@article {pmid42818491,
year = {2026},
author = {Bao, R and Zhang, S and Wang, F and Cheng, W and Zhang, T and Ding, W},
title = {MRI-derived periventricular diffusivity contextualizes plasma pTau217 associations with Alzheimer pathology: a discovery-validation study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42818491},
issn = {2693-5015},
support = {P41 EB015922/EB/NIBIB NIH HHS/United States ; R01 AG054073/AG/NIA NIH HHS/United States ; R01 AG070862/AG/NIA NIH HHS/United States ; U19 AG078109/AG/NIA NIH HHS/United States ; R01 AG058533/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Plasma phosphorylated tau 217 (pTau217) is a promising scalable marker of Alzheimer pathology, but discordance with positron emission tomography (PET) limits context-free interpretation. We tested whether magnetic resonance imaging (MRI)-derived periventricular diffusivity (PVeD) modifies associations between pTau217 and Alzheimer pathology.

METHODS: In this observational discovery-validation study, standardized pTau217 × PVeD interactions were tested for amyloid PET, tau PET, structural and vascular MRI, and cognitive outcomes in 602 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 2,313 participants from the Health and Aging Brain Study-Health Disparities (HABS-HD). Analyses were adjusted for prespecified covariates and false discovery rate correction.

RESULTS: In ADNI, pTau217 associations with amyloid Centiloid (interaction β = -0.096, 95% confidence interval [CI] - 0.154 to - 0.037; adjusted P = .018) and meta-temporal tau PET (β = -0.092, 95% CI - 0.158 to - 0.027; adjusted P = .018) were stronger at lower PVeD. Among participants with high pTau217, low PVeD was associated with faster cognitive decline than high PVeD (difference = - 0.100 Preclinical Alzheimer Cognitive Composite [PACC] units/year, 95% CI - 0.161 to - 0.038; adjusted P = .002). HABS-HD replicated the amyloid interaction (β = -0.109, 95% CI - 0.147 to - 0.070; adjusted P < .001) and multiple tau PET interactions; the high-pTau217/low-PVeD profile also declined faster (difference = - 0.037 PACC units/year; adjusted P = .002).

CONCLUSIONS: PVeD reproducibly contextualized associations between plasma pTau217 and PET-defined Alzheimer pathology across cohorts with different participant composition, pTau217 assays, PET tracers, and cognitive measures. The findings motivate prospective evaluation of MRI-informed interpretation of blood biomarkers, but PVeD is an indirect diffusion marker and the observational design does not establish mechanism, clinical utility, or decision thresholds.},
}

@article {pmid42818507,
year = {2026},
author = {Baumel, J and Lutz, M and Ding, C and Capal, J and Ritter, D and Krueger, D and Salter, A and Werner, K and Liu, AJ},
title = {Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.09.26362677},
pmid = {42818507},
abstract = {BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function mutations in TSC1 or TSC2 , resulting in chronic hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. TSC patients experience a wide spectrum of cognitive, behavioral, and psychiatric features collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND). Moreover, these patients develop a clinical trajectory in adulthood with clinical and neuropathological features overlapping those of Alzheimer's disease (AD). Prior neuropathological studies have shown accumulation of AD-type mixed 3R/4R tau isoforms in adults with TSC that is amyloid-independent.

METHODS: To further explore the biological convergence of TSC and AD, this study compared plasma levels of phosphorylated tau-217 (ptau-217), a sensitive and specific marker of early AD pathology, in 63 TSC, 25 AD, and 116 cognitively unimpaired (CU) patients.

RESULTS: Findings revealed elevated levels of plasma ptau-217 in individuals with TSC at younger ages with a parallel age-related trajectory between TSC, AD, and CU cohorts. Multivariable linear regression showed that the log 2 ptau-217 concentrations were significantly lower in the CU cohort relative to TSC (β = -0.21, SE = 0.05, p < 0.0001) but were not significantly different between the TSC and AD cohorts (β = 0.17, SE = 0.09, p < 0.071). The comparison of slopes analysis (ANCOVA) supported that the slopes for the regression of log 2 ptau-217 versus age are not significantly different for the TSC and CU cohorts (TSC slope = 0.030, SE = 0.008; CU slope = 0.019, SE = 0.006; p = 0.26), nor for the TSC and AD cohorts (TSC slope = 0.030, SE = 0.01; AD slope = 0.06, SE = 0.03; p = 0.099).

CONCLUSIONS: These results suggest a novel link between TSC and AD that substantiates shared downstream neurodegenerative pathways. Furthermore, these results support the potential utility of ptau-217 as a minimally invasive biomarker for TAND severity, neurodegenerative risk, and AD-like prognosis in TSC and as a tool to guide new mTOR-targeted therapeutic strategies.},
}

@article {pmid42818509,
year = {2026},
author = {Kim, H and Zang, C and Lee, J and Haddad, E and Park, G and Zhang, J and Kim, J and Choi, K and Chai, Y and Irimia, A and Rajagopalan, P and Moon, WJ and Shi, Y and Yang, HJ and Toga, A and Jahanshad, N},
title = {Tissue- and compartment-resolved brain age reveals vascular-metabolic and neurodegenerative aging.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42818509},
issn = {2693-5015},
support = {R01 NS134712/NS/NINDS NIH HHS/United States ; R01 EB032169/EB/NIBIB NIH HHS/United States ; RF1 AG084072/AG/NIA NIH HHS/United States ; P41 EB015922/EB/NIBIB NIH HHS/United States ; R01 NS114382/NS/NINDS NIH HHS/United States ; },
abstract = {Brain aging reflects heterogeneous vascular-metabolic and neurodegenerative processes, yet brain age is often reduced to a gray matter (GM)-dominant estimate. Emerging evidence suggests that subtle "dirty-appearing" T2-FLAIR abnormalities may mark diffuse white matter (WM) vulnerability that precedes or extends beyond overt WM hyperintensities (WMH). Here we developed a compartment-resolved framework integrating T1-weighted GM features with unthresholded T2-FLAIR WM signal across depth- and lobe-specific surfaces. In 26,446 UK Biobank and 992 ADNI participants, WM brain age captured variation beyond WMH burden and was preferentially associated with cardiometabolic risk before age 65; periventricular WM age statistically linked cardiometabolic burden to cognition. Across the Alzheimer's disease continuum, GM and WM brain age increased with diagnostic severity but showed distinct molecular associations: GM aging aligned more closely with amyloid burden, whereas WM aging showed prominent tau associations. These findings reveal complementary vascular-metabolic and neurodegenerative dimensions of brain aging obscured by global brain age estimates.},
}

