbial alterations. A three-metabolite panel (citric acid, 3-hydroxyoctanoic acid, and glyoxylic acid) achieved a cross-validated area under the curve of 0.865, with a modest sensitivity of 62.2% and specificity of 100.0%, positioning it as a confirmatory auxiliary tool rather than a broad screening instrument. The panel score correlated negatively with Mini-Mental State Examination scores (r = -0.544, P < 0.001), and integration with clinical cognitive assessment yielded an area under the curve of 0.978.

CONCLUSION: These findings potentially advance the translational understanding of the gut-brain metabolic axis in neurodegeneration and support the exploratory clinical utility of microbiota-linked peripheral metabolic signatures as non-invasive auxiliary diagnostic tools for AD, awaiting external validation in larger, multi-center cohorts.},
}

@article {pmid42688139,
year = {2026},
author = {Zupan, M and Prelog, PR and Kramberger, MG and Frol, S},
title = {Anti-amyloid treatment in Alzheimer disease: updated implications for patients with cerebral amyloid angiopathy and other cerebrovascular conditions.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1889769},
pmid = {42688139},
issn = {1664-2295},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/drug therapy/complications ; *Alzheimer Disease/drug therapy/complications ; *Cerebrovascular Disorders/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; },
abstract = {Anti-amyloid treatment (AAT) with monoclonal antibodies represents a major therapeutic advance in early Alzheimer disease (AD), but its introduction has important and underappreciated implications for vascular neurology. Because many patients with AD also have cerebral amyloid angiopathy and other cerebrovascular pathology, AAT influences stroke diagnosis, acute reperfusion therapy, and long-term antithrombotic management. Clinical trials of lecanemab and donanemab enrolled highly selected patients with minimal baseline cerebrovascular pathology, limiting generalizability to real-world populations with prevalent vascular comorbidity. Amyloid-related imaging abnormalities, particularly vasogenic edema and microhemorrhages, constitute a central safety concern and may clinically mimic acute ischemic stroke, complicating emergency decision-making and increasing the risk of inappropriate intravenous thrombolysis (IVT). Emerging reports of intracerebral hemorrhage following IVT in treated patients underscore the need for revised acute stroke pathways and support consideration of mechanical thrombectomy when otherwise indicated, although AAT-specific safety data are lacking. Beyond the hyperacute phase of stroke, concomitant use of anticoagulants or dual antiplatelet therapy raises unresolved questions regarding hemorrhagic risk, particularly in patients with atrial fibrillation or those requiring complex antithrombotic regimens. Alternative strategies, including left atrial appendage closure, may be considered in selected patients, although evidence in AAT recipients remains limited. As AAT enters routine practice, multidisciplinary collaboration, dedicated imaging protocols, and prospective safety registries will be essential to integrate disease-modifying AD treatment with safe and effective cerebrovascular care.},
}

Humans
*Cerebral Amyloid Angiopathy/drug therapy/complications
*Alzheimer Disease/drug therapy/complications
*Cerebrovascular Disorders/drug therapy
*Antibodies, Monoclonal/therapeutic use

@article {pmid42688145,
year = {2026},
author = {Dai, X and Nicholson, SI and Lawlor, HR and Carr, S and Steinmetz, JD and Chen, NM and McLaughlin, SA and Hay, SI and Ong, KL and Aravkin, AY and Zheng, P and Sorensen, RJD and Gilbertson, NM and Mullany, EC and O'Connell, EM and Murray, CJL and Gakidou, E},
title = {Health effects associated with alcohol consumption: a Burden of Proof study.},
journal = {Nature health},
volume = {1},
number = {9},
pages = {979-999},
pmid = {42688145},
issn = {3005-0693},
abstract = {The relationship between alcohol and health is complex, and the evidence relating alcohol consumption to various cardiovascular diseases, cancers and other conditions is evolving. Moreover, alcohol drinking guidelines vary widely. Here we conducted 16 systematic reviews across four databases and conservatively re-evaluated dose-response relationships between alcohol consumption and 20 health outcomes, analysing 843 cohort and case-control studies using the Burden of Proof meta-analytic framework. We found that levels of current alcohol consumption are associated with increased risks for cancers of the breast, colorectum, oesophagus, larynx, lip and oral cavities, pharynx, liver, stomach, pancreas and prostate, as well as pancreatitis, cirrhosis and other chronic liver diseases, lower respiratory infections, tuberculosis, and atrial fibrillation and flutter. We found J- or U-shaped relationships between alcohol consumption and type 2 diabetes, Alzheimer's disease and other dementias, ischaemic heart disease, ischaemic stroke and haemorrhagic stroke. While potential health impacts at low-to-moderate levels varied by outcome, high levels of alcohol consumption were associated with increased risk across all outcomes.},
}

@article {pmid42688218,
year = {2026},
author = {Abu-Amara, H and Zhao, W and Li, Z and Leung, YY and Schellenberg, GD and Wang, LS and Crimmins, EM and Thyagarajan, B and Anwar, M and Hu, P and Dey, S and Dey, AB and Zhou, X and Thangaraj, K and Lee, J and Kardia, SLR and Smith, JA},
title = {Association between Alzheimer's disease-related genes and neurodegenerative blood-based biomarkers in Indian adults.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1832155},
pmid = {42688218},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) and related dementias are a growing health and economic burden in India. Blood levels of amyloid beta (Ab), tau, and other proteins marking neuronal injury are biomarkers of AD risk and are potentially important for AD prevention.

METHODS: In 2,224 participants from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD), we performed gene-based analyses on (1) missense/loss-of-function (LoF) single-nucleotide variants (SNVs) and (2) brain-specific promoter/enhancer SNVs across 84 genes selected from AD GWAS and 25 gene-biomarker pairs selected from biomarker GWAS. We used variant-Set Test for Association using Annotation infoRmation (STAAR) across 7 neurodegenerative biomarkers measured in blood: Ab40, Ab42, Ab42/Ab40, total tau (tTau), tau phosphorylated at threonine 181 (pTau), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). We adjusted for age, sex, and genetic ancestry, with random intercepts for genetic relatedness and biomarker plate. Analyses incorporated weighted annotation scores (e.g., deleteriousness). Significant results (FDR-q < 0.1) were followed up with single variant analysis. Genes were also assessed for sex- and age-interactions using iSKAT.

RESULTS: Missense/LoF variants in 6 AD-associated genes (ECHDC3, CLU, APOE, EPHA1, ICA1L, CASS4) and 1 biomarker-associated gene (APOE) were associated with Ab40, Ab42/Ab40, pTau, and/or GFAP (FDR q < 0.1), with the most significant SNVs tending to be rare/low-frequency (MAF ≤ 0.05) and potentially deleterious. Promoter/enhancer variants in 1 AD-associated gene (CCDC6) were associated with Ab42/Ab40, with the index SNV being a potentially deleterious common variant (MAF = 0.27). Several associated variants appeared to have higher frequency in India compared to other global populations. Missense/LoF SNVs in two AD genes (EPHA1, MS4A6A) had sex-specific effects on Ab42 and/or tTau, and promoter/enhancer SNVs in four AD genes (DGKQ, MS4A6A, MS4A4A, JAZF1) had sex-specific effects on tTau and/or pTau. Missense variants in 12 AD genes and promoter/enhancer variants in two AD genes showed interaction with age on at least one biomarker, primarily GFAP and NfL with genetic effects tending to be stronger at older ages.

CONCLUSION: Rare and common variants in AD- and neurodegenerative biomarker-associated genes with increased frequency in India compared to other populations may impact blood levels of neurodegenerative biomarkers in South Asians.},
}

@article {pmid42688484,
year = {2026},
author = {Li, X and Li, L and Liu, X and Liu, S and Yang, W and Gao, J and Kang, S and Wang, L and Li, J and Wang, X and Du, H and Su, S and Li, Z and Xu, W},
title = {α2-3-sialylated glycosphingolipids in neuroinflammation, immunity, and programmed cell death: mechanistic evidence and context-dependent regulation: a comprehensive review.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1865721},
pmid = {42688484},
issn = {1664-3224},
mesh = {Humans ; *Glycosphingolipids/metabolism/immunology ; Animals ; *Neuroinflammatory Diseases/metabolism/immunology ; *Apoptosis/immunology ; Signal Transduction ; Membrane Microdomains/metabolism ; Neurodegenerative Diseases/metabolism/immunology ; *Immunity ; },
abstract = {α2-3-sialylated glycosphingolipids (α2-3-GSLs) are major constituents of neuronal membranes and lipid rafts, where they shape receptor compartmentalization, signal-complex assembly, and cell-cell communication. Their biological effects, however, vary by molecular subtype, cell type, disease stage, concentration, and local microenvironment. This review synthesizes evidence on spatiotemporal alterations in α2-3-GSL profiles and their relationships to neuroinflammation, immune responses, proteostasis, and programmed cell death across Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and Guillain-Barré syndrome. Particular attention is given to GM1, GD1a, and GD3 and to mechanisms involving TLR4/NF-κB, PI3K/AKT, autophagy-lysosomal function, complement, damage-associated molecular patterns (DAMPs) recognition, and death-receptor signaling. Evidence is stratified into relatively well-supported, model-specific or incomplete, and conceptually inferred mechanisms. On this basis, we propose a lipid-inflammation-immunity-cell death framework that organizes potentially shared downstream processes while explicitly retaining disease-specific differences. This framework is not a validated universal causal pathway; rather, it provides an analytical structure for identifying evidence gaps and testable hypotheses. Disease-specific and parallel cross-disease studies, coupled with spatial lipidomics, in vivo tracing, and subtype-selective interventions, will be required to determine when α2-3-GSL manipulation is protective, neutral, or harmful and to support rational clinical translation.},
}

Humans
*Glycosphingolipids/metabolism/immunology
Animals
*Neuroinflammatory Diseases/metabolism/immunology
*Apoptosis/immunology
Signal Transduction
Membrane Microdomains/metabolism
Neurodegenerative Diseases/metabolism/immunology
*Immunity

@article {pmid42688514,
year = {2026},
author = {Pang, Y and Chen, L and Dodge, HH and Zhou, J},
title = {Bridging language markers and pathology: correlations between digital speech measures and surrogate CSF biomarkers in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70466},
pmid = {42688514},
issn = {2352-8729},
abstract = {INTRODUCTION: Digital language markers show promise in detecting early cognitive impairment related to Alzheimer's disease (AD), yet their relationship with cerebrospinal fluid (CSF) biomarkers of AD pathology remains unclear mainly due to the lack of data with both CSF and language markers.

METHODS: Using National Alzheimer's Coordinating Center (NACC) clinical data as anchor variables, language makers in the Internet-Based Conversational Engagement Randomized Controlled Clinical Trial (I-CONECT) study were linked to NACC CSF data. Surrogate CSF biomarkers were created for I-CONECT subjects using machine learning models from common NACC clinical variables. Correlations assessed associations between CSF and language markers.

RESULTS: Lower predicted CSF amyloid beta correlated significantly with reduced syntactic complexity and shorter speech responses. Higher predicted total tau and phosphorylated tau correlated with reduced syntactic complexity.

DISCUSSION: This study demonstrates novel links between language markers and fluid biomarkers, highlighting conversational language as a potential accessible, non-invasive approach for early detection and monitoring of Alzheimer's pathology.},
}

@article {pmid42688574,
year = {2026},
author = {Mohanraj, S and Radhakrishnan, S},
title = {Systematic review of unveiling the potential of AI using machine learning and deep learning methods in neurodegenerative diseases.},
journal = {PeerJ. Computer science},
volume = {12},
number = {},
pages = {e3860},
pmid = {42688574},
issn = {2376-5992},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs) are becoming a major worldwide issue, especially for the elderly because they are incurable and permanent. It is extremely difficult to provide any medication to people suffering from NDDs. Comprehending essential processes of NDDs are essential to establishing alternative strategies that can increase survival rates in patients. This review is an effort to provide insight into NDDs, innovative therapeutic methods along with their clinical significances and thus provide opportunities for improving therapies for NDDs in the near future.

OBJECTIVE: This work aims at a thorough, methodical and critical evaluation of Machine Learning (ML)/Deep Learning (DL) efforts in diagnostics of NDDs, as well as their potential for use in pharmacological, clinical and research settings. An additional objective is to discuss problems and limitations of models, with an eye on furthering research directions.

METHODS: The databases of Elsevier, Sage, Wiley, Springer Link, Emerald Insights and Research Gate were searched for useful assessments of NDDs using ML/DL approaches.

RESULTS: Numerous potential diagnostic ML/DL models have been suggested and effectively applied to detect NDDs. Biological, neuroimaging and key clinical characteristics in patients have been used to evaluate prognostic models. Additionally, these models provide options for patient categorization, facilitate earlier detections, enhanced diagnosis and better disease outcome predictions for personalized therapies.

CONCLUSION: This work points out the rising burden of NDDs on the global elderly while highlighting the significances of ML/DL technological advancements with their limitations for NDDs in diagnostics, identification of effective disease bio-markers and management.},
}

@article {pmid42688663,
year = {2026},
author = {Svintozelskiy, PV and Wahlert, AJ and Harrod, C and Kay, DG and Grady, KP and Grossberg, GT},
title = {Nicotinic Acetylcholine Receptor Modulation Distinguishes Clinical Benefits of Galantamine in Alzheimer's Disease.},
journal = {Sage open aging},
volume = {12},
number = {},
pages = {30495334261485634},
pmid = {42688663},
issn = {3049-5334},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and represents a public health challenge in aging populations. Acetylcholinesterase inhibitors (AChEIs) remain first-line symptomatic therapy for mild to moderate AD, with real-world effectiveness largely influenced by tolerability, adherence, and treatment persistence. Galantamine and its inactive prodrug benzgalantamine are differentiated within the class by a dual mechanism that combines reversible acetylcholinesterase inhibition with positive allosteric modulation of nicotinic acetylcholine receptors. This narrative review synthesizes preclinical and clinical evidence examining galantamine-based therapy, with a focus on aspects related to nicotinic acetylcholine receptors: behavioral symptoms and sleep-related effects. Across randomized, observational, and longitudinal studies, galantamine has been associated with improvement or stabilization in behavioral domains including aberrant motor behavior, agitation/aggression, anxiety, apathy, delusions, disinhibition, and hallucinations. However, like other members of the AChEI class, gastrointestinal tolerability issues may affect treatment persistence. Benzgalantamine was developed to address gastrointestinal tolerability, with the aim of improving adherence and long-term treatment continuity.},
}

@article {pmid42688836,
year = {2026},
author = {Walsh, A and Wendland, A and Uriarte, S and Oliynyk, C and Akella, A and Padron, L and Lorusso, L and Tsybulski, A and Davis, N and Sartipi, P and Spencer, C},
title = {Neurons and Glia Exhibit Distinct Age-Associated MitoTimer-Based Mitochondrial Dynamics in the Drosophila Mushroom Body Calyx.},
journal = {microPublication biology},
volume = {2026},
number = {},
pages = {},
pmid = {42688836},
issn = {2578-9430},
abstract = {Aging increases the prevalence of diseases with mitochondrial dysfunction, notably Alzheimer's and Parkinson's. This study assesses MitoTimer-based mitochondrial dynamics across the lifespan between neurons and glia. MitoTimer was expressed in neurons using nSyb-Gal4 and in glia using Repo-Gal4. MitoTimer red:green fluorescence ratios were quantified within or surrounding the mushroom body calyx of young, middle-aged, and old female Drosophila melanogaster . Paraquat-supplemented food increased red:green ratios relative to controls, supporting our use of MitoTimer. Neuronal red:green ratios peaked in middle age, whereas glial ratios were highest in young flies. These findings reveal distinct, age-dependent mitochondrial dynamics in neurons and glia.},
}