@article {pmid42818529,
year = {2026},
author = {Shao, M and Banerjee, D and Paul, A and Girirajan, S and Lüscher, B},
title = {Transcriptome changes of disinhibited somatostatin neurons in the medial prefrontal cortex mediating male-specific stress resilience.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42818529},
issn = {2693-5015},
support = {R01 MH099851/MH/NIMH NIH HHS/United States ; },
abstract = {Somatostatin (SST)-expressing interneurons are critical modulators of vulnerability to chronic stress and are strongly implicated in the pathophysiology of stress-related affective disorders. Consistent with this role, we have recently demonstrated that selective enhancement of SST neuron activity-achieved via cell type-specific Cre-mediated inactivation of GABAA receptors (SSTCre:γ2[f/f] mice)-robustly promotes resilience to chronic variable stress (CVS) at the behavioral and tissue transcriptomic levels. Notably, the neural substrate underlying this resilience is sex-specific: in males, it localizes to the medial prefrontal cortex (mPFC), whereas in females it maps to the ventral hippocampus. Building on these findings, we sought to define the SST neuron-specific transcriptomic and biological properties associated with stress resilience in male mice. We compared purified SST neurons from the mPFC of stress-vulnerable (SSTCre) and stress-resilient (SSTCre:γ2[f/f]) male mice, using corresponding female mice as negative controls. Our analyses reveal a striking, sex-specific transcriptomic resilience phenotype. Specifically, we found that the transcriptome of mPFC SST neurons from male-but not female-SSTCre:γ2[f/f] mice exhibits marked resistance to CVS-induced perturbations. In male SSTCre:γ2[f/f] mice, SST neurons displayed a substantially reduced number of differentially expressed genes (DEGs) following CVS exposure, along with a loss of correlation of stress-induced transcriptional changes relative to SSTCre littermates. In contrast to males, SST neurons from the mPFC of female SSTCre:γ2[f/f] mice exhibited an increased number of CVS-responsive DEGs and a transcriptomic profile that was inversely correlated with that of SSTCre controls. In agreement with these transcriptomic changes, gene set enrichment analyses identified markedly fewer CVS-responsive biological functions in the resilient male mice compared to their vulnerable littermates. Normalized enrichment scores for gene ontology summary terms indicated that SST neurons from male SSTCre:γ2[f/f] mice are protected from CVS-induced downregulation of gene sets governing neural cell fate, apoptosis, and cell adhesion, and exhibit partial resilience to CVS-induced disruptions in mitogen-activated protein kinase signaling and cytoskeletal organization. By contrast, SST neurons from the female SSTCre mice showed no measurable CVS-induced alterations in these same gene programs. Collectively, these findings provide compelling evidence that the male-specific, SST neuron-intrinsic resilience mechanisms within the mPFC are key determinants of the previously described tissue-level and behavioral stress resilience phenotypes in SSTCre:γ2[f/f] mice.},
}

@article {pmid42818533,
year = {2026},
author = {You, Y and Nguyen, SN and Mann, SD and Vadakattu, P and Kanekiyo, T and Zhang, Z and Ray, NB and Duong, A and Tuck, T and Tcw, J and Goate, AM and Karch, CM and Shaffer, SA and Ikezu, S and Gonzalez-Perez, MP and Poon, WW and Ikezu, T},
title = {Human iPSC models reveal APOE4-induced microglial remodeling and extracellular vesicle dysregulation in AD pathogenesis.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42818533},
issn = {2693-5015},
support = {P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG067763/AG/NIA NIH HHS/United States ; R01 AG066429/AG/NIA NIH HHS/United States ; R01 AG054672/AG/NIA NIH HHS/United States ; R01 AG072719/AG/NIA NIH HHS/United States ; R01 AG054199/AG/NIA NIH HHS/United States ; R01 AG079859/AG/NIA NIH HHS/United States ; R01 AG083941/AG/NIA NIH HHS/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; R01 AG082362/AG/NIA NIH HHS/United States ; },
abstract = {The apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet the mechanistic underpinnings by which it alters human microglial function remain poorly understood. Here, we utilize CRISPR/Cas9-engineered isogenic human induced pluripotent stem cell-derived microglia-like cells (iMGs) expressing APOE3 or APOE4 to systematically interrogate genotype-dependent effects on microglial proteomes and their secreted extracellular vesicles (EVs) under basal and fibrillar amyloid-β (fAβ)-challenged conditions. Quantitative proteomics revealed that APOE4 iMGs exhibit downregulated RNA processing, impaired phagocytosis, and exacerbated pro-inflammatory signaling, particularly upon fAβ exposure. Functionally, APOE4 iMGs demonstrated increased NF-κB activation, enhanced neuronal apoptosis and tau pathology in 2D and 3D co-culture systems. Interestingly, APOE4 iMGs released greater amount of EVs enriched in proteasomal components over APOE3 iMG. Integrated proteomic analyses further highlighted APOE4-specific selective packaging of EV cargo linked to neuron-glia communication, inflammatory signaling, and proteostasis dysregulation, suggesting a potent, non-cell-autonomous mechanism driving neuronal damage. Consistently, these APOE4 iMGEVs were preferentially internalized by neurons, leading to disrupted neuronal proteostasis, impaired neuronal firing, and increased tau phosphorylation, particularly under pathological stress. Notably, pharmacologic inhibition of NF-κB in APOE4 iMGs reduced EV cargo-loading of proteasomal molecules and mitigated iMGEV-driven neuronal dysfunction and tau pathology. These findings establish a mechanistic link between APOE4, dysregulated microglial homeostasis, and microglial EV-mediated propagation of proteostatic dysfunction and neurodegeneration, advancing our understanding of how APOE4 contributes to AD pathogenesis.},
}

@article {pmid42818556,
year = {2026},
author = {Sharma, P and Devappa, R and Saroja, SR},
title = {Hippocampal/medial temporal sclerosis is associated with clinical severity, regional TDP-43, and hippocampal atrophy in Alzheimer disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.03.749099},
pmid = {42818556},
issn = {2692-8205},
abstract = {Alzheimer disease neuropathologic change (ADNC) does not fully explain clinical severity, suggesting important contributions from coexisting pathologies. We examined major co-pathologies in a multicenter autopsy cohort, focusing on hippocampal/medial temporal sclerosis (HS/MTL sclerosis), clinical severity, regional TDP-43 topography, clinical status near death, and gross hippocampal atrophy. We analyzed longitudinal clinical and neuropathology data from the National Alzheimer's Coordinating Center autopsy cohort. Form-specific definitions harmonized AD pathology, major co-pathologies, HS/MTL sclerosis, and regional TDP-43 findings across neuropathology versions 8-10. HS/MTL sclerosis was present in 13.0% of assessed AD cases and was associated with greater CDR® Dementia Staging Instrument sum-of-boxes severity in non-AD (odds ratio [OR], 4.93; 95% confidence interval [CI], 3.66-6.63) and AD strata (OR, 2.56; 95% CI, 2.15-3.04). In version 10, HS/MTL sclerosis was associated with higher regional TDP-43 topography (OR, 6.54; 95% CI, 3.88-11.02) and greater gross hippocampal atrophy (OR, 6.43; 95% CI, 4.97-8.32). Among AD cases assessed within 2 years of death, HS-negative participants had greater odds of non-dementia status than HS-positive participants (OR, 5.81; 95% CI, 2.80-12.06). HS/MTL sclerosis marked greater clinical severity in both AD and non-AD strata and co-occurred with regional TDP-43 involvement and hippocampal atrophy. Its absence identified a subset with intermediate/high AD pathology but no dementia near death. Clinical severity therefore cannot be inferred from ADNC alone.},
}

@article {pmid42818649,
year = {2026},
author = {Skolasinska, P and Wearn, A and O'Sullivan, D and Stallworthy, I and Brynildsen, JK and Leppert, IR and Tardif, CL and Turner, GR and Bassett, DS and Spreng, RN and , },
title = {Longitudinal changes in control energy of brain networks in older adults at familial risk for Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {42818649},
issn = {2692-8205},
support = {R01 AG068563/AG/NIA NIH HHS/United States ; },
abstract = {The ability of structural brain networks to control neural dynamics is affected by healthy and pathological aging, including Alzheimer's disease (AD). According to network control theory, transitions between functional brain states incur energetic costs. How these costs change longitudinally with aging remains unknown. Here, in 279 older adults at familial risk for AD, control energy increased longitudinally for state maintenance and transitions between sensorimotor and attentional networks, while decreasing for another sensorimotor-attentional transition. Changes in transition costs between higher-order networks were associated with cognitive performance: greater DorsAttn⟷Executive cost was associated with poorer immediate memory, while lower Executive⟷Def+Lim cost was associated with poorer attention. Higher plasma p-tau181 was associated with lower DorsAttn⟷Def+Lim transition cost. These findings reveal transition-specific alterations in the energetic landscape of aging and distinct relationships with cognition and AD pathology. Together, they highlight energetic constraints on brain network reconfiguration as a complementary perspective on neurocognitive aging.},
}

@article {pmid42818734,
year = {2026},
author = {Wang, X and Liu, X and Wang, Z and Jia, C},
title = {Neutrophil-to-lymphocyte ratio predicts early cognitive decline associated with tau pathology in Alzheimer's disease: a longitudinal study of the ADNI cohort.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1872617},
pmid = {42818734},
issn = {1663-4365},
abstract = {BACKGROUND: Neuroinflammation is a key driver of Alzheimer's disease (AD). Although the neutrophil-to-lymphocyte ratio (NLR) is an easily accessible peripheral inflammatory marker, yet its longitudinal association with domain-specific cognitive decline and the underlying neuropathological mechanisms during the preclinical and early stages of AD remain unclear.