@article {pmid42688951,
year = {2026},
author = {Yao, SY and Du, MQ and Lin, LX and Kang, XH and Jiang, DY and Peng, Y},
title = {Shared Metabolic-Proteinopathy Axis in Alzheimer's Disease and Parkinson's Disease: Evidence for a Convergent but Not Identical Disease Spectrum.},
journal = {Aging medicine (Milton (N.S.W))},
volume = {},
number = {},
pages = {},
pmid = {42688951},
issn = {2475-0360},
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders globally and have long been classified as clinically and pathologically distinct syndromes. AD is defined by amyloid-β (Aβ) plaques and tau-positive neurofibrillary tangles, whereas PD is characterized by α-synuclein aggregation and progressive degeneration of nigrostriatal dopaminergic neurons. However, mounting evidence has blurred the traditional boundaries between these disorders, revealing extensive overlaps in pathogenic cascades, clinical phenotypes, and epidemiological risk factors. In this review, we propose an integrated mechanistic framework in which AD and PD represent distinct yet partially overlapping disorders along a convergent neurodegenerative spectrum, unified by a core metabolic-proteinopathy axis. We highlight cerebral insulin resistance and impaired brain glucose metabolism as pivotal upstream triggers that initiate a cascade of pathological events, including mitochondrial dysfunction, energy depletion, oxidative stress, chronic neuroinflammation, and disrupted proteostasis. These disturbances collectively drive aberrant folding and aggregation of Aβ, tau, and α-synuclein, establishing a mechanistic link between systemic metabolic dysregulation and region-selective neuronal vulnerability. We synthesize evidence from molecular studies, preclinical models, clinicopathological analyses, neuroimaging, and longitudinal epidemiological surveys to delineate the extent and limitations of mechanistic convergence. We also emphasize consistent divergences between AD and PD, including distinct patterns of neuroanatomical involvement, dominant clinical presentations, pathological propagation trajectories, and genetic architectures. Epidemiological data confirm that Type 2 diabetes and insulin resistance are associated with elevated risk of both AD and PD. Moreover, antidiabetic agents such as GLP-1 receptor agonists exhibit convergent neuroprotective efficacy in preclinical and early clinical investigations, supporting metabolic modulation as a promising cross-disease therapeutic strategy. Despite shared downstream pathways and therapeutic targets, AD and PD retain unique pathological signatures and clinical progression patterns. This review provides a balanced, evidence-based interpretation of the AD-PD relationship, highlighting partial pathogenic convergence driven by metabolic dysfunction while affirming their identities as distinct disorders. The proposed metabolic-proteinopathy framework advances mechanistic understanding and informs the development of novel disease-modifying therapies targeting shared upstream pathways.},
}

@article {pmid42688956,
year = {2025},
author = {Brown, E and Lu, A and Lu, W},
title = {AI-Based Noninvasive Pain Detection in Alzheimer's Patients Using Facial Micro-Expression Analysis.},
journal = {Proceedings. International Conference on Advanced Information Networking and Applications},
volume = {247},
number = {},
pages = {105-116},
pmid = {42688956},
issn = {2332-5658},
abstract = {Assessing pain in Alzheimer's patients with communication limitations is a significant challenge, as traditional self-reporting methods are ineffective. In this paper, we introduce an AI-based, noninvasive system that detects pain levels by analyzing facial micro-expressions and physiological responses. Utilizing the Multimodal Intensity Pain (MIntPAIN) dataset, we extracted facial features using the InceptionResNetV1 model pre-trained on VGGFace2, producing 512-dimensional embeddings for each image, and then balanced the MIntPAIN dataset by equalizing the number of 'no pain' and 'pain' sequences. The proposed classification system includes a dimensionality reduction performed using Principal Component Analysis with a 0.99 threshold and a three-layered CNN-RNN model combining Conv1D and Bidirectional LSTM layers. The experimental evaluation shows the model achieved a training accuracy of 99.19% and a validation accuracy of 90.22%, demonstrating its effectiveness in accurately detecting pain levels. This research facilitates real-time analysis and operational efficiency for secure cloud deployment and offers a viable solution for pain assessment in nonverbal Alzheimer's patients.},
}

@article {pmid42688976,
year = {2026},
author = {Gemein, LAW and Gaubert, S and Paquet, C and Paillard, J and Holst, SC and Tveitstøl, T and Haraldsen, IRJH and Kam-Thong, T and Hawellek, DJ and Hipp, JF and Engemann, DA},
title = {Clinically altered brain activity may not look like aged brain activity: Implications for brain-age modeling and biomarker strategies.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70302},
pmid = {42688976},
issn = {2352-8737},
abstract = {INTRODUCTION: Brain-age gap (BAG), the difference between predicted age and chronological age, is studied as a biomarker for the natural progression of neurodegeneration. The BAG captures brain atrophy as measured with structural magnetic resonance imaging (MRI). Electroencephalography (EEG) has also been explored for estimating the BAG (EEG-BAG). However, studies showed mixed results for the EEG-BAG including counterintuitive findings of younger predicted age in clinical populations, raising doubts about its utility as a clinical tool for mild cognitive impairment (MCI) and Alzheimer's disease (AD).

METHODS: This study critically examined brain-age estimation from spectral EEG power as a common measure of brain activity in two of the largest public EEG datasets containing heterogeneous clinical cases alongside controls including MCI and AD. EEG recordings were analyzed from individuals with heterogeneous neurological conditions (n = 898, Temple University Hospital Abnormal EEG corpus [TUAB] data; n = 417 MCI & n = 311 dementia, Chung-Ang University Hospital EEG [CAU] data) and controls (n = 1245, TUAB data; n = 459, CAU data).

RESULTS: We found that age-prediction models trained on the reference population systematically underpredicted age in clinical conditions showing strong and systematic, age-related differences in EEG power compared to controls. Data exploration and simulations revealed how diverging age-related trends in specific EEG frequencies can account for a negative EEG-BAG.

DISCUSSION: The utility of brain age as an interpretable biomarker relies on the observation from structural MRI that progressive neurodegeneration often broadly resembles aging. This assumption can be violated for functional assessments such as EEG spectral power related to different neurological and psychiatric conditions or medications. The sign of the BAG may therefore not be meaningfully interpreted as an individual aging metric, hence hampering its utility as an endpoint or biomarker in MCI and AD.},
}

@article {pmid42689220,
year = {2026},
author = {Kaur, R and Lang, DK and Sood, A and Singh, TG and Chandrasekaran, B and Al-Sha'er, MA},
title = {Recent medicinal chemistry efforts of targeting protein kinases for treating neurological conditions of Parkinson's and Alzheimer's diseases.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42689220},
issn = {2046-2069},
abstract = {The human genome encodes a wide variety of protein kinases that regulate multiple cellular functions. These enzymes play a crucial role in amplifying and propagating intracellular signals during signal transduction. Dysregulation of protein kinase signaling is associated with vascular diseases, inflammatory disorders, cancer, and various neurological conditions. Kinase-targeted therapies have already demonstrated clinical efficacy in oncology and inflammatory diseases, prompting growing interest in their potential application in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Several kinases, including PDK1, CK1, CK2, c-Abl, p38 MAPK, PKA, GSK-3β, PINK1, and ROCK, have been implicated in the pathogenesis of AD and PD, highlighting their potential as therapeutic targets. However, the development of kinase inhibitors for central nervous system (CNS) disorders remains challenging due to limited blood-brain barrier (BBB) penetration and cytochrome P450-mediated metabolism. This review summarizes protein kinase targets involved in AD and PD, discusses kinase inhibitors under preclinical and clinical investigation, and highlights emerging strategies to overcome pharmacokinetic and therapeutic limitations in the development of disease-modifying therapies.},
}

@article {pmid42689362,
year = {2026},
author = {Megha, and Srivastava, R and Singh, R},
title = {Progress in Synthesis and Pharmacology of Telmisartan.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {9},
pages = {e71667},
doi = {10.1002/cbdv.71667},
pmid = {42689362},
issn = {1612-1880},
support = {//Delhi Technological University/ ; },
mesh = {*Telmisartan/chemical synthesis/pharmacology ; Humans ; *Benzimidazoles/chemical synthesis/pharmacology/chemistry/therapeutic use ; PPAR gamma/metabolism/agonists ; *Benzoates/chemical synthesis/pharmacology/chemistry ; *Antihypertensive Agents/chemical synthesis/pharmacology/chemistry/therapeutic use ; Animals ; Renin-Angiotensin System/drug effects ; Hypertension/drug therapy ; *Angiotensin II Type 1 Receptor Blockers/chemical synthesis/pharmacology/chemistry ; },
abstract = {Telmisartan is a benzimidazole derivative and a well-known drug to treat hypertension. This is an angiotensin II receptor blocker (ARB) which helps to relax blood vessels. Studies have shown that telmisartan is effective in reducing cardiovascular disease, with a safety and efficacy profile. This review paper provides an overall understanding of telmisartan as an antihypertensive drug. The goal is to highlight the synthetic methodology of telmisartan, from its first synthesis in 1993. This review also discusses its two mechanisms of action: the Renin-Angiotensin-Aldosterone System (RAAS) inhibitor and partial agonist activity at the Peroxisome Proliferator-activated receptor gamma (PPARγ) receptor. Effective repurposing of this drug for various diseases like chronic kidney illness, diabetes, fatty liver, and Alzheimer's has also been discussed.},
}

*Telmisartan/chemical synthesis/pharmacology
Humans
*Benzimidazoles/chemical synthesis/pharmacology/chemistry/therapeutic use
PPAR gamma/metabolism/agonists
*Benzoates/chemical synthesis/pharmacology/chemistry
*Antihypertensive Agents/chemical synthesis/pharmacology/chemistry/therapeutic use
Animals
Renin-Angiotensin System/drug effects
Hypertension/drug therapy
*Angiotensin II Type 1 Receptor Blockers/chemical synthesis/pharmacology/chemistry

@article {pmid42689376,
year = {2026},
author = {Li, B and Zhang, Z and Bao, H and Wang, Y and Ye, X and Tu, H and Fang, W},
title = {Treadmill exercise rescues cognitive deficits in Alzheimer's mice by repairing axonal mitochondrial transport and synaptic function.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002300},
pmid = {42689376},
issn = {1473-558X},
support = {No.31571225//the National Natural Science Foundation of China/ ; No. L100-2-24109//Shanghai Education Commission science and technology innovation project/ ; },
abstract = {OBJECTIVE: Alzheimer's disease is a progressive neurological disorder characterized by synaptic injury and loss in its early stage. This study aimed to investigate the effects of treadmill exercise on Alzheimer's disease mice, focusing on the related molecular mechanism of axonal transport.

METHOD: In this study, 3-month-old male APP/PS1 mice and C57BL/6J mice were used and divided into four groups (n = 9). Behavioral performance was evaluated using the Morris water maze, open field test, and tail suspension test. Transmission electron microscopy and ELISA were used to assess the morphology and function of mitochondria and synapses, individually. The colocalization of mitochondria and synapses was analyzed by double-labeling immunofluorescence. Finally, the underlying mechanism of treadmill exercise on Alzheimer's disease mice was evaluated by Western blotting.

RESULTS: APP/PS1 mice exhibited significant deficits in spatial learning and memory, accompanied by abnormal ultrastructure and dysfunction in hippocampal mitochondria and synapses. Treadmill exercise could ameliorate cognitive impairments and affective disorders in Alzheimer's disease mice, reduce amyloid-beta levels, improve the morphology and function of mitochondria and synapses, and enhance mitochondrial axonal transport, which might be regulated by the related proteins of kinesins, syntabulin, and dyneins.

CONCLUSION: These results suggest that exercise-induced modulation of mitochondrial dynamics can provide neuroprotection and support the development of novel therapeutic strategies for Alzheimer's disease (Video Abstract, SDC 1).},
}

@article {pmid42689388,
year = {2026},
author = {Wang, Z and Liu, M and Xu, J and Liu, Y and Liu, T},
title = {sAPPα acts as an endogenous ligand for TREM2 to regulate microglial survival and inflammatory responses in Alzheimer's disease.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002307},
pmid = {42689388},
issn = {1473-558X},
support = {(No. GZ2024YLJ063)//the Ganzhou Municipal Science and Technology Plan Fund/ ; },
abstract = {BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial functions in Alzheimer's disease, whereas soluble amyloid precursor protein alpha (sAPPα) has neuroprotective effects. Whether sAPPα directly interacts with TREM2 remains unclear.

METHODS: Single-cell RNA sequencing data from wild-type and APP/PS1 mouse cortices and bulk RNA-seq data (GSE18309) were analyzed. Solid-phase binding, pull-down, and co-immunoprecipitation assays were used to examine TREM2-sAPPα binding and map the interacting regions. LPS-stimulated BV-2 cells were used to assess the effects of TREM2 knockdown and sAPPα supplementation on viability, apoptosis, invasion, phagocytosis, cytokine production, and polarization.

RESULTS: A TREM2-positive microglial subpopulation was more abundant in the APP/PS1 dataset and showed relatively restrained inflammatory signaling. Cell-cell communication analysis predicted enhanced APP-(TREM2+TYROBP) signaling. Biochemical assays confirmed direct binding between TREM2 and sAPPα. The TREM2 51-71 amino acid region and the APP E1+Ac fragment contributed to this interaction, whereas TREM2 variants Y38C, R47H, R62H, and T66M reduced binding affinity. TREM2 knockdown aggravated LPS-induced loss of viability, apoptosis, inflammatory cytokine production, and M1-like polarization in BV-2 cells. Exogenous sAPPα reversed these changes.

CONCLUSION: sAPPα directly binds TREM2 and may limit excessive inflammatory activation of microglia under LPS stimulation. The TREM2-sAPPα interaction may represent a regulatory pathway relevant to Alzheimer's disease.},
}

@article {pmid42689394,
year = {2026},
author = {Liu, Y and Wu, J},
title = {Low-dose N-methyl-D-aspartate protects against amyloid-β-induced neurotoxicity by suppressing the MLK3-MKK7-JNK3 pathway and activating the PI3K-PDK1-Akt pathway.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002310},
pmid = {42689394},
issn = {1473-558X},
abstract = {OBJECTIVE: Oligomeric amyloid-β (Aβ) peptide-induced neuronal apoptosis is a key process in Alzheimer's disease pathogenesis. Low-dose N-methyl-D-aspartate (NMDA) has been shown to promote cell survival both in vitro and in vivo, but its effect on Aβ neurotoxicity remains largely unknown. This study aimed to investigate whether low-dose NMDA protects against Aβ-induced neurotoxicity and to elucidate the underlying molecular mechanisms.

METHODS: Primary rat cortical neurons were exposed to 10 μM Aβ25-35 to establish a neurotoxicity model. Neuronal apoptosis was assessed by 4',6-diamidino-2-phenylindole staining. The effects of low-dose NMDA (10 μM) on the PI3K-Akt and MLK3-MKK7-JNK3 signaling pathways were examined by immunoprecipitation and Western blotting. The PI3K inhibitor LY294002 was used to verify the role of PI3K signaling in NMDA-mediated regulation of the JNK3 pathway.

RESULTS: Low-dose NMDA (10 μM) significantly reduced 10 μM Aβ25-35-induced neuronal apoptosis. Mechanistically, NMDA reversed the Aβ-induced decrease in p-PDK1 and p-Akt levels and concurrently suppressed the activation of the MLK3-MKK7-JNK3 cascade. Moreover, treatment with LY294002 attenuated the inhibitory effect of NMDA on the MLK3-MKK7-JNK3 pathway.

CONCLUSION: Low-dose NMDA exerts neuroprotective effects against Aβ-induced neurotoxicity. These effects are mediated by the dual modulation of the pro-survival PI3K-PDK1-Akt pathway and the pro-apoptotic MLK3-MKK7-JNK3 pathway.},
}

@article {pmid42689607,
year = {2026},
author = {Min, X and Yu, M and Huang, J and Shi, J and Jin, H and Gao, X and Sun, L and He, J},
title = {A High-Throughput Workflow for High-Content Microplate-Based Assays via Mass Spectrometry Imaging.},
journal = {Analytical chemistry},
volume = {98},
number = {34},
pages = {24817-24830},
doi = {10.1021/acs.analchem.6c01560},
pmid = {42689607},
issn = {1520-6882},
support = {20230484474//Beijing Nova Program/ ; GZYSE2024G07//Guangzhou University of Chinese Medicine/ ; 2025ZD0545900//National Science and Technology Major Project/ ; 2025-JKCS-18//Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ ; 82473887//National Natural Science Foundation of China (NSFC)/ ; HBCAD2025-05//Hubei Key Laboratory of Cognitive and Affective Disorders/ ; Z240014//Beijing Municipal Natural Science Foundation/ ; },
mesh = {Animals ; Mice ; *High-Throughput Screening Assays/methods ; Metabolomics/methods ; Formaldehyde/blood/chemistry ; Workflow ; Humans ; *Spectrometry, Mass, Electrospray Ionization/methods ; Spermidine/chemistry ; Irinotecan ; },
abstract = {Microplate-based assays are indispensable in life sciences and drug discovery; however, conventional optical readouts provide limited chemical information. Here, we report a microplate-based mass spectrometry imaging (MP-MSI) workflow based on air flow-assisted desorption electrospray ionization (AFADESI) that enables high-throughput molecular analysis of complex biological samples with minimal sample consumption (down to 1 μL). In contrast to existing MSI-based high-throughput strategies that primarily perform single-mode screening, this platform integrates targeted quantitation and untargeted metabolomics from the same sample spot. Using formaldehyde (FA) as a model analyte, we developed a rapid spermidine derivatization method and performed full method validation in blank mouse plasma. The targeted assay achieved an interbatch precision of 6.18% RSD for the analyte-to-internal standard ratio across 0.01-0.8 mmol/L, with a minimum detectable concentration change of 1.12-fold. For untargeted metabolomics, the median within-run RSD evaluated from 180 repeated spottings of blank mouse plasma was 19.1%, corresponding to a minimum detectable fold change of 1.38, at a throughput of 2.2 min per sample. To demonstrate dual-mode integration, we applied the validated FA method to plasma from an Alzheimer's disease mouse model (APP/PS1 and wild-type, 10 and 12 months of age), simultaneously quantifying FA and profiling the global metabolome from the same acquisition. Age- and genotype-dependent metabolic alterations were revealed. The platform was further extended to cell coculture models and to drug quantitation (e.g., irinotecan in plasma), demonstrating versatility across sample types and analytes. This integrated strategy offers a versatile platform for high-content screening in biomedical and pharmacological research.},
}

Animals
Mice
*High-Throughput Screening Assays/methods
Metabolomics/methods
Formaldehyde/blood/chemistry
Workflow
Humans
*Spectrometry, Mass, Electrospray Ionization/methods
Spermidine/chemistry
Irinotecan

@article {pmid42689906,
year = {2026},
author = {Jamuna, NA and Thomas, M and Arumugam, D and Mandal, S},
title = {Conjugation of Biomolecules to PEG as a Strategy for Efficient Protein Aggregation Inhibition.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c00990},
pmid = {42689906},
issn = {2576-6422},
support = {P4114//Ministry of Education, India/ ; P4114//Indian Institute of Technology Kharagpur/ ; },
abstract = {Neurodegenerative diseases are a group of progressive disorders characterized by the degeneration of neurons with significant cognitive decline and motor and autonomic dysfunction. They are linked to protein aggregation that leads to cellular toxicity, neuronal death, and brain atrophy due to the accumulation of amyloid plaques and tau tangles in the brain. Recent advances in biomaterials have introduced several biocompatible polymers and conjugated biomolecules as potential inhibitors for protein aggregation. Conjugation to biocompatible polyethylene glycol (PEG) is the most widely used strategy for enhancing bioavailability, biocompatibility, and pharmacokinetic properties of small molecular drugs. In this work, we have designed and synthesized two biomolecule-polymer conjugates, namely, Tre-CA-mPEG and LA-CA-mPEG, by combining a biocompatible, nontoxic polymer monomethoxy PEG (mPEG), a steroid bile acid, cholic acid (CA), and a functional biomolecule, trehalose (Tre) or lipoic acid (LA). These building blocks have significant protein stabilization and neuroprotective attributes, which are important for protein aggregation inhibition. The size distributions of the self-assemblies formed by the Tre-CA-mPEG and LA-CA-mPEG bioconjugates were determined by dynamic light scattering (DLS) measurements. Both the PEGylated bioconjugate assemblies show promising results for inhibition of protein aggregation. The hydrophobic interactions provided predominantly by the steroidal core moiety, together with hydrogen bonding interactions within the PEG corona of the self-assemblies, play a crucial role in protein stabilization and fibrillation inhibition. LA-CA-mPEG bioconjugate exhibits superior effects in delaying aggregation kinetics and enhancing the inhibition of protein aggregation compared to the Tre-CA-mPEG bioconjugate. This enhanced protein fibrillation inhibition can be attributed to the larger hydrophobic surface and stronger interactions arising from the LA-CA-mPEG nanoassemblies.},
}

@article {pmid42689975,
year = {2026},
author = {Pupyshev, AB and Ovsyukova, MV and Akopyan, AA and Tenditnik, MV and Korolenko, TA and Dubrovina, NI and Tikhonova, MA},
title = {Role of AMPK Signaling in the Neuroprotective Effects of Trehalose in Mice With a Pharmacological Model of Alzheimer's Disease.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {8},
pages = {53657},
doi = {10.31083/FBL53657},
pmid = {42689975},
issn = {2768-6698},
support = {theme no. 126020316369-9 (2026-2028)//Ministry of Science and Higher Education of the Russian Federation for the Scientific Research Institute of Neurosciences and Medicine/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; *Trehalose/pharmacology ; Mice ; *AMP-Activated Protein Kinases/metabolism ; Disease Models, Animal ; Signal Transduction/drug effects ; Male ; Mice, Inbred C57BL ; Autophagy/drug effects ; Amyloid beta-Peptides/metabolism ; Brain/drug effects/metabolism/pathology ; Hippocampus/drug effects/metabolism ; Cognition/drug effects ; Pyrazoles ; Pyrimidines ; },
abstract = {BACKGROUND: Trehalose (TRE) has demonstrated neuroprotective potential in models of Alzheimer's disease (AD)-like pathology and has been shown to activate AMP-activated protein kinase (AMPK) and induce autophagy in hepatocytes. The molecular mechanisms underlying the neuroprotective effects of TRE in the brain, including the involvement of AMPK signaling and autophagy, remain unclear.

METHODS: AD was modeled in C57BL/6 mice by intracerebroventricular administration of the amyloid-β (Aβ) fragment Aβ(25-35). The effects of TRE treatment (a 3% water solution in drinking water for 20 days) on AD-like pathology in the brain (frontal cortex, amygdala, and hippocampus) were assessed by immunohistochemical analysis, while cognitive function was evaluated using the passive avoidance test. AMPK activation was assessed by measuring AMPK (p-AMPK) levels in the brain and by evaluating the effects of its inhibitor dorsomorphin (DM; 10 mg/kg, i.p., 20 days, every other day for 20 days).

RESULTS: Aβ-treated mice exhibited markedly increased Aβ levels and neuroinflammatory responses in the brain, whereas levels of the autophagy marker LC3-II and p-AMPK were moderately reduced. TRE markedly reduced Aβ accumulation and neuroinflammation and restored cognitive performance to levels comparable to those of the Control group; it also increased LC3-II immunoreactivity and p-AMPK levels in the hippocampus and amygdala. DM did not abolish the neuroprotective effects of TRE but moderately inhibited AMPK in the hippocampus.

CONCLUSIONS: Marked changes in brain Aβ levels and cognitive performance were not associated with either p-AMPK or autophagy marker levels, suggesting that additional mechanisms contribute to the neuroprotective effects of TRE in AD. Markers of autophagy initiation and AMPK activity responded similarly to AD modeling and TRE treatment and were positively correlated in the hippocampus, suggesting a role for AMPK in the regulation of TRE-induced hippocampal autophagy.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
*Neuroprotective Agents/pharmacology
*Trehalose/pharmacology
Mice
*AMP-Activated Protein Kinases/metabolism
Disease Models, Animal
Signal Transduction/drug effects
Male
Mice, Inbred C57BL
Autophagy/drug effects
Amyloid beta-Peptides/metabolism
Brain/drug effects/metabolism/pathology
Hippocampus/drug effects/metabolism
Cognition/drug effects
Pyrazoles
Pyrimidines

@article {pmid42689984,
year = {2026},
author = {Liu, X and Fan, S and Pan, X and Pang, H and Su, W and Liu, S},
title = {Endophilin Proteins in Membrane Dynamics, Neurodegeneration, Cancer, and Cardiovascular Disease.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {8},
pages = {49204},
doi = {10.31083/FBL49204},
pmid = {42689984},
issn = {2768-6698},
support = {B2024122//Medical Scientific Research Foundation of Guangdong Province/ ; 2025GXJK0400//2025 Guangdong Provincial Education Science Planning Project/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics ; *Neoplasms/metabolism/genetics ; *Cardiovascular Diseases/metabolism/genetics ; *Acyltransferases/metabolism/genetics ; Animals ; *Cell Membrane/metabolism ; Adaptor Proteins, Signal Transducing ; },
abstract = {The endophilin protein family comprises a group of evolutionarily highly conserved Bin-Amphiphysin-Rvs (BAR) domain proteins that play key roles in cell membrane morphogenesis, endocytic trafficking, and organelle dynamics. The human endophilin family includes five main members, encoded by the genes SH3GL2 (endophilin A1), SH3GL1 (endophilin A2), SH3GL3 (endophilin A3), SH3GLB1 (endophilin B1), and SH3GLB2 (endophilin B2). Notably, SH3GLB1 gives rise to functionally distinct splice variants, including the ubiquitously expressed B1a and the neuron-enriched B1b/c, which play critical, opposing roles in conditions such as Alzheimer disease (AD). These isoforms perform distinct, often opposing functions in disease pathogenesis via specific molecular mechanisms. For instance, endophilin A1 acts as a tumor suppressor; its gene, SH3GL2, is frequently deleted or downregulated in cancers such as non-small cell lung cancer, and its loss promotes tumor progression by sustaining epidermal growth factor receptor (EGFR) signaling. Conversely, endophilin A2 drives cancer metastasis. In AD, endophilin A1 expression is significantly elevated, exacerbating synaptic dysfunction, while neuron-specific endophilin B1 isoforms are decreased, worsening amyloid pathology. The regulation of endophilins involves intricate networks, including post-transcriptional control by microRNAs (e.g., miR-330 targeting SH3GL2 in glioblastoma) and post-translational modifications. This review provides a comprehensive overview of the structural characteristics and regulation of expression and activity. It delineates the molecular mechanisms by which their dysfunction contributes to disease pathogenesis, aiming to provide new insights into these multifaceted proteins in health and disease.},
}

Humans
*Neurodegenerative Diseases/metabolism/genetics
*Neoplasms/metabolism/genetics
*Cardiovascular Diseases/metabolism/genetics
*Acyltransferases/metabolism/genetics
Animals
*Cell Membrane/metabolism
Adaptor Proteins, Signal Transducing

@article {pmid42690003,
year = {2026},
author = {Sonkodi, B},
title = {Alzheimer's Disease, Piezo2 Channelopathy, Piezo1 Channelopathy, and the Body-Wide Piezo2 System.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {8},
pages = {52555},
doi = {10.31083/FBL52555},
pmid = {42690003},
issn = {2768-6698},
support = {23-2026/ HUSS_PUBL_FUND//Hungarian University of Sports Science/ ; },
mesh = {*Alzheimer Disease/metabolism/genetics/physiopathology ; *Ion Channels/metabolism/genetics ; Humans ; Animals ; *Channelopathies/metabolism/genetics ; Mice ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; },
abstract = {Alzheimer's disease initiates pathophysiology in the 10 to 20 years prior to detectable clinical symptoms. A recent genetic analysis implicated the critical role of Piezo2 in Alzheimer's disease pathophysiology. A recent genetic study, involving PIEZO1 manipulation, showed that phosphatidylinositol 4,5-bisphosphate (PIP2) rectified brain capillary endothelial Piezo1 channelopathy in a mouse model of Alzheimer's disease. However, the present opinion paper posits that the initiating microdamage is in the prefrontal cortex, further upstream of pathophysiology, namely an irreversible Piezo2 channelopathy of glutamatergic terminals that is proposed to finely regulate oxytocin release resulting from stressful ultradian events, leading to impaired ultradian rhythm. The involvement of Piezo2 in the defensive arousal response reveals an underlying body-wide Piezo2 system of which the proposed prefrontal Piezo2 channelopathy is possibly a critical locus. PIP2 is emerging as a potential treatment method for Piezo channelopathy in Alzheimer's disease. However, the challenge of its more precise administration to target affected regions of the brain still remains.},
}

*Alzheimer Disease/metabolism/genetics/physiopathology
*Ion Channels/metabolism/genetics
Humans
Animals
*Channelopathies/metabolism/genetics
Mice
Phosphatidylinositol 4,5-Diphosphate/metabolism

@article {pmid42690079,
year = {2026},
author = {Vogl, DP and Migotti, M and Konrat, R and Conibear, AC and Becker, CFW},
title = {Modifications of Lysine Residues 294 and 311 Within the Microtubule-Binding Region Alter Tau Aggregation and Tubulin Binding Equilibria.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e1521091},
doi = {10.1002/anie.1521091},
pmid = {42690079},
issn = {1521-3773},
support = {LS17-008//Vienna Science and Technology Fund/ ; },
abstract = {Dysfunction of the microtubule-associated protein Tau is a central feature of Alzheimer's disease and related tauopathies, yet how site-specific lysine modifications modulate the functional and pathological states of Tau remains poorly understood. Here, we combine protein semi-synthesis with segmental isotope labelling and NMR spectroscopy of full-length Tau, to dissect how lysine acetylation and carboxymethylation within the microtubule-binding region of Tau regulate its interactions with tubulin, microtubules, and amyloid assembly. Site-specific modification at lysine 294 delays Tau-mediated tubulin polymerization and fibril formation, whereas acetylation at lysine 311 exerts more moderate effects, but alters fibril morphology. NMR spectroscopy of segmentally isotope-labelled Tau variants indicates that single lysine acetylation does not measurably weaken Tau binding to pre-formed microtubules; however, bivalent acetylation reduces microtubule binding, possibly by cumulative charge neutralization. Together, these results indicate that lysine acetylation redistributes Tau between functional states in a site- and valency-dependent manner. Our study helps to establish a mechanistic framework linking combinatorial lysine modifications to Tau dysfunction and highlights the utility of region-resolved structural approaches to decipher posttranslational modification-dependent equilibria in intrinsically disordered proteins.},
}

@article {pmid42690439,
year = {2026},
author = {Mastrangelo, A and Baiardi, S and Ruggeri, E and Bentivenga, GM and Vargiu, CM and Mammana, A and Sbriccoli, M and Polischi, B and Carlà, B and Capellari, S and Parchi, P},
title = {Changes in five cerebrospinal fluid and three plasma Alzheimer's disease biomarkers across increasing brain amyloid-beta and tau pathology burden.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42690439},
issn = {1432-0533},
support = {Ricerca Finalizzata-2021-12374386//Ministero della Salute/ ; },
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/blood/metabolism ; *Amyloid beta-Peptides/cerebrospinal fluid/blood/metabolism ; *Alzheimer Disease/pathology/blood/cerebrospinal fluid/metabolism ; Biomarkers/cerebrospinal fluid/blood ; Female ; Male ; Aged ; *Brain/pathology/metabolism ; Aged, 80 and over ; Peptide Fragments/cerebrospinal fluid/blood ; Middle Aged ; },
abstract = {Neuropathological validation studies of pathology-specific biomarkers for neurodegenerative diseases are essential but are often limited by long sampling-to-death intervals and the lack of semi-quantitative pathology measures. We assessed the associations of five cerebrospinal fluid (CSF) (Aβ42/Aβ40, p-tau181, p-tau217, Aβ42/p-tau181 and Aβ42/p-tau217) and three plasma (p-tau217, p-tau217/Aβ42 and Aβ42/Aβ40) biomarkers with post-mortem Aβ and tau pathology burden in 250 participants with ante-mortem CSF (n=230) and/or plasma (n=101), affected by prion (n=162) or non-prion diseases (n=88). Aβ and tau burden were scored across nine and six brain areas, respectively. We assessed the earliest biomarker changes across quartiles of Aβ and tau pathology burden and the discriminatory performance at progressively higher pathology thresholds using multivariable linear regression and sequential ROC analyses. Analyses on p-tau markers were restricted to non-prion participants. The median sampling-death interval was 1.5 months for CSF and 1 month for plasma. CSF Aβ42/Aβ40 decreased at the second quartile of Aβ burden (p<0.001), whereas p-tau181 (p<0.01) and p-tau217 (p<0.001) increased only from the third quartile. CSF Aβ42/Aβ40 achieved its highest accuracy at low/intermediate Aβ burden (AUC 0.984), while CSF p-tau and derived ratios performed best at advanced Aβ (AUCs 0.889 to 0.980) and intermediate tau pathology stages (AUCs 0.949 to 0.995). CSF p-tau217 and Aβ42/p-tau217 consistently showed higher accuracy than their p-tau181 counterparts across Aβ and tau pathology scores. Plasma p-tau217 and p-tau217/Aβ42 significantly increased in the highest Aβ and tau burden quartiles, where they achieved their best performance (AUCs 0.893 to 0.928). These findings support a sequential model of biomarker changes across the Alzheimer's disease neuropathological continuum. CSF Aβ42/Aβ40 best reflects low/intermediate Aβ burden, while CSF p-tau markers are more closely related to high Aβ and intermediate tau load. Plasma markers primarily identify advanced Aβ and tau pathology burden. Notably, current fluid biomarkers do not capture the earliest phases of Aβ deposition.},
}