METHODS: A total of 1,190 non-people living with dementia older adults from the AD Neuroimaging Initiative cohort were included, comprising 405 cognitively normal participants and 785 participants with mild cognitive impairment (MCI). Participants were stratified according to baseline NLR (≥ 3versus < 3). Linear mixed-effects models were used to examined the association between baseline NLR and longitudinal decline across multiple cognitive domains. Cox proportional hazards model assessed progression risk to MCI or AD. Mediation analyses evaluated whether cerebrospinal fluid (CSF) biomarkers, including amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau), statistically accounted for the association between NLR and cognitive decline.

RESULTS: During follow-up, a high baseline NLR (≥ 3) was independently associated with accelerated decline in global cognition, memory, executive function, language, and visuospatial abilities (all p < 0.05), as well as a 20% higher risk of clinical progression per 1-unit increase in NLR (hazard ratio = 1.20, 95% confidence interval: 1.12-1.29, p = 0.001). Mediation analyses indicated that CSF t-tau and p-tau, but not Aβ42, partially explained the association between NLR and cognitive decline. The observed associations remained robust across sensitivity and subgroup analyses.

CONCLUSION: Elevated NLR was significantly and independently associated with accelerated decline across multiple cognitive domains and an increased risk of clinical progression in older adults at risk for AD. The observed associations with tau pathology are consistent with a potential role for peripheral immune dysregulation in early disease trajectories; however, formal predictive modeling and external validation are required before clinical application.},
}

@article {pmid42818797,
year = {2026},
author = {Le, HN and Ishrat, S and Yaghooti, B and Murad, T and Sapkota, R and Thakuri, DS and Wong, DF and Cruchaga, C and , and Chand, GB},
title = {Machine learning-derived Alzheimer's disease dimensions: neuroanatomical, cognitive, clinical, functional, and genetic risk heterogeneity signatures.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42818797},
support = {P30 AG066444/AG/NIA NIH HHS/United States ; RF1 AG071706/AG/NIA NIH HHS/United States ; RF1 AG087271/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; P30 NS048056/NS/NINDS NIH HHS/United States ; RF1 AG044546/AG/NIA NIH HHS/United States ; K01 AG083230/AG/NIA NIH HHS/United States ; R01 AG078964/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; RF1 AG058501/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is characterized by substantial clinical and biological heterogeneity, with diverse neuroanatomical, cognitive, clinical, functional, and genetic risk profiles that are poorly captured by current diagnostic frameworks. Identifying reproducible disease dimensions is critical for understanding divergent pathophysiological mechanisms and designing future stratified therapeutic interventions. Herein, we applied a semi-supervised machine learning clustering framework and robust reproducibility validation strategies to structural MRI data from 1,757 participants, comprising 1,108 cognitively normal controls (CN) and 649 patients with mild cognitive impairment (MCI) or dementia due to AD. We identified two MRI-based neuroanatomical dimensions of AD: Dimension 1 (n = 393; prevalence ~ 61%) and Dimension 2 (n = 256; prevalence ~ 39%). Dimension 1 exhibited widespread cortical and subcortical atrophy, including involvement of the hippocampus, amygdala, parahippocampal, temporal, frontal, and occipital regions, while Dimension 2 showed relatively preserved brain patterns. The two dimensions were not statistically different in demographic characteristics, including age, sex, race, and education (all p > 0.05). Compared to Dimension 2, Dimension 1 had more severe cognitive and clinical impairment, greater functional impairment, elevated APOE ε4 carrier burden, and higher polygenic risk for AD (p < 0.05). Analysis of individual-level summary neuroanatomical signature expression scores, quantifying each subject's continuous position along two disease dimensions, revealed that Dimension 1 signature expression correlated strongly with cognitive impairment, clinical severity, functional impairment, and genetic risk, while Dimensional 2 signature expression showed relatively weaker associations. These results reveal that AD encompasses at least two biologically distinct dimensions identifiable from structural MRI profiles and their distinct associations with cognitive, clinical, functional, and genetic profiles. These findings may aid in AD patient stratification for designing targeted therapeutic approaches in the future.},
}

@article {pmid42818825,
year = {2026},
author = {Raeesi, S and Zeighami, Y and Morrison, C and Dadar, M},
title = {Sex Differences in the Associations between Education, Neuropathology, and Cognition.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.03.26362216},
pmid = {42818825},
abstract = {IMPORTANCE: Autopsy evidence on sex-specific associations of education with neuropathology and cognition is limited.

OBJECTIVE: To test sex differences in education associations with neuropathologic burden and cognition.

DESIGN: Cohort study of data collected from September 2005 through August 2024.

SETTING: Multicenter autopsy cohort from the National Alzheimer's Coordinating Center.

PARTICIPANTS: Adults aged 55 years or older; cross-sectional eligibility required a final CDR-SB assessment within 2 years before death, and longitudinal eligibility additionally required at least 3 assessments.

EXPOSURES: Years of formal education.

MAIN OUTCOMES AND MEASURES: Neuropathologic measures and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Linear regression and mixed-effects models tested associations and interactions of education with sex, neuropathology, and linear and quadratic time. Benjamini-Hochberg correction addressed multiple comparisons.

RESULTS: Among 2592 participants (mean [SD] age at death, 81.6 [10.8] years; 1188 [45.8%] female), 1969 contributed to longitudinal analyses. In female participants, higher education was associated with lower Thal amyloid phase, diffuse plaques, neuritic plaques, and Braak stage (β range, -0.097 to -0.071; q FDR <.026); none was significant among male participants. Education-by-sex interactions supported differences in Thal amyloid phase, and diffuse and neuritic plaques (β range, -0.119 to -0.097; q FDR <.045). Education was unrelated to final CDR-SB among female (β, -0.007; 95% CI, -0.052 to 0.038; P =.767) and male participants (β, -0.026; 95% CI, -0.071 to 0.019; P =.254), with no education-by-sex interaction (P =.660). The education-by-Braak-stage-by-sex interaction indicated that higher education was associated with a weaker Braak stage-CDR-SB association among females than males (β, -0.104; 95% CI, -0.171 to -0.038; q FDR =.022). Longitudinally, education was unrelated to linear CDR-SB change in either sex. Education-by-quadratic-time associations were observed among females (β, 0.002; 95% CI, 0.001-0.003; P <.001) and male participants (β, 0.001; 95% CI, 0-0.002; P =.037). The corresponding interaction with sex was also significant (P =.043).

CONCLUSIONS AND RELEVANCE: Among female participants, higher education was associated with lower selected Alzheimer's disease neuropathologic measures and weaker associations of tau pathology with cognition. Longitudinal trajectories were nonlinear, with slower earlier decline followed by later acceleration at higher education levels.