Humans
*tau Proteins/cerebrospinal fluid/blood/metabolism
*Amyloid beta-Peptides/cerebrospinal fluid/blood/metabolism
*Alzheimer Disease/pathology/blood/cerebrospinal fluid/metabolism
Biomarkers/cerebrospinal fluid/blood
Female
Male
Aged
*Brain/pathology/metabolism
Aged, 80 and over
Peptide Fragments/cerebrospinal fluid/blood
Middle Aged

@article {pmid42690440,
year = {2026},
author = {Holleman, J and Kåreholt, I and Näsholm, MS and Sørensen, C and Hagman, G and Aspö, M and Kivipelto, M and Solomon, A and Sindi, S},
title = {Insomnia symptoms and stress exposure interact in relation to Alzheimer's disease biomarkers.},
journal = {Journal of neurology},
volume = {273},
number = {10},
pages = {},
pmid = {42690440},
issn = {1432-1459},
support = {P21-0173//Riksbankens Jubileumsfond/ ; 2020-02325//Vetenskapsrådet/ ; 804371//H2020 European Research Council/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/complications ; Female ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid ; *Stress, Psychological/cerebrospinal fluid/complications/epidemiology ; *tau Proteins/cerebrospinal fluid ; *Sleep Initiation and Maintenance Disorders/cerebrospinal fluid/complications/epidemiology ; Biomarkers/cerebrospinal fluid ; Aged ; *Peptide Fragments/cerebrospinal fluid ; Cross-Sectional Studies ; Cohort Studies ; Aged, 80 and over ; },
abstract = {BACKGROUND: Several modifiable factors affect Alzheimer's disease (AD) risk. However, evidence on how these factors interact remains scarce, limiting our understanding of their role in AD development. This study aims to assess interactions between chronic stress exposure and insomnia in relation to AD biomarkers beta-amyloid (Aβ42), total tau, and phosphorylated tau.

METHODS: The present study included 124 memory clinic patients without dementia from the Cortisol and Stress in Alzheimer's disease (Co-STAR) cohort study. Insomnia symptoms, stressful life events (SLEs) and current perceived stress were self-reported via questionnaires, while AD biomarkers were assessed from the cerebrospinal fluid (CSF). Cross-sectional interactions between stress and insomnia in relation to AD biomarkers were examined using linear regression models.

RESULTS: Insomnia and SLEs interacted in relation to Aβ42. Greater stressor exposure was associated with reduced CSF Aβ42 levels, reflecting greater brain amyloid accumulation, only in those with moderate-to-high insomnia scores. No interactions were found for total or phosphorylated tau.

CONCLUSIONS: This study suggests that chronic stress and sleep disturbances exhibit an interactive relationship in their associations with AD pathology, and highlights the need for further research into interactive effects of multiple modifiable risk factors in the development of AD.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/complications
Female
Male
*Amyloid beta-Peptides/cerebrospinal fluid
*Stress, Psychological/cerebrospinal fluid/complications/epidemiology
*tau Proteins/cerebrospinal fluid
*Sleep Initiation and Maintenance Disorders/cerebrospinal fluid/complications/epidemiology
Biomarkers/cerebrospinal fluid
Aged
*Peptide Fragments/cerebrospinal fluid
Cross-Sectional Studies
Cohort Studies
Aged, 80 and over

@article {pmid42690514,
year = {2026},
author = {Sehgal, J and Bagri, K and Deshmukh, R},
title = {Fibroblast growth factors in Alzheimer's Disease pathogenesis: neuropharmacological implications for neuroprotection, neurogenesis, and therapeutic development.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42690514},
issn = {1573-4978},
support = {EMDR/IG/9/2024-01026//Indian Council of Medical Research/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Neurogenesis/drug effects ; *Fibroblast Growth Factors/metabolism ; Animals ; Signal Transduction/drug effects ; *Neuroprotection/drug effects ; Receptors, Fibroblast Growth Factor/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Neuronal Plasticity ; Neurons/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by neuroinflammation, synaptic dysfunction, mitochondrial impairment, and cognitive loss. Despite extensive research, disease-modifying therapies remain elusive, underscoring the need to identify novel signalling pathways that could be pharmacologically modified. The diverse family of ligands known as fibroblast growth factors (FGFs) regulates neurogenesis, synaptic plasticity, neuronal survival, and metabolic balance by binding to fibroblast growth factor receptors (FGFRs). Numerous elements of AD pathogenesis, including energy metabolism, tau pathology, amyloid-β-toxicity, and neuroinflammation, are linked to dysregulated FGF-FGFR signalling according to an increasing number of studies. This study critically examines the neuropharmacological roles of FGFs in the central nervous system and their relationship to AD. We discuss how FGF modulates intracellular signalling cascades, including MAPK/ERK, PI3K-AKT, and STAT pathways, and how these changes affect synaptic integrity, glial activation, and neuronal resilience. We also highlight novel relationships among FGFs, metabolic dysfunction in AD, mitochondrial signalling, and gut-brain communication. Finally, we evaluate the therapeutic potential and challenges of targeting FGF signalling, including issues with receptor selectivity, blood-brain barrier penetration, and long-term safety. Collectively, this review positions FGF signalling as a promising yet underexplored neuropharmacological axis for developing disease-modifying strategies in Alzheimer's disease.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
*Neurogenesis/drug effects
*Fibroblast Growth Factors/metabolism
Animals
Signal Transduction/drug effects
*Neuroprotection/drug effects
Receptors, Fibroblast Growth Factor/metabolism
Neuroprotective Agents/pharmacology/therapeutic use
Neuronal Plasticity
Neurons/metabolism

@article {pmid42690718,
year = {2026},
author = {Nam, MK and Oh, Y and Choi, Y and Lee, J and Jeong, GH and Park, S and Yoo, SA and Kim, M and Kang, S and Rhim, H},
title = {Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {17},
pages = {3156-3168},
doi = {10.1021/acschemneuro.5c00977},
pmid = {42690718},
issn = {1948-7193},
support = {RS-2022-NR070495//National Research Foundation of Korea/ ; RS-2026-25504267//National Research Foundation of Korea/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics ; *Superoxide Dismutase-1/metabolism/genetics ; Humans ; Animals ; Mutation ; *Superoxide Dismutase/metabolism/genetics ; Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, with familial ALS (fALS) frequently caused by mutations in Cu/Zn superoxide dismutase (SOD1). The G93A mutation, one of the most aggressive forms, promotes the formation of cytotoxic protein aggregates through cross-β-sheet structures, leading to neuronal dysfunction and death. In this study, we investigated the therapeutic potential of NABi (natural Aβ binder and Aβ-aggregation inhibitor), a stable small engineered protein composed of the N-terminal 90 amino acids of SOD1, originally developed to target amyloid-β aggregation in Alzheimer's disease. Given the shared β-sheet-rich aggregation mechanisms between amyloid-β and mutant SOD1 proteins, we hypothesized that NABi could serve as a dual-action therapeutic for both diseases. Through an integrated approach involving structural, biochemical, and cellular analyses, we demonstrate that NABi exhibits a 4-fold greater binding affinity for SOD1G93A compared to SOD1WT, selectively targeting the mutant protein via specific hydrophobic interactions. Structural modeling using AlphaFold2 reveals that the G93A mutation exposes hydrophobic residues that create an optimal binding interface for NABi. Functionally, NABi effectively inhibits SOD1G93A aggregation, as demonstrated by filter trap assays and immunofluorescence microscopy, while maintaining the protein in a soluble, nontoxic state. Importantly, coexpression of NABi reduces SOD1G93A-induced cytotoxicity by approximately 4-fold, significantly enhancing neuronal survival. These findings establish NABi as a promising therapeutic candidate for SOD1G93A-associated familial ALS, demonstrating its capacity to selectively target pathological protein conformations while preserving normal cellular function. Our results support the development of NABi as an innovative pan-therapeutic approach targeting shared aggregation pathways across multiple neurodegenerative diseases.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/genetics
*Superoxide Dismutase-1/metabolism/genetics
Humans
Animals
Mutation
*Superoxide Dismutase/metabolism/genetics
Protein Aggregates/drug effects
*Protein Aggregation, Pathological/drug therapy/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42690719,
year = {2026},
author = {Ratis, RC and Bonini, JS and Bold, ABW},
title = {Protein Aggregates as Drivers of Receptor Clustering and Pathological Signaling: A Framework Linking Extracellular Amyloid-β to Tau Dysregulation.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {17},
pages = {3150-3155},
doi = {10.1021/acschemneuro.6c00331},
pmid = {42690719},
issn = {1948-7193},
support = {001//Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior/ ; 311230/2025-3//Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico/ ; NA//Funda??o Arauc?ria/ ; },
mesh = {Humans ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; *Signal Transduction/physiology ; *Alzheimer Disease/metabolism/pathology ; *Protein Aggregates/physiology ; *Protein Aggregation, Pathological/metabolism ; Proto-Oncogene Proteins c-fyn/metabolism ; },
abstract = {Extracellular protein aggregates have long been viewed primarily as toxic deposits, yet this framing fails to explain a critical clinical observation: removal of amyloid-β oligomers does not halt or reverse Alzheimer's disease progression. Here, we propose that this paradox reflects the emergence of a self-sustaining intracellular signaling state, initiated by aggregate-driven receptor clustering but capable of persisting independently of the original extracellular trigger. We argue that oligomeric assemblies act as multivalent scaffolds that cross-link cell-surface receptors, inducing nanoscale clustering and the formation of signaling-competent membrane platforms. In Alzheimer's disease, this mechanism links amyloid-β to a receptor complex involving PrPc and mGluR5, leading to Fyn activation and downstream tau hyperphosphorylation. Critically, redistributed tau enhances Fyn recruitment to postsynaptic compartments, establishing a positive feedback loop in which kinase activity and tau pathology become mutually reinforcing, and progressively decoupled from the initiating amyloid signal. This self-amplifying circuit provides a mechanistic basis for the limited efficacy of amyloid-targeted therapies and reframes the therapeutic window problem in neurodegeneration. Beyond Alzheimer's disease, we propose that clustering-driven feedback loops may represent a generalizable principle in proteinopathies involving extracellular or membrane-associated aggregates─such as α-synuclein─though the applicability of this principle appears to depend on whether the aggregating protein directly engages cell-surface receptor systems. This framework shifts the focus from aggregate burden to membrane organization and feedback topology as determinants of disease progression, and identifies the tau-Fyn feedback loop as a candidate therapeutic target in proteinopathies.},
}

Humans
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Animals
*Signal Transduction/physiology
*Alzheimer Disease/metabolism/pathology
*Protein Aggregates/physiology
*Protein Aggregation, Pathological/metabolism
Proto-Oncogene Proteins c-fyn/metabolism

@article {pmid42690731,
year = {2026},
author = {Ba, W and Bao, C and Gong, Y and Liu, Z and Yang, J and Li, Y and , },
title = {Comparison of baseline characteristics between cognitively normal and mild cognitive impairment and association of white matter hyperintensity trajectories with diagnostic outcomes, cognition, and amyloid-β protein: A longitudinal study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261482151},
doi = {10.1177/13872877261482151},
pmid = {42690731},
issn = {1875-8908},
abstract = {BackgroundWhite matter hyperintensity (WMH) is linked to mild cognitive impairment (MCI) and vascular dementia, but its longitudinal change as an independent risk factor remains unclear.ObjectiveThis study aims to compare baseline WMH across diagnostic outcomes, and evaluate how WMH trajectory relates to outcomes, cognition, and amyloid-β (Aβ) deposition.MethodsData from the Alzheimer's Disease Neuroimaging Initiative (ADNI) included demographics, medical history, WMH, diagnosis, cognition, and amyloid-PET. A total of 857 participants (372 cognitively normal [CN], 485 MCI) were categorized by diagnostic outcome. Baseline WMH differences were analyzed. WMH trajectories (higher/lower) were used in logistic models to predict outcomes, and in linear models to assess cognitive and Aβ changes, adjusting for age, sex, hypertension, BMI, education level, total brain volume and APOE ε4.ResultsBaseline WMH was significantly higher in the CN-MCI group compared to the CN-CN group and lower in the MCI-CN group than in the MCI-MCI and MCI-AD dementia groups (p < 0.05). Controlling for covariates, regression models found that CN participants with higher WMH trajectories had higher odds of MCI (OR = 3.710, 95%CI [1.836,7.499], p < 0.001), and that participants with higher WMH trajectories had greater impairments in domains of memory (β=-0.331, 95%CI[-0.454,-0.208], p < 0.001), executive function (β=-0.275, 95%CI[-0.370,-0.179], p < 0.001), and language (β=-0.248, 95%CI[-0.344,-0.152], p < 0.001). In [18F] florbetapir (FBP) tracers, increased Aβ deposition was also observed in higher WMH groups (β = 0.056, 95% CI[0.018,0.095], p = 0.004).ConclusionsWMH baseline and trajectory changes are key risk factors for CN cognitive decline. WMH trajectory changes are linked to cognitive function and brain Aβ deposition.},
}

@article {pmid42690737,
year = {2026},
author = {Ma, L and Ma, Y and Geng, C and Zhang, Y and Wang, Z and Zhao, Y and Gao, X and Guo, Y and Ma, L and Tang, Y},
title = {Cross-sectional associations of cumulative triglyceride-glucose index with cognitive function and mild cognitive impairment: Evidence from two community-based cohorts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261482078},
doi = {10.1177/13872877261482078},
pmid = {42690737},
issn = {1875-8908},
abstract = {BackgroundThe triglyceride-glucose (TyG) index is a surrogate marker of insulin resistance, implicated in cognitive decline and Alzheimer's disease (AD), but whether long-term TyG exposure is associated with cognitive health remains unclear.ObjectiveTo examine whether cumulative TyG index is associated with cognitive performance, mild cognitive impairment (MCI), and follow-up cognitive performance in two community-based cohorts.MethodsWe analyzed adults aged ≥60 years in the Beijing Disability Risk and Ageing Monitoring Study (BEAM) and ≥45 years in the China Health and Retirement Longitudinal Study (CHARLS). Cumulative TyG was estimated from four annual measurements (2020-2023) in BEAM and two measurements (2012 and 2015) in CHARLS. Cognitive outcomes were assessed in 2023 and 2015, respectively. Multivariable linear and logistic regression models were applied.ResultsA total of 3857 participants were included, comprising 585 participants from BEAM (mean age 73.0 ± 5.1 years; 64.4% women) and 3272 participants from CHARLS (mean age 58.9 ± 8.8 years; 51.4% women). Higher cumulative TyG was associated with higher global cognitive scores in BEAM (β=0.11, 95% CI 0.02-0.20, p = 0.013) and CHARLS (β=0.13, 95% CI 0.05-0.23, p = 0.003). Higher cumulative TyG was also associated with lower odds of MCI (BEAM: OR = 0.85, 95% CI 0.73-0.98, p = 0.028; CHARLS: OR = 0.92, 95% CI 0.86-0.99, p = 0.041). However, cumulative TyG was not associated with follow-up cognitive performance after adjustment for baseline cognition.ConclusionsCumulative TyG was modestly associated with higher cognitive performance and lower odds of MCI in cross-sectional analyses, but not with follow-up cognitive performance.},
}

@article {pmid42690741,
year = {2026},
author = {Moon, Y and Seo, SW and Noh, MY and Kim, HJ and Jeon, HJ and Kim, D and Kwon, KJ and Han, SH and Kim, SH},
title = {Longitudinal CDR-Sum of Boxes trajectories in mild cognitive impairment reveal functional heterogeneity beyond cognitive decline: A latent class growth analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261481096},
doi = {10.1177/13872877261481096},
pmid = {42690741},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) is clinically heterogeneous, yet most prognostic studies rely on binary conversion endpoints or expensive biomarkers unavailable in routine practice.ObjectiveTo identify trajectory classes of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) progression in MCI using latent class growth analysis (LCGA) and to determine whether they capture clinically relevant variation not reducible to Mini-Mental State Examination (MMSE) trajectories.MethodsLCGA was applied to longitudinal CDR-SB data from 121 MCI patients (baseline global CDR = 0.5) with two or more serial assessments across up to eight visits at three tertiary hospitals. Models with one through four classes were compared using BIC, AIC, entropy and minimum class size, with annual MMSE change and dementia conversion (global CDR ≥ 1) as external validators.ResultsA four-class model was selected: Stable (n = 20, 16.5%; -0.08 per visit; 0% conversion), Slow (n = 46, 38.0%; +0.41 per visit; 47.8%), Moderate (n = 22, 18.2%; +0.75 per visit; 81.8%), and Fast (n = 33, 27.3%; +2.07 per visit; 100%); conversion-free survival differed across classes (log-rank p < 0.001). Two classes with near-identical MMSE decline differed markedly in CDR-SB slope and conversion. The stability of the Stable class persisted when all classes were restricted to their first two visits.ConclusionsIn this tertiary-care cohort, serial CDR-SB trajectory classification identified clinically meaningful MCI subgroups, including functional heterogeneity invisible to MMSE monitoring alone; pending external validation it may offer practical, low-cost prognostic value where biomarkers are unavailable.},
}

@article {pmid42690762,
year = {2026},
author = {Crowley, P and O'Donovan, MR and Flanagan, E and O'Caoimh, R},
title = {Associations between sleep and cognition among middle-aged and older adults in Europe.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261481093},
doi = {10.1177/13872877261481093},
pmid = {42690762},
issn = {1875-8908},
abstract = {BackgroundThe Survey of Health, Ageing and Retirement in Europe (SHARE) is a longitudinal multi-country study of community-dwelling middle-aged and older adults including data on sleep and cognition.ObjectiveTo examine the cross-sectional association between sleep-related issues and cognition in the SHARE (pooling waves 8 and 9; 2019-2022).MethodsSubjective sleep data were obtained from SHARE waves 8 and 9. Objective data were available from wave 8. The SHARE Cognitive Instrument (SHARE-Cog) assessed cognition. Participants were divided into three groups: probable dementia, cognitive impairment no dementia (CIND), and normal cognition (NC). Survey-weighted generalized linear regression models were used to compare groups.Results88,889 interviews were included (55% females; mean age 68.88), categorized as: probable dementia 7%, CIND 12%, and NC 81%. While, in the unadjusted analysis, a characteristic 'inverted U' shaped association was observed between sleep duration and cognition, only the association between cognition and longer sleep durations ≥10 hours remained statistically significant after adjusting for potential confounders. Cognitive impairment was significantly associated with subjective reports of recent trouble sleeping, weekly use of medication to aid sleep, and daytime napping, although only the association with daytime napping remained statistically significant after adjusting for potential confounders.ConclusionsThis analysis confirmed an association between sleep duration ≥10 hours and lower cognitive scores among community-dwelling middle-aged and older Europeans. Cognitive impairment was also significantly associated with daytime napping. Further research is required to understand the clinical significance of these findings and establish the underlying causal relationships.},
}

@article {pmid42678362,
year = {2026},
author = {K, AB and Abraham, MK and Indongo, G and Rajeevan, G and Dhahir, DM and Haridas, N and Prakash S, N and R, R and George, DS},
title = {A sandwich ECL immunoassay system for tau protein detection using Ru(II)-AuNP signal probes integrated with copper nanoclusters.},
journal = {Analytical methods : advancing methods and applications},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ay01267a},
pmid = {42678362},
issn = {1759-9679},
abstract = {Tau protein is an important biomarker which is associated with neurodegenerative disorders, particularly Alzheimer's disease, where abnormal tau aggregation and hyperphosphorylation contribute to neuronal dysfunction and cognitive decline. The sensitive and early detection of tau protein is therefore crucial for the diagnosis, prognosis and therapeutic monitoring of neurodegenerative diseases. Owing to its clinical significance, the development of rapid, highly sensitive and reliable analytical platforms for tau detection has gained considerable attention in biomedical diagnostics. In this work, a Ru(II) based homogeneous sandwich ECL immunosensor was developed for the turn-on detection of tau. A polyclonal antibody was conjugated with Ru(II)@AuNP, which served as the ECL signal probe, and further integrated with monoclonal antibody conjugated L-Cys-CuNC to construct the ECL immunoassay system. Upon the addition of tau protein, the ECL intensity was enhanced due to the specific antigen-antibody interaction. The probe is selective and sensitive towards tau with a limit of detection of 0.23 pg mL[-1]. Also, the probe is validated with spiked human serum samples with a recovery percentage of 90 to 104%.},
}

@article {pmid42678458,
year = {2026},
author = {Ahmad, M and Aijaz, M and Ansari, MA and Afzal, M},
title = {Phosphatidylethanolamine-mediated metabolic membrane remodeling in obesity-associated Alzheimer's disease: mechanisms, neuroimmune crosstalk, and therapeutic potential.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42678458},
issn = {1573-7365},
mesh = {*Alzheimer Disease/metabolism/etiology ; Humans ; Animals ; *Obesity/metabolism/complications ; *Phosphatidylethanolamines/metabolism ; *Neuroimmunomodulation/physiology ; Brain/metabolism ; Mitochondria/metabolism ; },
abstract = {Alzheimer's disease is increasingly recognized as a multifactorial neurodegenerative disorder characterized by complex interactions among metabolic dysfunction, chronic inflammation, mitochondrial impairment, and lipid dysregulation. Although the amyloid cascade hypothesis has long dominated Alzheimer's disease research, limited clinical success of amyloid-targeted therapies has highlighted the need for broader mechanistic frameworks integrating systemic metabolic and cellular dysfunction. Emerging evidence suggests that obesity-associated phospholipid remodeling, particularly dysregulation of phosphatidylethanolamine (PE), may critically influence neurodegenerative progression through alterations in membrane dynamics, mitochondrial homeostasis, autophagy, oxidative stress, and neuroimmune signaling. This review critically examines the molecular and cellular mechanisms underlying PE-mediated adipose-brain crosstalk in obesity-associated Alzheimer's disease, with emphasis on mitochondrial dysfunction, blood-brain barrier disruption, ferroptosis, membrane remodeling, and microglial activation. The review further discusses how altered PE metabolism may impair synaptic integrity, promote lipotoxicity, and enhance neuronal vulnerability under chronic metabolic stress. Current evidence, however, remains constrained by methodological heterogeneity, inconsistent lipidomic findings, and substantial reliance on experimental animal models, limiting translational interpretation. In addition, this review proposes the concept of a "metabolic membrane remodeling axis" as an integrative framework linking obesity-driven phospholipid dysregulation with neuroimmune and neurodegenerative progression. A deeper understanding of PE-driven neuroimmunometabolic dysfunction may facilitate biomarker discovery and support the development of lipid-targeted therapeutic strategies for obesity-associated Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/etiology
Humans
Animals
*Obesity/metabolism/complications
*Phosphatidylethanolamines/metabolism
*Neuroimmunomodulation/physiology
Brain/metabolism
Mitochondria/metabolism

@article {pmid42678559,
year = {2026},
author = {He, S and Han, X and Chen, J and Li, C and Li, J and Zhou, Y and Mao, W and Zhang, X and Chen, Y and Zhan, J and Wang, Y},
title = {Hepatic-targeted low-intensity pulsed ultrasound attenuates cerebral amyloidosis via upregulating insulin-degrading enzyme.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42678559},
issn = {1573-7365},
support = {82427901//The Project Supported by National Natural Science Foundation of China/ ; KJZD-M202200403//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; W0155//Program for Youth Innovation in Future Medicine, Chongqing Medical University/ ; XZ202501ZY0120//Science and Technology Program Project of the Xizang Autonomous Region/ ; 12004059//Science and Technology Program Project of the Xizang Autonomous Regionand National Natural Science Foundation of China/ ; },
mesh = {Animals ; Up-Regulation/physiology ; Mice, Transgenic ; *Liver/metabolism ; Mice ; *Ultrasonic Waves ; *Insulysin/metabolism/biosynthesis ; Male ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; Alzheimer Disease/metabolism ; Diet, High-Fat/adverse effects ; Maze Learning ; },
abstract = {This study aimed to investigate whether low-intensity pulsed ultrasound (LIPUS) targeted at the liver can alleviate cerebral Aβ pathology by improving peripheral metabolism and enhancing hepatic Aβ clearance in a comorbid mouse model. 5xFAD transgenic mice were fed a high-fat diet (HFD) to induce peripheral IR. Mice received hepatic LIPUS intervention for four weeks. Outcomes were assessed using metabolic tests, in vivo and ex vivo fluorescence imaging of Aβ trafficking, neuropathological analysis, proteomics, and the Morris water maze. LIPUS ameliorated HFD-induced IR, hepatic steatosis, and pancreatic islet hyperplasia. It upregulated hepatic expression of Aβ-clearance proteins (IDE, LRP-1), enhanced peripheral Aβ catabolism, and reduced Aβ infiltration into the brain. Consequently, LIPUS attenuated cerebral Aβ deposition, neuronal apoptosis, and partially rescued spatial learning and memory deficits. Proteomic analysis confirmed systemic upregulation of metabolic and clearance pathways. Hepatic LIPUS modulates the peripheral metabolism-central clearance axis, reducing brain Aβ burden and improving cognitive function. This non-invasive approach presents a novel strategy for AD, particularly in the context of metabolic dysfunction.},
}

Animals
Up-Regulation/physiology
Mice, Transgenic
*Liver/metabolism
Mice
*Ultrasonic Waves
*Insulysin/metabolism/biosynthesis
Male
Amyloid beta-Peptides/metabolism
*Brain/metabolism
Alzheimer Disease/metabolism
Diet, High-Fat/adverse effects
Maze Learning

@article {pmid42678603,
year = {2026},
author = {Hey, JA and Abushakra, S and Power, A and Watson, D and Porsteinsson, A and Sabbagh, M and MacSweeney, E and Cohen, S and Boada, M and Doraiswamy, PM and Elahi, FM and Rissman, RA and Liang, E and Flint, S and Hristova, E and Kesslak, P and McLaine, R and Albayrak, A and Schaefer, JF and Yu, JY and Tolar, L and Tolar, M},
title = {Plasma Biomarker Effects of Oral Valiltramiprosate/ALZ-801 in Early Alzheimer's Disease from Phase 3 and Phase 2 Trials: Analysis of Core Biomarkers and Correlations with Clinical and Neuroimaging Outcomes.},
journal = {Drugs},
volume = {},
number = {},
pages = {},
pmid = {42678603},
issn = {1179-1950},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with few treatment options, especially for APOE4/4 homozygotes who carry high genetic risk. Valiltramiprosate/ALZ-801 is an oral small-molecule inhibitor of amyloid-beta oligomer formation in late-stage development as a disease-modifying therapy for AD. A recent Phase 3 trial did not meet its primary clinical endpoint in the overall population, but demonstrated significant benefits in cognition, function, and brain volumetric MRI (vMRI) in the prespecified subgroup with mild cognitive impairment (MCI). Here, we report plasma p-tau217, p-tau217/Aβ42, and neurofilament light chain (NfL) results from the Phase 3 trial, along with 4-year fluid biomarker data from the Phase 2 study in APOE4 carriers with early AD.

METHODS: The 78-week, APOLLOE4 Phase 3 trial randomized APOE4/4 homozygotes to placebo (n = 162) or valiltramiprosate 265 mg BID (n = 163). The Phase 2 trial was an open-label biomarker study in APOE4 carriers with early AD who received valiltramiprosate 265 mg BID (N = 84) for 104 weeks, followed by a 2-year extension on the same regimen. Plasma p-tau217 and p-tau217/Aβ42 were measured every 6 months in both trials using FDA-approved Fujirebio Lumipulse G assay. Plasma NfL was measured in the Phase 3 trial using the Simoa assay. Associations between plasma biomarkers and clinical or vMRI outcomes were assessed using Spearman's correlation. Data are reported separately by study.

RESULTS: Baseline plasma p-tau217/Aβ42 confirmed amyloid positivity in 94% of 294 Phase 3 APOE4/4 subjects, including 91% of those with MCI, as well as in 97% of 80 Phase 2 subjects. In the overall Phase 3 population, valiltramiprosate significantly reduced plasma p-tau217 compared with placebo at weeks 26, 52, and 78 (all p < 0.025, observed values). A similar effect was seen in the Phase 3 MCI subgroup (p < 0.05 at weeks 52 and 78), whereas the Mild AD subgroup showed only a numerical trend. In observed case analyses of MCI subjects, plasma p-tau217 decreased by 36% from baseline with valiltramiprosate and increased by 17% with placebo. In the same subgroup, the p-tau217/Aβ42 ratio decreased by 40% with valiltramiprosate and increased by 7% with placebo. Among Phase 3 MCI subjects, week 78 reductions in p-tau217 correlated significantly with improvements in ADAS-Cog13 (r = 0.276, p = 0.039), CDR-SB (r = 0.377, p = 0.005), hippocampal volume (r = - 0.353, p = 0.013), cortical thickness (r = - 0.337, p = 0.018), and whole brain volume (r = - 0.312, p = 0.029). Plasma NfL was also significantly lower with valiltramiprosate than placebo at week 78 in MCI subjects (p = 0.032). NfL stability over 78 weeks correlated significantly with improvements in ADAS-Cog13 (r = 0.29, p = 0.03) and hippocampal volume (r = - 0.282, p = 0.047), and with reductions in p-tau217 (r = 0.42, p = 0.001). In Phase 2 APOE4 carriers, valiltramiprosate-induced reductions in plasma p-tau217 were sustained over 4 years and remained significantly lower in both MCI APOE4 carriers and heterozygotes than in the Phase 3 APOE4/4 MCI placebo group at weeks 26, 52, and 78 (all p < 0.001).

CONCLUSIONS: Valiltramiprosate 265 mg BID produced early and sustained reductions in plasma p-tau217 and p-tau217/Aβ42 in APOE4 homozygotes and carriers with MCI. In Phase 3 MCI subjects, drug effects on both p-tau217 and NfL correlated significantly with clinical and vMRI benefits, and the two biomarkers were also significantly correlated with each other. These findings suggest that valiltramiprosate engages its central target, thereby reducing Aβ aggregation, tau hyperphosphorylation, and downstream neurodegeneration. The consistent associations of plasma p-tau217 and NfL changes with positive clinical and vMRI outcomes in MCI indicate that the pharmacodynamic biomarker response reflects broader disease-modifying biological effects and are consistent with valiltramiprosate's mode of action. Together with the previously reported favorable safety and absence of increased ARIA-E risk, these biomarker findings and their clinical correlations support the promising benefit-risk profile of valiltramiprosate in APOE4/4 MCI patients.