KEY POINTS: Question: Do associations between education, neuropathologic burden and cognition differ by sex?Findings: In this cohort study of 2592 autopsy participants, higher education was associated with lower Alzheimer's disease neuropathologic burden among female but not male participants, and education-by-sex interactions were significant for Thal amyloid phase, diffuse and neuritic plaques. Higher education was associated with a weaker Braak stage-CDR-SB association among female than male participants and with lower CDR-SB five years before death in both sexes. The associations persisted after adjustment for neuropathologic burden.Meaning: Education-neuropathology associations and the clinical expression of neuropathology may be sex-specific.},
}

@article {pmid42818865,
year = {2026},
author = {Metz, A and Polizzi, C and Moqadam, R and Chadwick, K and Tremblay, C and Chen, Z and Zeighami, Y and Villeneuve, S and , and , and , and , and Dadar, M},
title = {Data-driven subtypes of Alzheimer's Disease: A multicohort study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.09.26362683},
pmid = {42818865},
abstract = {INTRODUCTION: Individuals with Alzheimer's disease (AD) exhibit substantial heterogeneity in the severity of vascular changes and neurodegeneration, making the identification of biologically meaningful subtypes across the AD spectrum critical for improving prognosis and tailoring interventions. We aimed to determine whether data-driven subtyping of individuals at risk for or diagnosed with AD, based on magnetic resonance imaging (MRI), can identify distinct trajectories of disease progression and clinical outcomes.

METHODS: We analyzed baseline biomarkers and longitudinal clinical and cognitive assessments from the PREVENT-AD, CIMA-Q, ALLFTD, and ADNI cohorts, including 1396 participants. Regional atrophy and White Matter Hyperintensity (WMH) burden were derived from T1-weighted MRI. The SuStaIn algorithm was applied to baseline data to infer individuals' subtypes and stages based on MRI biomarker profiles. The resulting subtypes were compared in terms of baseline molecular biomarker levels and vascular risk factors, longitudinal cognitive decline trajectories, and clinical and neuropathological outcomes.

RESULTS: Two distinct subtypes were identified across all cohorts: one characterized by early parahippocampal and cortical atrophy, and a second by initially elevated WMH volumes. Both subtypes showed abnormal tau and amyloid levels in- and ex-vivo, and subtype two exhibited increased vascular risk factors. Longitudinally, the atrophy-first subtype exhibited steeper cognitive decline than the WMH-first subtype. Accordingly, the atrophy-first subtype carried a higher risk of conversion to AD than the WMH-first group.

DISCUSSION: These findings, replicated in four diverse and independent datasets, support imaging-based subtyping as a scalable and clinically translatable approach for capturing heterogeneity in AD pathophysiology and associated cognitive trajectories.},
}

@article {pmid42818869,
year = {2026},
author = {Fin, S and Moayedikia, A},
title = {Structural, Functional and Cognitive Validation of a Deep-Learning MCI-to-AD Conversion Model in OASIS-3.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.05.26362318},
pmid = {42818869},
abstract = {BACKGROUND: Deep-learning models predict mild cognitive impairment (MCI)-to-Alzheimer's disease (AD) conversion from structural MRI with high accuracy. However, they are typically validated within a single cohort and judged on discrimination alone. Whether their risk scores are biologically grounded, and whether they generalise to independent data, remains unclear.

METHODS: We applied the ADNI-trained Temporal Adaptive Fusion Network (TAF-Net), without retraining, to 101 MCI participants from OASIS-3 (25 converters, 76 stable) and tested whether its conversion-risk scores were grounded in independent structural, functional, and cognitive markers of AD. Regional atrophy rates were derived from longitudinal FreeSurfer, cognition from longitudinal MMSE and CDR-Sum-of-Boxes, and baseline resting-state functional connectivity from fMRIPrep, in structural and functional subsamples of 41 and 40 participants. Associations used rank-based statistics with false-discovery-rate correction.

RESULTS: Higher TAF-Net risk tracked faster atrophy in medial-temporal AD-signature regions but not in AD-spared cortex - an anatomically specific coupling that survived adjustment for global atrophy. In external validation, risk discriminated converters (AUC = 0.72), comparable to native atrophy and strongly concordant with it; atrophy statistically accounted for the model's prognostic signal. Discrimination transferred but calibration did not: the two lowest tertiles of risk were assigned near-zero probability yet converted at 15%. Risk also tracked the multi-year rate of cognitive decline and, at baseline, was associated with reduced within-network functional-connectivity integrity, concentrated in salience and default-mode hubs; longitudinal functional analyses were underpowered.

CONCLUSIONS: A conversion model trained on one cohort produced risk scores that, in an independent cohort, were grounded in the structural, functional, and cognitive hallmarks of Alzheimer's disease - supporting biological validity and external generalisation. The score, however, largely re-expresses the neurodegenerative substrate captured by structural atrophy. Rank ordering transferred across cohorts but absolute risk did not, so the score requires recalibration before its values can be interpreted as individual probabilities.},
}

@article {pmid42818882,
year = {2026},
author = {Ramedani, M and Terli, JC and Singh, D and Peters, O and Hellmann-Regen, J and Priller, J and Spruth, EJ and Spottke, A and Boehlen, A and Weydt, P and Wüllner, U and Dinter, E and Günther, R and Wiltfang, J and Schott, BH and Düzel, E and Glanz, W and Buerger, K and Janowitz, D and Levin, J and Stockbauer, A and Mladinov, M and Prudlo, J and Hermann, A and Synofzik, M and Mengel, D and Petzold, GC and Schneider, A and Lüsebrink, F and Hetzer, S and Dechent, P and Ewers, M and Scheffler, K and Stöcklein, S and Teipel, S and Dyrba, M},
title = {Hybrid multimodal late fusion frameworks for bvFTD classification in imbalanced dementia datasets.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1892568},
pmid = {42818882},
issn = {1663-4365},
support = {R01 AG032306/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is an irreversible neurodegenerative disorder characterized by progressive changes in personality and behavior. Magnetic Resonance Imaging (MRI) is widely used to detect and assess structural brain alterations associated with the disease. However, due to the low prevalence of bvFTD among neurodegenerative diseases causing the dementia syndrome, conventional machine learning approaches may struggle to capture comprehensive feature representations. Therefore, this study proposes two late fusion frameworks that integrate a 3D convolutional neural network and a multilayer perceptron (MLP) for improved bvFTD diagnosis.

METHODS: A total of 5,928 participants were included, comprising 3,415 healthy controls (HC), 2,276 Alzheimer's disease (AD), and 237 bvFTD, resulting in a class imbalanced setting with bvFTD as the minority class. To address class imbalance, bvFTD data were initially augmented. A 3D-DenseNet was used to extract features from 3D T1-weighted MRI scans, while an MLP-based model was applied to regional brain volumetric measurements obtained from automated MRI-based brain segmentation. Twelve CNN models with different hyperparameter configurations were trained. Models with and without data augmentation, as well as two fusion-based approaches, were evaluated using accuracy, F1-score, and area under the curve (AUC).

RESULTS: Both fusion strategies improved accuracy, F1-score, and AUC compared to the baseline model without data augmentation. Notable improvement was also observed for the bvFTD class, with up to a 120% increase in F1-score. In one of the fusion frameworks, an accuracy of 0.95 ± 0.01 was achieved for bvFTD vs. HC classification. The results demonstrate the effectiveness of the fusion-based approaches compared to non-fused models, outperforming several state-of-the-art methods.