CLINICAL TRIAL REGISTRY: NCT04770220 and NCT04693520.},
}

@article {pmid42678676,
year = {2026},
author = {Zhang, L and Liu, T and He, CH and Russo, A and Coffey, S and Yin, D and Hsu, IU and Zhang, C and Ye, Y and Su, C and Spurrier, J and Nicholson, L and Kunkle, BW and Martin, ER and Rodriguez, OG and Gomez, L and Chang, R and Rothlin, CV and Ghosh, S and Gopal, PP and Hafler, DA and Zhao, H and Strittmatter, SM},
title = {Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480719},
doi = {10.1177/13872877261480719},
pmid = {42678676},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD), the most common age-related neurodegenerative disease, is closely associated with both amyloid-β plaque and neuroinflammation. Two thirds of AD patients are female, and they have a higher disease risk; women with AD have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration.ObjectiveThis study aimed to determine how sex difference induces structural brain changes and molecular cell vulnerabilities in AD, with a focus on identifying sex-specific transcriptional alterations and genetic risk factors.MethodsWe performed single nucleus RNA sequencing on postmortem brains from individuals with AD and age- and sex-matched controls, focusing on the middle temporal gyrus, a cortical brain region strongly affected by the disease, and integrated single nucleus RNA sequencing results with genome-wide association study (GWAS) data using cell type-specific enrichment and generalized gene-set analysis approaches. The analysis pipeline is provided with threshold information.ResultsWe identified a selectively vulnerable subpopulation of layer 2/3 excitatory neurons that were RORB-negative and CDH9-expressing in both males and females. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of AD brains differed between males and females. Integrating single cell transcriptomic data with results from GWAS, we identified MERTK genetic variation as a candidate novel risk factor for AD selectively in females.ConclusionsTaken together, our single cell atlas of middle temporal gyrus revealed a unique cellular-level view of sex-specific transcriptional changes in AD, illuminating GWAS identification of sex-specific AD genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of AD.},
}

@article {pmid42678678,
year = {2026},
author = {Shim, Y and Park, SK},
title = {APOE ε4 genotype-dependent reduction of amyloid-related imaging abnormality in real-world lecanemab use: Implications for risk-stratified prescribing.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480386},
doi = {10.1177/13872877261480386},
pmid = {42678678},
issn = {1875-8908},
abstract = {Real-world amyloid-related imaging abnormality (ARIA) rates with lecanemab are consistently lower than in the Clarity AD trial, yet whether this reduction is genotype-specific is unknown. We compared published APOE ε4-stratified ARIA-E and ARIA-H rates from Clarity AD with a US real-world cohort and Japanese post-marketing surveillance. ARIA rates were largely unchanged in APOE ε4 noncarriers, whereas reductions were concentrated among carriers, especially homozygotes. This pattern was observed for both ARIA subtypes across both settings. These early real-world findings suggest that the apparent attenuation of ARIA during the initial clinical introduction of lecanemab is consistent with genotype-informed risk selection rather than a uniform population-wide decrease.},
}

@article {pmid42678680,
year = {2026},
author = {Lee, E and Pyun, JM and Jeong, H and Bae, YJ and Park, YH and , },
title = {Model-based ordering of the ALPS index among Alzheimer's disease biomarkers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480387},
doi = {10.1177/13872877261480387},
pmid = {42678680},
issn = {1875-8908},
abstract = {Glymphatic dysfunction has been implicated in Alzheimer's disease (AD), but its position relative to amyloid and tau biomarkers remains unclear. We examined the relative position of the diffusion tensor image analysis along the perivascular space (ALPS) index within the AD biomarker cascade using Alzheimer's Disease Neuroimaging Initiative data. Amyloid PET, tau PET, plasma amyloid-β 42/40 ratio, plasma phosphorylated-tau 217, and ALPS index were analyzed with a data-driven event-based model. The ALPS index was ranked between plasma amyloid-β 42/40 alteration and amyloid PET positivity in the model-based ordering of biomarker detectability, preceding tau-related biomarkers in the estimated sequence.},
}

@article {pmid42678681,
year = {2026},
author = {Lee, JH and Won, GH and Lee, SI and Shin, CJ and Son, JW and Kim, S and Ju, G and Chung, S and Jung, JH and , },
title = {Cerebrospinal fluid homocysteine, but not plasma homocysteine, is associated with markers of tau pathology and neurodegeneration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261481063},
doi = {10.1177/13872877261481063},
pmid = {42678681},
issn = {1875-8908},
abstract = {BackgroundGrowing evidence links cardiovascular health to Alzheimer's disease (AD). While elevated plasma homocysteine (Hcy) is associated with cognitive decline, the relationship between cerebrospinal fluid (CSF) Hcy and the core pathological biomarkers of AD remains unclear.ObjectiveThis study aimed to investigate the associations of CSF Hcy and plasma Hcy with CSF amyloid-β (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau).MethodsA total of 294 non-demented participants (110 cognitively normal, 184 with mild cognitive impairment) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were analyzed. Multivariate linear regression was used to analyze the relationships between CSF and plasma Hcy levels and CSF Aβ42, phosphorylated tau (p-tau), and total tau (t-tau). Logistic regression analyses assessed the association between Hcy levels and Aβ42 positivity, tau positivity, and neurodegeneration positivity.ResultsCSF Hcy levels showed significant positive associations with CSF p-tau and t-tau, as well as tau and neurodegeneration positivity. In contrast, no significant association was found between CSF Hcy and Aβ42 pathology. Notably, plasma Hcy was not associated with any AD-related biomarkers.ConclusionsCSF Hcy, rather than plasma Hcy, was associated with markers of tau pathology and neurodegeneration in non-demented older adults. These findings suggest that CSF Hcy may be more closely associated with tau-related pathological processes during the pre-dementia stages of AD. Further research is needed to explore the mechanisms underlying these associations.},
}

@article {pmid42678691,
year = {2026},
author = {Chen, Z and Xu, Z and Zhang, C and Wei, Y and Li, Z},
title = {Early-life gastric disease history and long-term cognitive risk: Evidence from a nationwide cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480573},
doi = {10.1177/13872877261480573},
pmid = {42678691},
issn = {1875-8908},
abstract = {BackgroundGastric disorders have been linked to health outcomes beyond the gastrointestinal system. However, the long-term implications of early-life gastric morbidity for aging-related outcomes remain unclear. We investigated the association between early-life gastric disorders and cognitive impairment in later adulthood, a key outcome in population aging.ObjectiveThe objective of this study is to investigate the association between a history of early-life gastric disorders and cognitive outcomes across midlife and aging.MethodsWe analyzed data from 6744 participants in the Health and Retirement Study (2006-2016). Early-life gastric disorders were defined as self-reported stomach problems before age 16. Incident cognitive impairment was identified based on self-reported physician diagnosis. Cox proportional hazards models were used to estimate risk, with adjustment for relevant covariates, and stratified analyses were conducted.ResultsEarly-life gastric disorders were associated with a higher risk of cognitive impairment (HR = 1.89; 95% CI: 1.03-3.48). Subgroup analyses indicated variation across population groups. However, the association was not statistically significant after excluding early incident casesConclusionsEarly-life gastric disorders may be linked to later cognitive impairment, although this association was sensitive to analytical assumptions and should be interpreted with caution. Further studies are needed to clarify underlying mechanisms.},
}

@article {pmid42678692,
year = {2026},
author = {Spratt, MA and Khangura, MS and Manhapra, A and Gao, A and Siegel, NH and Poulaki, V and Ness, S and Subramanian, ML},
title = {The association between retinal vascular occlusions and dementia using TriNetX.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261481012},
doi = {10.1177/13872877261481012},
pmid = {42678692},
issn = {1875-8908},
abstract = {BackgroundRetinal vascular occlusions have been associated with higher incidence of dementia and may serve as clinical indicators for underlying cognitive disease.ObjectiveThis study investigated whether retinal vascular occlusion and their subtypes are linked to increased risk of dementia, including all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD).MethodsParticipants age 65 and over were categorized into eight groups using the TriNetX global database: 1) Retinal vascular occlusion, 2) Retinal artery occlusions (RAO), 3) Retinal vein occlusions (RVO), 4) Central retinal artery occlusions (CRAO), 5) Branch retinal artery occlusions (BRAO), 6) Central retinal vein occlusions (CRVO), 7) Branch retinal vein occlusions (BRVO), and 8) No retinal vascular occlusions. Groups were propensity score matched 1:1 for demographic and clinical covariates. Outcomes include the risk of all-cause dementia, AD, and VaD, assessed using Cox proportional hazard ratios with 95% confidence intervals. Kaplan-Meier analysis evaluated time to dementia onset.ResultsThe TriNetX database identified 21,367 individuals with retinal vascular occlusion who were followed for an average of 6.29 years. Participants with retinal vascular occlusions, RVOs, or BRVOs demonstrated higher risk of all-cause dementia and VaD. There were no increased associations for retinal vascular occlusions and AD.ConclusionsRetinal vascular occlusions and RVOs were associated with an increased risk of all-cause dementia and VaD, but not AD. No associations were found with RAOs. Retinal vein occlusions may serve as a potential clinical marker for underlying neurodegenerative disease and emphasize the need for careful monitoring in patients with retinal vascular occlusions.},
}

@article {pmid42678693,
year = {2026},
author = {Zhang, Q and Zhou, Q and Yang, M and Zou, S and Li, Y and Wang, Z},
title = {Non-pharmacological interventions for sleep improvement in Alzheimer's disease: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261480066},
doi = {10.1177/13872877261480066},
pmid = {42678693},
issn = {1875-8908},
abstract = {BackgroundSleep disturbances are common in Alzheimer's disease (AD) and may worsen neuropsychiatric symptoms, caregiver burden, quality of life, and disease progression. Non-pharmacological strategies are increasingly used because long-term hypnotic or antipsychotic treatment may be limited by safety concerns, but their effects on subjective and objective sleep outcomes remain uncertain.ObjectiveTo evaluate the efficacy of non-pharmacological interventions for improving sleep in patients with AD.MethodsFollowing PRISMA guidelines, we searched PubMed, Embase, the Cochrane Library, Web of Science, and CINAHL through June 6, 2025, for randomized controlled trials of non-pharmacological interventions in AD. The primary outcome was the Pittsburgh Sleep Quality Index (PSQI); secondary outcomes were actigraphy-derived sleep efficiency, total sleep time, wake after sleep onset, number of awakenings, and time in bed. Standardized mean differences were pooled using fixed- or random-effects models. Subgroup, sensitivity, publication-bias, and meta-regression analyses were performed where appropriate.ResultsFourteen randomized controlled trials comprising 937 participants were included. Non-pharmacological interventions significantly reduced PSQI scores (SMD = -0.46, 95% CI -0.70 to -0.21). Neuromodulation-based interventions showed potentially favorable effects on PSQI, and caregiver-delivered programs such as NITE-AD modestly reduced nocturnal awakenings. No significant effects were observed for sleep efficiency, total sleep time, wake after sleep onset, or time in bed.ConclusionsNon-pharmacological interventions may modestly improve subjective sleep quality in AD, but objective sleep benefits remain limited. Larger, multicenter trials with standardized protocols, longer follow-up, harmonized subjective and objective outcomes, and AD-related biomarker assessment are needed.},
}

@article {pmid42678698,
year = {2026},
author = {Luster, CB and Nowinski, CJ and Abdolmohammadi, B and Feigel, ED and Mastrodicasa, MJ and Finegan, B and Goldstein, L and Katz, DI and Cantu, RC and Dwyer, B and Tripodis, Y and Stein, TD and Alosco, ML and McKee, AC and Mez, J and Daneshvar, DH},
title = {Neurodegenerative Disease Death Certification Among National Football League Players With Dementia.},
journal = {JAMA network open},
volume = {9},
number = {9},
pages = {e2631614},
doi = {10.1001/jamanetworkopen.2026.31614},
pmid = {42678698},
issn = {2574-3805},
mesh = {Humans ; Male ; *Dementia/mortality ; *Death Certificates ; *Football/statistics & numerical data ; *Neurodegenerative Diseases/mortality ; Aged ; Retrospective Studies ; Middle Aged ; United States/epidemiology ; *Athletes/statistics & numerical data ; Cohort Studies ; },
abstract = {IMPORTANCE: Researchers frequently use death certificate data to evaluate occupational risks among National Football League (NFL) players, demonstrating elevated neurodegenerative mortality risk. Robust epidemiologic data suggest deaths attributable to neurodegenerative disease (NDD) are frequently underreported on death certificates, leading to substantial underascertainment of neurodegenerative mortality. Better characterization of the factors underlying neurodegenerative death certification is critical to addressing underreporting of NDDs, informing disease surveillance and resource allocation.

OBJECTIVE: To elucidate clinical, exposure, and neuropathologic factors associated with neurodegenerative death certification.

This cohort study included 202 brain donors with clinician-adjudicated dementia who underwent postmortem neuropathologic assessment and retrospective clinical assessment with informants from February 15, 2008, to December 30, 2021, to ascertain clinical and lifetime exposure history. Statistical analysis was performed from October 2025 to June 2026.

EXPOSURE: NFL career.

MAIN OUTCOMES AND MEASURES: Neuropathologic diagnosis based on established diagnostic criteria, as well as informant-reported clinical measures and exposure history. Multiple logistic regression analysis was conducted to examine the association between factors and NDD death certification, adjusted for age at death, race and ethnicity, and educational level.

RESULTS: Of 202 male brain donors (mean [SD] age at death, 73.1 [10.5] years) with clinician-adjudicated dementia, 62 (30.7%) had a neurodegenerative underlying cause of death listed on their death certificate. Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Global Executive Composite T-score (odds ratio [OR], 1.04; 95% CI, 1.01-1.06), BRIEF-A Metacognition Index T-score (OR, 1.03; 95% CI, 1.01-1.06), Cognitive Difficulties Scale score (OR, 1.02; 95% CI, 1.01-1.03), and Functional Activities Questionnaire score (OR, 1.13; 95% CI, 1.06-1.21), as well as a history of emergency department treatment for head injury (OR, 4.11; 95% CI, 1.72-9.82), were associated with increased odds of neurodegenerative death certification. High Alzheimer disease neuropathology (OR, 5.27; 95% CI, 1.93-14.40), frontotemporal lobar degeneration (OR, 4.48; 95% CI, 1.61-12.50), Braak stage IV to VI (OR, 2.99; 95% CI, 1.54-5.79), frequent diffuse plaques (OR, 4.21; 95% CI, 1.56-11.38), moderate to severe neuritic plaques (OR, 3.42; 95% CI, 1.55-7.54), and Thal phase 4 (OR, 4.50; 95% CI, 1.39-14.60) were associated with increased odds of neurodegenerative death certification.