CONCLUSION: The proposed frameworks demonstrate that data augmentation and fusion strategies can improve accuracy, F1-score, and AUC, with statistically significant gains. Overall, the frameworks improve diagnostic performance and support the identification of relevant biomarkers associated with bvFTD pathology.},
}

@article {pmid42818885,
year = {2026},
author = {Kuik, EJ and Baena-Tan, C and Moriguchi, S and Braga, J and Miler, L and Rusjan, P and Bagby, M and Husain, MI and Vasdev, N and Tomoda, T and Banasr, M and Kloiber, S and Meyer, JH},
title = {Effects of sex, treatment resistance, and antidepressant treatment on monoamine oxidase B total distribution volume.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42818885},
support = {R01 MH115014/MH/NIMH NIH HHS/United States ; },
abstract = {Monoamine oxidase B (MAO-B) is a high-density protein located mainly in astrocytes that influences mitochondrial function and transition to astrogliosis. MAO-B produces hydrogen peroxide while metabolizing non-serotonergic monoamines. Elevated MAO-B level is implicated in the pathophysiology of several common neuropsychiatric diseases. The aims are to examine the effect of treatment resistant major depressive episodes, sex, and antidepressant treatment on MAO-B total distribution volume ([[11]C]SL25.1188 VT), index of MAO-B level. [[11]C]SL25.1188 PET was applied in 95 adults (29 with MDE and no history of treatment-resistance (NTR-MDE), 26 with MDE and history of treatment-resistance (TRD), and 40 healthy control (HC)). A subset of NTR-MDE and TRD (n=13) were scanned before and after treatment with phenelzine, rasagiline, or duloxetine. [[11]C]SL25.1188 VT was higher in grey matter regions in females (10%, p<.001). [[11]C]SL25.1188 VT was also higher in prefrontal cortex in TRD compared to HC (23%, p<.001) and TRD compared to NTR-MDE (6%, p=.033). Duloxetine had minimal effect on [[11]C]SL25.1188 VT, but occupancy of rasagiline and phenelzine was ~94%. This study discovered sex differences in MAO-B level, which may explain sex differences in prevalence or trajectory of illnesses with greater MAO-B level like Alzheimer's disease, traumatic brain injury and major depressive disorder. Given our findings of greater MAO-B level in prefrontal cortex of TRD and its insensitivity to serotonin reuptake inhibition, combined with potential harm of highly elevated MAO-B level, development of MAO-B inhibitors could be considered for a subset of TRD. Rasagiline and phenelzine demonstrate similarly potent occupancy in vivo at clinical dosage.},
}

@article {pmid42818896,
year = {2026},
author = {He, Y and Yang, H and Pan, T and Wang, F and Zeng, X and Huang, J and Yang, Q},
title = {Exploring the role of statin interventions on cognitive function by Mendelian randomization study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261440863},
pmid = {42818896},
issn = {2542-4823},
abstract = {BACKGROUND: While statin use is linked to cognitive impairment, causal relationships with specific dementia subtypes remain unclear.

OBJECTIVE: To investigate causal effects of statin medication, genetically mimicked statin effects, and plasma lipids on various cognitive impairments using Mendelian randomization (MR).

METHODS: Utilizing summary genome-wide association studies data, we identified genetic variants associated with statin medication, cholesterol-dependent/independent statin effects, and dementia subtypes, such as Alzheimer's disease (AD), dementia in Alzheimer's disease (ADD), late-onset Alzheimer's disease, dementia with Lewy body (DLB), dementia with Lewy body in APOE ε4[+] carriers, frontotemporal dementia, Parkinson's disease dementia, and vascular dementia. Univariable MR assessed causality, primarily via inverse variance weighting (IVW). Mediation effects were evaluated using the coefficient product method. Sensitivity analyses ensured robustness.

RESULTS: IVW-MR indicated statin medication significantly reduced AD risk but increased ADD and DLB risk. Elevated total cholesterol (TC) increased dementia, ADD, and DLB, while higher low density lipoprotein cholesterol decreased AD risk. Specific DHCR24 variants reduced DLB risk, while HMGCS1 variants increased it. RAC1 variants lowered AD risk, whereas RHOC mitigated ADD risk. Critically, TC mediated 93.91% (95% CI = 68.27%∼119.55%) of statins' effect on dementia, 84.37% (95% CI = 62.21%∼106.52%) on ADD, and 61.94% (95% CI = 43.47%∼80.42%) on DLB. The genetically mimicked effect of statins does not show a mediating role.

CONCLUSIONS: Statin medication, plasma lipids, and their genetic proxies exhibit causal links to cognitive impairment. Crucially, TC mediates statin-associated risks for cognitive impairment.},
}

@article {pmid42818907,
year = {2026},
author = {Ward, EL and Nelson, PT and Katsumata, Y and Fardo, DW and Jicha, GA and , and Miller, JB},
title = {Rare extreme polygenic risk scores strongly indicate Alzheimer's disease risk.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42818907},
support = {RF1 AG058066/AG/NIA NIH HHS/United States ; U01 AG049505/AG/NIA NIH HHS/United States ; HHSN268201100012C/HL/NHLBI NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; R01 AG069013/AG/NIA NIH HHS/United States ; R01 AG042188/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; RC2 HL102419/HL/NHLBI NIH HHS/United States ; P41 EB015922/EB/NIBIB NIH HHS/United States ; R01 AG064877/AG/NIA NIH HHS/United States ; R01 AG018016/AG/NIA NIH HHS/United States ; R01 AG060747/AG/NIA NIH HHS/United States ; HHSN268201100009I/HL/NHLBI NIH HHS/United States ; N01 HC085080/HL/NHLBI NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; U01 AG058654/AG/NIA NIH HHS/United States ; U01 HL096812/HL/NHLBI NIH HHS/United States ; U54 AG052427/AG/NIA NIH HHS/United States ; R01 NS017950/NS/NINDS NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; R01 AG063689/AG/NIA NIH HHS/United States ; R01 AG054076/AG/NIA NIH HHS/United States ; R01 AG046949/AG/NIA NIH HHS/United States ; R01 AG042210/AG/NIA NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; R01 AG057909/AG/NIA NIH HHS/United States ; HHSN268201100010C/HL/NHLBI NIH HHS/United States ; U01 AG058922/AG/NIA NIH HHS/United States ; P20 AG068053/AG/NIA NIH HHS/United States ; R01 AG009029/AG/NIA NIH HHS/United States ; R01 NS069719/NS/NINDS NIH HHS/United States ; R01 AG015928/AG/NIA NIH HHS/United States ; R01 AG044546/AG/NIA NIH HHS/United States ; P01 NS026630/NS/NINDS NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; R01 AG009956/AG/NIA NIH HHS/United States ; HHSN268201100008C/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; U01 HL096917/HL/NHLBI NIH HHS/United States ; HHSN268201100008I/HL/NHLBI NIH HHS/United States ; HHSN268201100005G/HL/NHLBI NIH HHS/United States ; N01 HC085082/HL/NHLBI NIH HHS/United States ; U01 AG049507/AG/NIA NIH HHS/United States ; U24 AG057437/AG/NIA NIH HHS/United States ; U01 AG052411/AG/NIA NIH HHS/United States ; R01 AG019085/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; RF1 AG053303/AG/NIA NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; HHSN268201100007C/HL/NHLBI NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; N01 HC085086/HL/NHLBI NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; N01 HC085083/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; R01 AG048234/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; HHSN268201100011I/HL/NHLBI NIH HHS/United States ; HHSN268201100011C/HL/NHLBI NIH HHS/United States ; RF1 AG054074/AG/NIA NIH HHS/United States ; U24 AG067418/AG/NIA NIH HHS/United States ; P50 NS039764/NS/NINDS NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; U01 HL096902/HL/NHLBI NIH HHS/United States ; U24 AG056270/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; RC2 HG005605/HG/NHGRI NIH HHS/United States ; RF1 AG058501/AG/NIA NIH HHS/United States ; R56 AG051876/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; R01 AG028786/AG/NIA NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; R01 AG049607/AG/NIA NIH HHS/United States ; UF1 AG047133/AG/NIA NIH HHS/United States ; U01 AG057659/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; R01 AG054047/AG/NIA NIH HHS/United States ; R01 AG054073/AG/NIA NIH HHS/United States ; R01 AG061155/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; R01 AG027161/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; RF1 AG054080/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; U01 AG062943/AG/NIA NIH HHS/United States ; RF1 AG051504/AG/NIA NIH HHS/United States ; HHSN268201100006C/HL/NHLBI NIH HHS/United States ; U24 AG041689/AG/NIA NIH HHS/United States ; R01 AG044829/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; N01 HC025195/HL/NHLBI NIH HHS/United States ; R01 AG033193/AG/NIA NIH HHS/United States ; HHSN268201100005I/HL/NHLBI NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R37 AG015473/AG/NIA NIH HHS/United States ; N01 HC055222/HL/NHLBI NIH HHS/United States ; U01 AG058589/AG/NIA NIH HHS/United States ; U01 NS041588/NS/NINDS NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; R01 AG059716/AG/NIA NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; U01 AG049508/AG/NIA NIH HHS/United States ; P50 AG008012/AG/NIA NIH HHS/United States ; N01 HC085079/HL/NHLBI NIH HHS/United States ; U01 AG052410/AG/NIA NIH HHS/United States ; U01 HL096814/HL/NHLBI NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; U01 AG006781/AG/NIA NIH HHS/United States ; R01 AG041797/AG/NIA NIH HHS/United States ; K23 AG030944/AG/NIA NIH HHS/United States ; RC4 AG039085/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; U01 AG062602/AG/NIA NIH HHS/United States ; R01 NS029993/NS/NINDS NIH HHS/United States ; R01 AG047649/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; R01 AG064614/AG/NIA NIH HHS/United States ; R01 AG021547/AG/NIA NIH HHS/United States ; P30 AG038072/AG/NIA NIH HHS/United States ; R01 AG070862/AG/NIA NIH HHS/United States ; R01 AG032289/AG/NIA NIH HHS/United States ; R01 AG048927/AG/NIA NIH HHS/United States ; U54 HG003079/HG/NHGRI NIH HHS/United States ; R01 AG019757/AG/NIA NIH HHS/United States ; U01 AG052409/AG/NIA NIH HHS/United States ; R01 AG033040/AG/NIA NIH HHS/United States ; RF1 AG054052/AG/NIA NIH HHS/United States ; R01 AG022018/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; R01 AG020098/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; HHSN268201100009C/HL/NHLBI NIH HHS/United States ; U19 AG078109/AG/NIA NIH HHS/United States ; R01 HL070825/HL/NHLBI NIH HHS/United States ; R01 AG027944/AG/NIA NIH HHS/United States ; HHSN268201100005C/HL/NHLBI NIH HHS/United States ; P20 AG068024/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; R01 AG025259/AG/NIA NIH HHS/United States ; RF1 AG057519/AG/NIA NIH HHS/United States ; U01 HL096899/HL/NHLBI NIH HHS/United States ; HHSN268201100007I/HL/NHLBI NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; RF1 AG015473/AG/NIA NIH HHS/United States ; U01 AG049506/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 AG011101/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; R01 AG058533/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; R01 AG021136/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; U01 AG058635/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; U19 AG066567/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; R01 AG031272/AG/NIA NIH HHS/United States ; R01 AG011380/AG/NIA NIH HHS/United States ; P50 NS071674/NS/NINDS NIH HHS/United States ; N01 HC085081/HL/NHLBI NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; RF1 AG058267/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) pathology often accumulates years before memory loss, creating a need to identify high-risk individuals presymptomatically. Polygenic risk scores (PRS) stratify AD risk, but individual-level predictions remain uncertain. Extreme PRS may identify high-risk individuals independent of APOE.