CONCLUSIONS AND RELEVANCE: This cohort study found that only 30.7% of brain donors with clinician-adjudicated dementia had neurodegenerative death certification. These results add to growing evidence of frequent NDD underascertainment where more severe disease is associated with neurodegenerative death certification, offering insight into factors that must be considered when using death certificate data to assess NDD burden. Factors such as worsened executive functioning and cognitive symptoms, greater functional impairment, and more severe neuropathology may be associated with an increased likelihood of neurodegenerative death certification among NFL players.},
}

Humans
Male
*Dementia/mortality
*Death Certificates
*Football/statistics & numerical data
*Neurodegenerative Diseases/mortality
Aged
Retrospective Studies
Middle Aged
United States/epidemiology
*Athletes/statistics & numerical data
Cohort Studies

@article {pmid42679157,
year = {2026},
author = {Knez, D and Malinak, D and Meden, A and Ferjančič Benetik, S and Pišlar, A and Kohoutova, Z and Vondrackova, I and Psotka, M and Lycka, A and Pulkrabkova, L and Soukup, O and Skarka, A and Andrys, R and Brazzolotto, X and Igert, A and Dias, J and Nachon, F and Detka, J and Targosiński, F and Hliabovich, D and Brunzelle, JS and Shuvalova, L and Sałat, K and Roy, SM and Watterson, DM and Musílek, K and Gobec, S},
title = {Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction.},
journal = {Journal of medicinal chemistry},
volume = {69},
number = {16},
pages = {19891-19917},
pmid = {42679157},
issn = {1520-4804},
support = {AG043415/AG/NIA NIH HHS/United States ; AG062095/AG/NIA NIH HHS/United States ; N42/DBS/000454//Uniwersytet Jagiellonski Collegium Medicum/ ; 2206/2025-2026//Univerzita Hradec Kr?lov?/ ; GF23-42701L//Grantov? Agentura Cesk? Republiky/ ; UHHK, 00179906//Ministerstvo Zdravotnictv? Cesk? Republiky/ ; DEC-2021/43/I/NZ7/00342//Narodowe Centrum Nauki/ ; N1-0277//The Slovenian Research and Innovation Agency/ ; P1-0208//The Slovenian Research and Innovation Agency/ ; P4-0127//The Slovenian Research and Innovation Agency/ ; NA//Univerza v Ljubljani/ ; NA//European Regional Development Fund/ ; NBC-5-C-2316//Minist?re des Arm?es/ ; BI-FR/23-24-PROTEUS-002//bilateral cooperation gran/ ; NA//Ministarstvo za visoko ?olstvo, znanost in inovacije Republike Slovenije/ ; },
mesh = {Animals ; *Butyrylcholinesterase/metabolism/chemistry ; Humans ; Mice ; *Mitogen-Activated Protein Kinase 14/antagonists & inhibitors/metabolism ; *Cognitive Dysfunction/drug therapy ; *Neuroinflammatory Diseases/drug therapy ; *Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; Structure-Activity Relationship ; Crystallography, X-Ray ; *Pyridazines/pharmacology/chemistry/therapeutic use/chemical synthesis ; Lipopolysaccharides ; Microglia/drug effects ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use ; Amnesia/drug therapy/chemically induced ; Cognitive Enhancement ; Male ; Models, Molecular ; },
abstract = {Chronic neuroinflammation and cholinergic dysfunction are major contributors to cognitive decline in Alzheimer's disease. Here, we report a series of pyridazine-based multitarget-directed ligands that simultaneously inhibit human butyrylcholinesterase (hBChE) and p38α mitogen-activated protein kinase (p38α MAPK). Pyridazines 8 and 21 were identified as potent dual inhibitors with submicromolar inhibitory potencies against target enzymes and high selectivity over acetylcholinesterase. X-ray crystallographic analyses revealed the experimental binding modes of 8 and 21 in hBChE and p38α MAPK, and identified conserved π-π, π-cation, and hinge region interactions that rationalize dual-target engagement. Both compounds were blood-brain barrier permeable, exhibited low cytotoxicity, and significantly attenuated lipopolysaccharide-induced proinflammatory responses and apoptosis in BV2 microglia. In vivo, compound 21 enhanced cognitive performance in mouse models of scopolamine-induced amnesia and LPS-stimulated neuroinflammatory cognitive impairment. Collectively, these results document the potential of structure-assisted design to achieve selective dual-target pharmacology within a single molecular entity.},
}

Animals
*Butyrylcholinesterase/metabolism/chemistry
Humans
Mice
*Mitogen-Activated Protein Kinase 14/antagonists & inhibitors/metabolism
*Cognitive Dysfunction/drug therapy
*Neuroinflammatory Diseases/drug therapy
*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis
Structure-Activity Relationship
Crystallography, X-Ray
*Pyridazines/pharmacology/chemistry/therapeutic use/chemical synthesis
Lipopolysaccharides
Microglia/drug effects
*Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use
Amnesia/drug therapy/chemically induced
Cognitive Enhancement
Male
Models, Molecular

@article {pmid42679336,
year = {2026},
author = {Wagemann, O and Nuebling, GS and Sandkühler, K and Wlasich, E and Loosli, SV and Prix, C and Stockbauer, AC and Marth, L and Forte, A and Vöglein, J and Katzdobler, S and Bernhardt, AM and Martinez-Murcia, FJ and Jiménez-Mesa, C and Höglinger, GU and Levin, J},
title = {Longitudinal Dynamics of the Blood Proteome Within the Alzheimer Spectrum in Down Syndrome.},
journal = {Neurology},
volume = {107},
number = {6},
pages = {e218494},
doi = {10.1212/WNL.0000000000218494},
pmid = {42679336},
issn = {1526-632X},
mesh = {Humans ; Female ; *Down Syndrome/blood/complications ; Male ; Longitudinal Studies ; *Alzheimer Disease/blood/complications ; Adult ; Middle Aged ; *Proteome/metabolism ; Neuropsychological Tests ; Biomarkers/blood ; Cross-Sectional Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Adults with Down syndrome (DS) have an increased risk of developing early Alzheimer disease. While our previous cross-sectional study investigated the blood proteome in the context of Alzheimer in DS, identifying CBLN4, CD14, C-X-C motif chemokine 17 (CXCL17), ectodysplasin A2 receptor (EDA2R), glial fibrillary acidic protein (GFAP), insulin-like growth factor binding protein-2 (IGFBP2), neurofilament light (NFL), SEPTIN3, and SPON1 as proteins of interest, longitudinal trajectories remain mostly unexplored. We aimed to characterize the longitudinal dynamics of these plasma proteins to evaluate their potential contribution to disease pathophysiology and associated cognitive decline.

METHODS: Adults with diagnosis of DS and ability to understand instructions of neuropsychological assessments were recruited at Ludwig Maximilians University Hospital Munich, returning for at least 1 annual follow-up visit for repeated clinical assessment, neuropsychological testing, and blood sample collection after baseline visit. Longitudinal blood protein dynamics were assessed using OLINK technology. Bayesian modeling analyzed longitudinal protein trajectories and their impact on cognitive performance. Spearman correlations of regression-derived rates of change investigated relationships between proteins and cognitive subdomains stratified by clinical diagnosis.

RESULTS: We included 59 adults with DS (46% female, median age = 32 years [interquartile range: 27-47]). All completed the first annual follow-up visit (median duration 13.37 months [12.35-20.95]), with 14 of them returning for a follow-up 2 visit (median 25.43 months [24.79-33.8]). Stratified analysis included 13 individuals with DS with (38% female, 54 years [49-58]) and 41 without diagnosis of cognitive decline (49% female, 29 years [24-35]). Cluster of differentiation 14, CXCL17, EDA2R, GFAP, IGFBP2, NFL, SEPTIN3, and SPON1 exhibited longitudinal increase, while CBLN4 decreased (all posterior distributions ≥ 99.12%), with age. Protein baseline levels were associated with cognitive decline over time while controlling for age in the whole cohort (all posterior distributions ≥ 94.75%). After correction for multiple comparisons, no longitudinal changes in protein markers exhibited a significant relationship when correlated with changes in cognitive subdomain performance within subcohorts.

DISCUSSION: In DS, longitudinal characterization of all previously identified proteins revealed distinct trajectories over time and an association of baseline levels with future cognitive decline. This suggests potential contributions of these proteins to the complex underlying pathophysiology of Alzheimer in DS and should motivate further investigation.},
}

Humans
Female
*Down Syndrome/blood/complications
Male
Longitudinal Studies
*Alzheimer Disease/blood/complications
Adult
Middle Aged
*Proteome/metabolism
Neuropsychological Tests
Biomarkers/blood
Cross-Sectional Studies

@article {pmid42679748,
year = {2026},
author = {Zhao, L and Wang, C and Zhu, Y and Xiao, Q and Tao, J},
title = {Piezo1 and Piezo2 in neurological disorders: From mechanotransduction to therapeutic potential.},
journal = {Current opinion in pharmacology},
volume = {91},
number = {},
pages = {102663},
doi = {10.1016/j.coph.2026.102663},
pmid = {42679748},
issn = {1471-4973},
abstract = {Mechanosensitive Piezo1 and Piezo2 channels convert mechanical forces into intracellular signals, playing essential roles in both physiological homeostasis and disease pathogenesis. This review synthesizes current evidence on their involvement in major neurological disorders, including stroke, Alzheimer's disease, traumatic brain injury, and glioma. Piezo1 primarily contributes to neuroinflammation, blood-brain barrier disruption, and tumor mechanosignaling, whereas Piezo2 dysfunction leads to sensory deficits, mechanical allodynia, and impaired proprioception. Notably, the functional consequences of Piezo activation are context-dependent: Piezo1 exacerbates ischemic brain damage but promotes amyloid-β clearance in Alzheimer's disease. Pharmacological modulators such as GsMTx4 and Yoda1 show promise in preclinical models, yet challenges remain regarding subtype selectivity and blood-brain barrier penetration. Targeting Piezo channels represents a promising therapeutic frontier, but success will require precise, cell-specific modulation based on disease stage and molecular context. This review highlights key pathogenic mechanisms, evaluates current pharmacological strategies, and outlines future directions for translating Piezo-targeted interventions into clinical practice.},
}

@article {pmid42679757,
year = {2026},
author = {Wang, B and Yuan, F and Zhou, W and Pan, Y},
title = {Cross-tissue multi-omics integration highlights BPHL and mitochondrial targets in Alzheimer's disease.},
journal = {Psychiatry research. Neuroimaging},
volume = {363},
number = {},
pages = {112308},
doi = {10.1016/j.pscychresns.2026.112308},
pmid = {42679757},
issn = {1872-7506},
abstract = {BACKGROUND: Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD), yet specific molecular targets remain to be fully characterized.

METHODS: A summary-data-based Mendelian randomization (SMR) framework integrated AD genome-wide association study (GWAS) statistics (39,918 cases) with blood DNA methylation quantitative trait loci (mQTL), gene expression (eQTL), and protein (pQTL) data for 1136 mitochondria-related genes. Associations were assessed using Bayesian colocalization and HEIDI testing. Tissue relevance was evaluated in four brain regions (hippocampus, amygdala, cortex, frontal cortex) using GTEx and external transcriptomic datasets.

RESULTS: Screening identified eight candidates supported across blood mQTL and eQTL layers. Stepwise central nervous system (CNS) evaluation singled out biphenyl hydrolase-like (BPHL) as the consistent candidate. Higher genetically predicted BPHL expression was associated with reduced AD risk across the hippocampus (OR=0.920, 95% CI 0.873-0.970), amygdala (OR=0.925, 95%CI 0.880-0.973), cortex (OR=0.943, 95% CI 0.908-0.978), and frontal cortex (OR=0.938, 95%CI 0.901-0.976). These findings aligned with protein-protein interactions connecting BPHL to respiratory complexes and lower BPHL expression in independent AD brains. Functional enrichment converged on oxidative phosphorylation pathways.

CONCLUSIONS: By integrating multi-omics data with tissue-specific validation, this study nominates BPHL as a consistent protective candidate in the brain. These findings provide genetic support for mitochondrial molecular perturbations in AD, offering insights for future validation.},
}

@article {pmid42679930,
year = {2026},
author = {Kılınç, S and Yılmaz, ŞG and Bozkurt, AS and Balcı, SO},
title = {Bovine lactoferrin can reduce Aβ /TAU accumulation in two major pathological Alzheimer's Disease rat models.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116453},
doi = {10.1016/j.bbr.2026.116453},
pmid = {42679930},
issn = {1872-7549},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline. Bovine lactoferrin (bLf) is an iron-binding protein with immunomodulatory effects both in the intestine and throughout the body. In this study, the potential therapeutic effects of bLf were evaluated using two different rat models that mimic key aspects of AD pathology.

METHOD: Forty-two female Wistar albino rats (10-12 weeks old, weighing 200-250g) were included in the study and randomly assigned to 7 groups of 6 rats each. The groups were: 1- Control, 2- Phosphate-buffered saline (PBS), 3- bLf, 4- Colchicine (COL) (for the TAU model), 5- Okadaic acid (OKA) (for the Aβ model), 6- COL + bLf, 7- OKA + bLf. Cognitive deficits were tested using the Morris Water Maze (MWM). Motor coordination and anxiety levels were assessed using the OFT. Following these assessments, cerebrospinal fluid (CSF), hippocampal tissue, serum, and whole blood samples were collected. Aβ, TAU, Ferritin, TAS, and TOS levels in these samples were measured using ELISA. For genetic modulation, the gene expression patterns of Fpn, Bax, Bcl-2, p38, FoxO, and GSK-3β were analyzed by quantitative Real-Time PCR (qRT-PCR).

RESULTS: bLf reduced oxidative stress. Decreases in Aβ and TAU levels were observed in the hippocampus and CSF. Ferritin levels were relatively lower in the hippocampus, CSF, and serum. Fpn and Bcl-2 were downregulated in the hippocampus of AD models but upregulated after bLf treatment. Expression levels of Bax, p38, FoxO, and GSK-3β were also downregulated following bLf administration.

CONCLUSION: These findings were consistent across both models. Overall, bLf holds promise as a therapeutic candidate capable of simultaneously targeting two key pathological features of AD.},
}

@article {pmid42679987,
year = {2026},
author = {Lin, J and Wang, Z and Liu, C and Hua, Y and Li, S},
title = {Osmolytes suppress liquid‒liquid phase separation and the aggregation of Tau.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.08.019},
pmid = {42679987},
issn = {1638-6183},
abstract = {Tau liquid-liquid phase separation (LLPS) is increasingly recognized as an early event that promotes pathological aggregation in Alzheimer's disease and other tauopathies. Osmolytes are natural chemical chaperones that stabilize protein conformations, yet their effects on Tau phase behavior remain poorly understood. Here, we show that sucrose, trehalose, glucose, maltose, and betaine suppress Tau LLPS and dissolve preformed Tau droplets, shifting the equilibrium toward soluble monomers in vitro. Among the five osmolytes, trehalose and glucose exhibited the strongest inhibitory effects on Tau LLPS. They also suppressed the liquid-to-solid phase transition of Tau droplets, as evidenced by reduced Thioflavin T (ThT) fluorescence, inhibition of fibril formation observed by transmission electron microscopy (TEM), and improved condensate dynamics in fluorescence recovery after photobleaching (FRAP) assays performed in okadaic acid-treated cells. These results indicate that osmolytes interfere with multiple stages of Tau phase transition-from initial condensate formation to pathological maturation and fibrillization. Our findings establish osmolytes as effective modulators of Tau phase behavior and provide mechanistic insights into the physicochemical regulation of Tau phase transitions.},
}

@article {pmid42680070,
year = {2026},
author = {Wang, J and Luo, L and Zhang, J and Yu, L and Cui, L},
title = {The Gut Microbiota and Gut-Brain Axis in Alzheimer's Disease: From Pathogenesis to Treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103345},
doi = {10.1016/j.arr.2026.103345},
pmid = {42680070},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose pathological course involves amyloid-β (Aβ) deposition, tau abnormalities, neuroinflammation, and neurovascular dysfunction. Interest in the microbiota-gut-brain axis does not arise because gut dysbiosis has been established as an independent initiating cause of sporadic AD, but because this axis connects modifiable peripheral factors-including diet, medication, ageing, and intestinal physiology-with barrier homeostasis, immunometabolic state, neural afferent signaling, and the brain's response to pathology. Human studies have detected microbiota differences in biomarker-positive preclinical AD and suggest that barrier abnormalities may be associated with subsequent cognitive change; patient-derived microbiota transfer, APOE-dependent tau models, and immune-vagal circuit studies further support phenotype modifiability under defined experimental conditions. This review therefore integrates barrier, immune, metabolic, and neural pathways and emphasizes that diverse microbial alterations may converge on a limited set of measurable functional nodes that could be more informative than individual genera for mechanistic validation, risk stratification, and treatment monitoring. Although clinical intervention evidence remains at an early stage, the peripheral accessibility and modifiability of the microbiota provide a rationale for investigating it as an adjunctive target alongside standard AD therapy. Future work should concurrently evaluate the microbiome, metabolites, both barriers, and immune and neural readouts in longitudinal cohorts and stratified randomized trials to determine which patients, disease stages, and intervention modalities are most likely to benefit.},
}

@article {pmid42680107,
year = {2026},
author = {Suh, EC and Kim, YA and Lee, KE and Park, EM},
title = {Aβ-induced CaMKII hyperactivation is associated with impaired lysosomal maturation and mitophagy.},
journal = {Neurochemistry international},
volume = {200},
number = {},
pages = {106252},
doi = {10.1016/j.neuint.2026.106252},
pmid = {42680107},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ)-associated synaptic failure, intracellular Ca[2+] dysregulation, and progressive impairment of lysosome-dependent clearance pathways. Aβ induces sustained Ca[2+] overload, resulting in pathological hyperactivation of CaMKII, which normally participates in the regulation of autophagy. However, whether CaMKII hyperactivation contributes to Aβ-induced late-stage autophagy-lysosomal dysfunction and mitophagy failure remains unclear. This study aimed to examine the effects of the CaMKII inhibitor KN93 in Aβ25-35-exposed rat organotypic hippocampal slice cultures (OHSCs, ex vivo model) and the mouse brain in vivo. The results showed that Aβ25-35 induced intracellular Ca[2+] elevation, CaMKII hyperactivation, and marked accumulation of LC3-II and p62. Ultrastructural and biochemical analyses revealed impaired lysosomal maturation, defective autophagosome-lysosome coupling, and accumulation of autophagic vacuoles, consistent with a blockade of late-stage autophagic flux. Increased levels of immature cathepsin D and reduced colocalization of LC3 with lysosomal markers further supported compromised lysosomal competence. Damaged mitochondria were recruited to lysosomal compartments but failed to undergo effective degradation, indicating abortive mitophagy under Aβ25-35 exposure. KN93 attenuated Aβ25-35-induced defects in lysosomal protease maturation, autophagosome-lysosome fusion, and mitochondrial clearance in both the ex vivo OHSCs model and the in vivo mouse brain. KN93 also ameliorated cognitive impairment in Aβ25-35-exposed mice. Taken together, these findings indicate that CaMKII hyperactivation contributes to Aβ25-35-induced autophagy-lysosomal dysfunction and neuronal damage, and that pharmacological inhibition of CaMKII with KN93 restores intracellular degradative capacity and ameliorates cognitive impairment under Aβ stress.},
}