METHODS: Using GenoPred, extreme tails of 1,752 PRS methods were evaluated across four genetic ancestries using 11,200 autopsy- or clinically-defined AD cases and 19,321 controls (age ≥65) from the AD Sequencing Project (ADSP) Release 5.

RESULTS: Individuals in the extreme upper PRS tail were significantly enriched for AD in all ancestries: Admixed American (P adj =0.02727), African (P adj =0.004827), East Asian (P adj =0.02824), and European (P adj =2.3068×10[-13]). No controls were observed among the 42 European- and 12 African-ancestry individuals with extreme PRS. Extreme PRS spanned APOE diplotypes; 38% occurred in non-APOE ε4 carriers.

CONCLUSIONS: Rare subsets of individuals at the most extreme PRS thresholds have markedly elevated AD enrichment across ancestries and APOE diplotypes.},
}

@article {pmid42818911,
year = {2026},
author = {Han, S and Liu, F and Wang, D and Song, G},
title = {Aildenafil citrate with superior PDE5 selectivity ameliorates cognitive and behavioral impairments in APP/PS1 Alzheimer's disease mice: a preclinical phenotypic study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1933588},
pmid = {42818911},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) imposes a significant global healthcare burden, and current available pharmacotherapies provide limited therapeutic benefits. Disrupted phosphodiesterase 5 (PDE5) signaling has been implicated in the pathogenesis of AD and other neurodegenerative disorders, positioning PDE5 inhibitors (PDE5Is) as a promising therapeutic strategy for AD treatment. This study evaluated the preclinical therapeutic potential of aildenafil citrate (AC), a selective PDE5I approved in China for the treatment of erectile dysfunction (ED), in AD treatment.

METHODS: Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations were integrated to explore the molecular mechanisms of aildenafil. The APP/PS1 transgenic mouse model of AD was employed to assess the in vivo efficacy of AC through behavioral, pathological, and oxidative assessments.

RESULTS: In silico analyses indicated that aildenafil exhibited a higher predicted affinity through a strengthened electrostatic network anchored by key bidentate hydrogen bonds with Gln817 and enhanced π-π stacking interactions with Phe820. Behavioral assessments, including the Barnes maze and Open field tests, demonstrated that AC significantly ameliorates cognitive dysfunction and anxiety-like impairments. Pathological examinations revealed improved hippocampal morphology, upregulated neprilysin (NEP) expression, and reduced Aβ accumulation. The decreased malondialdehyde (MDA) levels further suggested a potential attenuation of systemic oxidative stress and provided preliminary support for further investigation into its effects on central redox status.

CONCLUSION: These findings offer an initial phenotypic characterization of AC in an AD mouse model, underscoring the need for comprehensive mechanistic studies to fully evaluate its potential as a repurposed AD therapeutic candidate.},
}

@article {pmid42818922,
year = {2026},
author = {Trujillo, AE and Sohn, M and Macias, MJ and Grochowska, MM and Joyce, J and Leber, I and Huh, D and Schulmann, A and McMahon, FJ and Van Keuren-Jensen, K and Latouche, M and Marsan, E},
title = {Selective vulnerability and resilience of thalamic neuronal populations in Frontotemporal Dementia.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42818922},
issn = {2693-5015},
support = {ZIA AG000554/ImNIH/Intramural NIH HHS/United States ; ZIA MH002810/ImNIH/Intramural NIH HHS/United States ; },
abstract = {Frontotemporal dementia (FTD) caused by progranulin (GRN) mutations is associated with pronounced thalamic degeneration, yet the cellular basis of selective thalamic vulnerability remains poorly understood. Here, we generated an integrated single-nucleus RNA-sequencing atlas of the human antero-median thalamus comprising 331,065 nuclei from 92 individuals across three independent cohorts spanning GRN-associated FTD, sporadic FTD with TDP-43 proteinopathy, Alzheimer's disease (AD), and neurologically normal aging. While AD samples exhibited minimal thalamic cellular remodeling, FTD cases were characterized by highly selective and reproducible degeneration of discrete neuronal populations across independent cohorts. In particular, two inhibitory neuronal populations were markedly depleted in FTD, which was accompanied by impaired GABAergic communication. Among excitatory neurons, RNF220+ neurons exhibited extensive transcriptional dysregulation, altered sterol metabolic pathways, together with robust TDP-43-associated STMN2 cryptic splicing pathology and reduced glutamatergic signaling. By contrast, RNF220- excitatory neurons were comparatively resilient, displaying preserved neuronal communication, and resistance to STMN2 cryptic exon accumulation. In control individuals, RNF220-excitatory neurons exhibited elevated GRN expression and an intrinsic enrichment of cytoskeletal maintenance programs. Spatial transcriptomics confirmed the anatomical distribution of vulnerable neuronal populations in the adult human thalamus. In parallel, FTD samples demonstrated expansion of vascular-associated and lymphocyte populations as well as reactive glial signatures. Together, these findings define a cellular framework for selective vulnerability and resilience in the human FTD thalamus and identify intrinsic molecular programs associated with resistance to neurodegeneration.},
}

@article {pmid42818937,
year = {2026},
author = {Aquino, J and Lee, A and Zheng, J and Ku, WL and Han, M and Chen, J},
title = {Isoform Remodeling and Promoter Switching Identify Altered Transcriptional Regulation in Alzheimer's Disease Frontal Cortex.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42818937},
issn = {2693-5015},
support = {R15 AG083618/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is associated with transcriptional dysregulation, but gene-level analyses may overlook isoform changes. We investigated how differential isoform usage, promoter selection, and splicing contribute to transcriptome remodeling in the AD frontal cortex.

METHODS: We analyzed Oxford Nanopore long-read RNA sequencing data from frontal cortex of six individuals with AD and six controls. Transcripts were quantified using Bambu, and differential isoform usage was assessed using IsoformSwitchAnalyzeR. Promoter usage and SUPPA2-derived percent-spliced-in values were tested using beta regression. Transcription factor motif enrichment was evaluated at differentially used promoters. Transcript-level effects were compared with an independent short-read cohort.

RESULTS: We identified 109 isoform-switching events involving 96 isoforms across 86 genes, including CLSTN3, SNCA, BECN1, USP10, and EGFR. Several switches altered predicted nonsense-mediated decay sensitivity. Eleven genes exhibited promoter switching, comprising 46 differentially used promoters: 31 with increased and 15 with decreased usage in AD. These promoters were enriched for 179 TF motifs. IRF7, IRF8, IRF9, and STAT1::STAT2 motifs were top-ranked among promoters with increased usage, whereas NFKB1 and NFKB2 motifs were top-ranked among those with decreased usage. Targeted analysis identified 14 significant differential splicing events with sex-associated effects, including BECN1. Although cross-platform concordance was weak, 16 of 26 transcripts with large effects in both datasets changed concordantly, and 13 showed large, concordant effects of similar magnitude.

CONCLUSIONS: AD-associated transcriptome remodeling extends beyond gene-level abundance to include changes in isoform proportions, promoter selection, and transcript structure. These findings implicate transcription initiation and RNA processing as complementary layers of dysregulation in AD.},
}

@article {pmid42818947,
year = {2026},
author = {Cheng, WKW and , },
title = {Separating ECog scale-score information from dyad availability: observation-process contributions to dyadic prediction of cognitive impairment in ADNI.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42818947},
issn = {2693-5015},
abstract = {BACKGROUND: Self- and informant-reported cognitive concerns are common, but their apparent incremental discriminative contribution can be inflated when missingness is structured by study protocol and assessment era. We tested the hypothesis that dyadic ECog would improve discrimination beyond conventional predictors, but that this increment would be attenuated after accounting for dyad availability and protocol-structured missingness.

METHODS: We included 1,643 cognitively unimpaired (CU) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 221 events: 213 mild cognitive impairment [MCI], 8 Alzheimer's disease [AD] dementia) and fit nested cross-validated elastic-net Cox models with fold-wise imputation.

RESULTS: The conventional model (M2) concordance index (C-index) was 0.680, but fell to 0.649 when missingness indicators were removed. M3 (M2 plus dyadic Everyday Cognition (ECog) mean and dyad availability) reached 0.758; after accounting for dyad availability, ECog scale scores showed a modest contribution beyond availability (ΔC = 0.026, 95% confidence interval (CI) 0.007 to 0.045), whereas the score-only comparison provided limited evidence for an independent contribution (ΔC = 0.010, 95% CI -0.004 to 0.024). In an inverse-probability-of-censoring-weighted (IPCW) sensitivity analysis, ΔC was 0.105 (95% CI 0.050 to 0.174).

CONCLUSIONS: In this ADNI analysis, missingness-indicator imputation may increase the apparent discriminative contribution of dyadic measures; much of the observed gain was associated with dyad availability, and limited evidence was found for an independent contribution from ECog scale scores.},
}

@article {pmid42818965,
year = {2026},
author = {Rafie, F and Azimi, D and Nekouei, AH and Kim, H and Carroll-Sauer, CM and Hajjar, I and Wharton, W and Qiu, D and Goldstein, F and Mckay, JL and Hackney, ME},
title = {Feasibility, Safety, and Preliminary Efficacy of Partnered Rhythmic Rehabilitation in Prodromal Alzheimer's Disease: A 12-Month Pilot Randomized Controlled Trial.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.11.26362767},
pmid = {42818965},
abstract = {BACKGROUND: Non-pharmacological interventions may enhance motor-cognitive integration in prodromal Alzheimer's disease (pAD). Partnered Rhythmic Rehabilitation (PRR), an adapted dance-based intervention, is designed to engage the motor, cognitive, and social domains. However, no randomized trial has evaluated its feasibility or efficacy in pAD. This study evaluated the feasibility, safety, and preliminary efficacy of PRR compared to group walking (WALK) in adults with pAD and amnestic mild cognitive impairment (aMCI).

METHODS: In this single-blind, randomized controlled pilot trial (NCT04029623), 68 adults with pAD and aMCI were randomized to PRR or WALK. Prespecified feasibility criteria were attrition ≤15% and no injurious falls during interventions. Preliminary efficacy was examined on the primary outcome, the Four-Square Step Test (FSST). Secondary cognitive, motor, and psychosocial outcomes were also assessed to inform future definitive trials. Several modifications were made to the original protocol to ensure compliance with safety measures associated with the COVID-19 pandemic.

RESULTS: Attrition in the PRR group (15.2%) did not significantly exceed the prespecified threshold (P = .848), and 0 injurious falls were reported during the supervised sessions, meeting both feasibility and safety criteria. No significant group-by-time interactions were observed for FSST, but significant group-by-time interactions favoring PRR were identified for Timed Up-and-Go (TUG; P = .021) and jump distance (P = .014).

CONCLUSION: PRR was feasible and safe in adults with aMCI consistent with pAD but did not meet the prespecified efficacy endpoint on FSST. Our results showed that TUG and standing board jump distance may serve as potential outcomes in future definitive trials.},
}

@article {pmid42818993,
year = {2026},
author = {Neufang, S and Akhrif, A and Beyan, OD and Initiative, N},
title = {Gender bias in the diagnosis of Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {42818993},
issn = {2693-5015},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; },
abstract = {Fairness in clinical machine-learning (ML) remains a critical challenge, particularly in neurodegenerative disease where demographic factors may confound disease-related patterns. We developed and evaluated bias-aware ML models for Alzheimer's disease (AD) classification using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), comprising 757 individuals with mild cognitive impairment (MCI) and AD. Four supervised learning algorithms (logistic regression, support vector machine, random forest, and XGBoost) were trained using demographic, genetic, neuropsychological, and MRI-derived features. Sex was treated as a protected attribute, and bias mitigation was implemented using pre-processing, in-processing, and post-processing methods within the IBM AI Fairness 360 framework. Bias mitigation reduced disparities in predictions, with disparate impact decreasing from 1.167 to 0.823. The logistic regression model with Disparate Impact Remover (LR/DIR) improved performance while maintaining fairness, whereas adversarial debiasing achieved the highest balanced accuracy (88.91%). Explainability analyses in the LR/DIR model using LIME showed altered feature attribution patterns with increased convergence between sexes and stronger contribution of clinical and gender-related variables after debiasing. SHAP analysis in the adversarial debiasing model confirmed that Mini-Mental State Examination score, functional status, age, and medial temporal lobe atrophy were the strongest predictors of AD. These findings demonstrate that fairness-aware ML can reduce sex-related bias in AD classification without loss of performance and improve interpretability through more balanced representation of disease determinants.},
}

@article {pmid42819170,
year = {2026},
author = {Silva-Olivares, F and Vidal, N and Acevedo-Hernández, P and Rabbia, V and Petermann-Rocha, F and Thomas-Valdés, S and Jorquera, G},
title = {Can live microbial interventions support healthy aging? A systematic review and meta-analysis of cognitive and muscle outcomes in aging adults.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1869929},
pmid = {42819170},
issn = {2296-861X},
support = {/WT_/Wellcome Trust/United Kingdom ; },
abstract = {INTRODUCTION: Preserving cognitive and physical function is central to healthy aging, and the gut microbiota may influence both brain and muscle physiology. We evaluated whether live microorganism-based interventions affect cognitive and muscle-related outcomes in aging adults.