@article {pmid42680110,
year = {2026},
author = {Nie, T and Li, J and Tan, S and Chen, S and Yang, D and Nepovimova, E and Wu, Q and Kuca, K},
title = {T-2 Toxin Disrupts Alzheimer's-relevant App/Tau Homeostasis via Circadian-p53-Senescence Crosstalk: Evidence from Human Neuroblastoma Cells.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103559},
doi = {10.1016/j.neuro.2026.103559},
pmid = {42680110},
issn = {1872-9711},
abstract = {Environmental mycotoxins are pervasive exposures, yet how they perturb Alzheimer's disease (AD)-relevant proteostasis remains unclear. We treated SH-SY5Y cells with low-dose T-2 toxin (6nM) for 24h, and profiled AD-relevant protein changes alongside transcriptomic, circadian, and senescence-related readouts. We report that T‑2 toxin remodels APP and Tau homeostasis, featuring an early decrease in full‑length APP and a delayed, sustained increase in Tau phosphorylation and total Tau, accompanied by dynamic cytokine release. RNA‑seq at 12h revealed a p53‑centered stress response and enrichment of circadian‑related pathways. Cosinor analysis indicated that CLOCK rhythmicity is preserved but reparameterized following T-2 toxin exposure, with a marked phase shift and an elevated mesor. Pharmacological disruption of CLOCK attenuated p53 induction and Tau elevation, whereas inhibition of p53 partially restored APP and reduced Tau changes while reshaping CLOCK abundance and localization, consistent with CLOCK-p53 cross‑regulation. T‑2 toxin also induced a time‑dependent senescence‑like phenotype that was attenuated by CLOCK and/or p53 inhibition. Post‑treatment with senolytic drugs dasatinib and quercetin reduced SA‑β‑gal burden, dampened p53 signaling, and improved the APP/Tau profile. Together, these data link T‑2 toxin exposure to AD‑relevant proteostasis remodeling through a CLOCK-p53-senescence axis and suggest circadian and senescence‑targeting strategies as complementary intervention points.},
}

@article {pmid42680479,
year = {2026},
author = {Jeon, J and Yu, J and Lee, SB and Seo, J},
title = {Alzheimer's disease through the lens of mesenchymal drift: the collapse of cellular identity.},
journal = {BMB reports},
volume = {},
number = {},
pages = {},
pmid = {42680479},
issn = {1976-670X},
abstract = {Cellular identity is maintained by precise epigenetic regulation, but chronic stress and aging can disrupt this control, leading to mesenchymal drift (MD). Unlike the coordinated process of epithelial-mesenchymal transition (EMT), MD is a stochastic, lineage-independent phenomenon marked by increased epigenetic noise and the widespread activation of profibrotic gene programs. As originally defined, MD requires two components to co-occur: a compromised original cellular identity together with the acquisition or intensification of mesenchymal traits. Applying the MD framework to Alzheimer's disease (AD) provides a new perspective on its pathogenesis. In AD, brain cells do not merely survive or die due to protein toxicity; instead, they lose their specialized identities in an uncoordinated fashion. This transcriptomic drift has been reported across major cell types in the central nervous system: neural progenitor cells differentiate prematurely, mature neurons undergo transcriptomic dedifferentiation, endothelial cells develop features of vascular fibrosis, and glial cells lose their homeostatic functions. Direct enrichment of the MD signature in the AD brain, however, has so far been demonstrated only in astrocytes, oligodendrocytes, and pericytes, and, in our own reanalysis, in human-induced pluripotent stem cell (hiPSC)-derived neural progenitor cells carrying an APP mutation; we distinguish this evidence from observations documenting identity loss or a reactive state alone. We further caution that the novel cell populations identified in recent single-cell transcriptomic studies should not be assumed to represent genuinely new cell types: such clusters may equally reflect a blurring of existing cell lineages, or technical artifacts that produce the same appearance. A drifting transcriptomic profile also does not always signify a corresponding physiological change. These possibilities warrant careful attention, and we therefore emphasize the critical need to integrate transcriptomic data with in vivo functional and morphological validation. This integration is essential to determine whether these identity shifts contribute to AD progression or merely reflect underlying epigenetic instability.},
}

@article {pmid42680853,
year = {2026},
author = {Korukonda, A and Blankenship, HE and Kam, K and Kour, D and Espinosa-Garcia, C and Jang, WE and Srivastava, U and Mulvey, B and Tish, MM and Witztum, R and Ramelow, CC and Pate, BS and Liles, LC and Lu, L and Atallah, J and Guo, E and Martinowich, K and Sharpe, AL and Varga, AW and Rangaraju, S and Beckstead, MJ and Weinshenker, D},
title = {Pathogenic tau in the mouse locus coeruleus produces noradrenergic hyperactivity and neuropsychiatric phenotypes reminiscent of early Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42680853},
issn = {1476-5578},
support = {AG079199//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG062581//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG081046//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG066511//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG079620//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG090054//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG066511//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG087922//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG093578//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG066870//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG088736//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG075820//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG079199//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; NS096050//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS135830//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; F32DA061631//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; AARG-22-928739//Alzheimer's Association/ ; ES037434//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; },
abstract = {Alzheimer's disease (AD), though defined as a cognitive disorder, often presents neuropsychiatric symptoms such as anxiety, depression, agitation, and sleep disruptions years before the onset of frank memory impairment. An early pathological feature is the accumulation of hyperphosphorylated "pretangle" tau (pTau) in the locus coeruleus (LC), the brain's primary source of norepinephrine (NE). While clinical studies link LC pTau burden to behavioral abnormalities, mechanisms underlying these phenomena remain unclear. We developed a translationally-relevant mouse model that recapitulates the 'LC-first' pattern using cell type-specific viral expression of pathogenic P364S mutant human tau in LC neurons. Three months post-infusion, pTau accumulation induced anxiety- and compulsive-like behaviors and reduced sleep spindles without altering overall sleep architecture. Consistent with the behavioral phenotypes, electrophysiological recordings revealed significant increases in spontaneous and evoked firing of LC neurons, accompanied by robust astrocytic reactivity with no apparent cell death. Transcriptomic analysis identified upregulation of Hcn2 and downregulation of Clic6, suggesting changes in neuronal excitability. To further define molecular mechanisms, we developed a cell type-specific proteomics approach, which showed synaptic and metabolic alterations associated with LC-specific tau pathology. While pTau burden persisted at 6 and 9 months after viral infusion, the anxiety-like behaviors observed at 3 months abated at these later timepoints. These findings demonstrate that pTau triggers phenotypes reflective of LC-NE hyperactivity in the early stages of AD pathogenesis, with implications for future noradrenergic-based interventions to address neuropsychiatric manifestations.},
}

@article {pmid42680904,
year = {2026},
author = {Yu, J and Li, F and Chen, XJ and Mou, C and Yao, D and Bi, Z and Chen, X and Du, L and Feng, Z and Zhang, X and Yu, X and Zacharias, LG and DeBerardinis, RJ and Zhang, L and Li, Z and Luo, B and Hu, XL and Ge, WP},
title = {Author Correction: Characterizing the metabolomes of microglia, astrocytes and neurons in ageing and Alzheimer's brains.},
journal = {Nature cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41556-026-02078-5},
pmid = {42680904},
issn = {1476-4679},
}

@article {pmid42680930,
year = {2026},
author = {Ballard, C and Doherty, P and Ismail, Z and Corbett, A and Cummings, JL},
title = {Symptomatic treatment for Alzheimer disease: current evidence and future directions.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {42680930},
issn = {1759-4766},
abstract = {Symptomatic treatment remains central to the clinical management of Alzheimer disease (AD), even as disease-targeted therapies emerge. This Review synthesizes current evidence for pharmacological and non-pharmacological symptomatic therapies targeting cognition, function and neuropsychiatric symptoms in AD. Non-pharmacological interventions, including cognitive training, physical exercise, cognitive stimulation therapy and multimodal lifestyle programmes, show small-to-moderate benefits, particularly in mild cognitive impairment, although implementation challenges persist. Established pharmacological treatments, notably cholinesterase inhibitors and memantine, deliver modest but significant benefits, with biomarker-stratified analyses suggesting the greatest benefit in individuals with confirmed AD pathology. Advances in muscarinic agonists, multitarget agents, neurotrophic modulators and repurposed drugs highlight emerging opportunities for broader symptomatic benefit. Neuropsychiatric symptoms remain highly prevalent and burdensome; personalized psychosocial interventions demonstrate meaningful reductions in agitation and depression, whereas atypical antipsychotics offer only modest efficacy with substantial safety concerns. Newer agents, including brexpiprazole for agitation and pimavanserin for psychosis, show promise but require careful interpretation of effect size and safety. Future progress will depend on biomarker-informed patient selection, integration of circuit-level measures, rational combination strategies spanning pharmacological and non-pharmacological modalities, and adoption of patient-centred outcomes. Symptomatic therapies will remain essential for improving quality of life in people with AD, even as disease-targeted therapies reshape disease trajectories.},
}

@article {pmid42680958,
year = {2026},
author = {Begum, MY and Rajkumar, M and Govindaraj, P and Prathap, N and Sudha, PN and Al Hamod, M and Alotaibi, H and Uvarajan, D},
title = {Curcumin nanoformulations for modulating neuroinflammation and oxidative stress in Alzheimer's disease: blood-brain barrier transport, formulation strategies and therapeutic applications.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42680958},
issn = {1568-5608},
support = {RGP2/5/47//King Khalid University/ ; },
abstract = {Alzheimer's disease (AD) remains a major therapeutic challenge owing to its complex and multifactorial pathogenesis, as well as the limited clinical efficacy of conventional therapeutics caused by poor pharmacokinetic properties, rapid systemic clearance, and restricted transport across the blood-brain barrier (BBB). Curcumin, a naturally derived polyphenolic compound, has gained considerable attention as a potential therapeutic agent for AD due to its broad neuroprotective and disease-modifying properties. Curcumin has been reported to inhibit amyloid-β (Aβ) aggregation and fibril formation, destabilize preformed amyloid plaques, suppress tau protein aggregation, reduce oxidative stress-induced neuronal damage, preserve mitochondrial integrity, modulate metal ion-induced neurotoxicity, and protect neuronal cells against apoptosis. Despite these promising therapeutic effects, the clinical translation of curcumin remains significantly limited by poor aqueous solubility, low chemical stability, rapid metabolism, limited systemic bioavailability, and insufficient BBB permeability. This review critically summarizes recent advances in curcumin-based nanocarrier systems for brain-targeted delivery in AD, with particular emphasis on pharmaceutical formulation strategies, physicochemical characterization, encapsulation efficiency, controlled drug release, colloidal stability, and preclinical therapeutic performance. Particular attention is given to the ability of curcumin nanoformulations to modulate neuroinflammatory pathways, including microglial activation, pro-inflammatory cytokine production, oxidative stress, and NLRP3 inflammasome signaling, which are central contributors to AD progression. This review focuses on polymeric nanoparticles, liposomes, nanoemulsions, and biomimetic nanoplatforms engineered to enhance BBB transport and improve brain biodistribution. Collectively, nanocarrier-mediated curcumin delivery represents a promising pharmaceutical strategy to improve brain-specific bioavailability and enable effective multitarget therapeutic intervention in AD.},
}

@article {pmid42680959,
year = {2026},
author = {Schloss, JV and Nguyen, T},
title = {The lithium-magnesium-zinc axis under stress: regulation of N-glycosylation-linked proteostasis and Alzheimer's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42680959},
issn = {1568-5608},
abstract = {Inflammation resulting from the unfolded protein response to glycosylation dysfunction may be the key driver in the progression of Alzheimer's disease. Stress increases the risk of Alzheimer's disease, in part, by depleting essential cofactors required by enzymes involved in N-glycosylation (the first and third, second, fourth, and fifth enzymes-essential cofactors required for dolichol diphosphate-sugar conjugate synthesis are, respectively: DHRSX-NAD/NADPH, SRD5A3-NADPH, DOLK-Zn[2+], and DPAGT1-Mg[2+]). Lithium reduces the risk of Alzheimer's disease by: (1) increasing transcription of DPAGT1, the gene for the first committed enzyme of N-glycosylation, stimulating levels of β-catenin through glycogen synthase kinase 3-β (GSK-3β) inhibition; (2) increasing transcription of SRD5A3, DHRSX, and DOLK, the genes for the enzymes of dolichol phosphate synthesis, stimulating levels of transcription factors through GSK-3β inhibition; and (3) inositol monophosphatase (IMPase) inhibition-increased autophagy clearance of amyloid produced by N-glycosylation pathway dysfunction. Together, lithium, magnesium, and zinc constitute a regulatory axis for protein N-glycosylation, in which lithium levels determine the threshold for pathology during magnesium and zinc depletion under stress. Magnesium is also required by the oligosaccharyltransferase complex, which catalyzes the conversion of dolichol-pyrophosphate-GlcNAc2-Mana9-Glc3 and a protein asparaginyl residue to an N-glycosylated protein and dolichol-pyrophosphate. Stress-induced Mg[2+] deficiency impairs the oligosaccharyltransferase complex by affecting MAGT1 (magnesium transporter 1) and the STT3A component, resulting in N-glycan defects and hypoglycosylation. Endoplasmic reticulum stress, resulting from the unfolded protein response, stimulates N-glycan branching (bisected N-glycans) and hyperglycosylation due to the effect on TUSC3 (a regulator of Mg[2+] influx) and the STT3B component of the oligosaccharyltransferase complex.},
}

@article {pmid42681024,
year = {2026},
author = {Kapadia, A and Schuhmann, F and Daskin, E and Walter, J and Lindahl, I and Rahmani, N and Morrema, THJ and Rozemuller, AJM and Boon, BDC and Pezeshkian, W and Hafner, AS},
title = {Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer's disease.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {},
pmid = {42681024},
issn = {1460-2075},
support = {101076961//EC | Horizon 2020 Framework Programme (H2020)/ ; NNF18SA0035142 & NNF22OC0079182//KU | Novo Nordisk Foundation Center for Protein Research, University of Copenhagen (CPR)/ ; 10.46540/2064-00032B//Independent Research Fund Denmark/ ; },
abstract = {The study of Alzheimer's disease (AD)-associated mutations has implicated dysregulation of amyloid precursor protein (APP) proteolysis in the disease. Brain recordings have revealed synaptic hyperexcitation during asymptomatic and early stages of AD, reverting to overinhibition as dementia progresses. Here, we show that endogenous APP and its proteolytic C-terminal fragments (APP-CTFs), the precursors of amyloid-β (Aβ), are enriched at excitatory synapses. Pharmacological modulation of endogenous APP metabolite levels suggests a role for APP-CTFs, in particular APP-CTFβ, in regulating glutamatergic synaptic transmission. Presynaptic accumulation of APP-CTFβ promotes its oligomerization, increases synaptic vesicle docking, and causes vesicle release defects, accompanied by enhanced neuronal network activity. Examination of post-mortem AD patient brains yields consistent results, namely, elevated APP-CTFβ levels at synaptic compartments and enlarged excitatory presynaptic boutons. Strikingly, acute application of Aβ preparations enriched in monomeric species counteracts APP-CTFβ-induced hyperexcitability. Our findings indicate a role for presynaptic APP-CTFβ in modulating excitatory synaptic function and network activity, suggesting that amyloidogenic APP processing intermediates may contribute to early synaptic alterations in Alzheimer's disease.},
}