METHODS: We systematically reviewed randomized placebo-controlled trials of probiotics, synbiotics, or fecal microbiota transplantation in populations with a mean age of at least 60 years. MEDLINE, Embase, Web of Science, and the Cochrane Library were searched. Random-effects meta-analyses used Hedges' g when at least three studies or independent comparisons reported sufficiently comparable outcomes. The protocol was prospectively registered in PROSPERO (CRD420251065993; https://www.crd.york.ac.uk/PROSPERO/view/CRD420251065993).

RESULTS: Twenty-four trials involving 1,809 participants were included qualitatively: 20 evaluated cognitive outcomes and four evaluated muscle-related outcomes. Eleven unique studies contributed to at least one meta-analysis. For Mini-Mental State Examination scores, the overall pooled estimate was positive (g = 1.02; 95% CI: 0.36-1.68; I [2] = 90.84%). In exploratory post hoc subgroup analyses, the estimate was positive in Alzheimer's disease (g = 1.46; 95% CI: 1.14-1.79) but not statistically significant in broader cognitive impairment (g = 0.49; 95% CI: -0.78 to 1.77); the subgroup difference was not significant (p = 0.15). Excluding both Akhgarjand et al. intervention arms yielded a positive estimate in Alzheimer's disease (g = 1.63; 95% CI: 1.21-2.06), although only two studies remained. The pooled Repeatable Battery for the Assessment of Neuropsychological Status result was not statistically significant (g = 0.46; 95% CI: -0.50 to 1.41). Handgrip strength showed a modest positive estimate (g = 0.46; 95% CI: 0.06-0.85), but exclusion of Qaisar et al. attenuated it to non-significance (g = 0.23; 95% CI: -0.27 to 0.73).

DISCUSSION: Live microorganism-based interventions showed preliminary short-term functional signals, but the small evidence base, high cognitive heterogeneity, short follow-up, and sensitivity to individual studies preclude firm efficacy conclusions. Subgroup and two-study sensitivity findings are exploratory. No eligible fecal microbiota transplantation trial was identified, so the evidence derives exclusively from probiotic and synbiotic studies.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251065993, unique identifier: CRD420251065993.},
}

@article {pmid42819414,
year = {2026},
author = {Bestard-Lorigados, I and Sterling, K and Li, L and Lin, Z and Wu, Z and Zhu, Q and Pan, W and Cai, F and Song, W},
title = {Presenilin 1 Mutations Converge on Aβ42/Aβ40 Elevation via Distinct Mechanisms.},
journal = {MedComm},
volume = {7},
number = {10},
pages = {e70978},
pmid = {42819414},
issn = {2688-2663},
abstract = {Mutations in Presenilin 1 (PS1) are the most common genetic cause of familial Alzheimer's disease (AD). However, the exact mechanisms by which these mutations alter amyloid precursor protein (APP) processing and drive amyloid β (Aβ) production remain unclear. In this study, five PS1 mutations (M146V, G384A, C410Y, Y115H, and the Notch-sparing mutation ΔS169) were transfected into neuroblastoma cells lacking endogenous PS1/PS2 expression and human embryonic kidney cells stably overexpressing either wild-type APP or the APP Swedish mutation. We investigated the effects of these mutations on APP processing, Aβ42/Aβ40 ratio, cytotoxicity, BACE1 expression, and PS1 endoproteolysis. Our results demonstrate that PS1 mutations differentially modulate APP processing, producing distinct Aβ profiles independent of their effects on Notch signaling. All mutations increased the Aβ42/Aβ40 ratio, while BACE1 levels were unchanged and no direct PS1-BACE1 interactions were found. All mutations increased cytotoxicity, whereas only the Notch-impairing mutations reduced cell viability, suggesting impaired Notch signaling may contribute to this effect. Lastly, the mutations exhibited distinct endoproteolytic rates that correlated only with APP-C83 levels. These findings provide novel insights into how distinct PS1 mutations impact amyloid pathology.},
}

@article {pmid42819435,
year = {2026},
author = {Li, Y and Menon, G and Long, JJ and Kim, B and Bae, S and Orandi, BJ and DeMarco, MP and Wu, W and Crews, DC and Purnell, TS and Thorpe, RJ and Szanton, SL and Segev, DL and McAdams-DeMarco, MA},
title = {Neighborhood Disadvantage and Dementia Risk Among Older Patients With Kidney Failure: Differences by Race/Ethnicity and Urbanicity.},
journal = {Kidney medicine},
volume = {8},
number = {10},
pages = {101479},
pmid = {42819435},
issn = {2590-0595},
support = {K01 DK139420/DK/NIDDK NIH HHS/United States ; P30 AG059298/AG/NIA NIH HHS/United States ; K02 AG059140/AG/NIA NIH HHS/United States ; R01 AG077888/AG/NIA NIH HHS/United States ; F32 AG082486/AG/NIA NIH HHS/United States ; DP1 AG069874/AG/NIA NIH HHS/United States ; },
abstract = {RATIONALE & OBJECTIVE: Among older patients with kidney failure, those who are minoritized or residing in rural areas experience a disproportionate burden of Alzheimer's disease and related dementias (ADRD). Neighborhood disadvantage drives health disparities, but few studies have directly examined its association with ADRD and whether this association varies by race/ethnicity and by urbanicity.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: United States Renal Data System data; older patients (age ≥ 55 years) initiating dialysis in 2003-2021.

EXPOSURES: Residential neighborhood disadvantage was measured using a ZIP-code level index across 9 domains (built environment, criminal justice, education, employment, housing, poverty, social fragmentation, transportation, and wealth).

OUTCOME: ADRD using diagnosis codes.

ANALYTICAL APPROACH: We used cause-specific hazards models to quantify the adjusted hazard ratios (aHR) of ADRD diagnoses. We then used interaction terms to quantify whether these associations differed by race/ethnicity and urbanicity.

RESULTS: After adjustments, older patients in high-disadvantage neighborhoods had a higher risk of ADRD diagnoses (dementia: aHR = 1.09, 95% CI: 1.08-1.10; AD: aHR = 1.25, 95% CI: 1.22-1.27) compared with older patients in low-disadvantage neighborhoods; these associations differed by race/ethnicity (dementia: P interaction = 0.03; AD: P interaction = 0.002) and urbanicity (P interactions < 0.001 for both). Specifically, older Black patients in high-disadvantage neighborhoods had a higher risk of ADRD (dementia: aHR = 1.19, 95% CI: 1.17-1.21; AD: aHR = 1.31, 95% CI:1.28-1.35) compared with older Black patients in low-disadvantage neighborhoods. Within suburban, rural, and small-town areas, older patients residing in high-disadvantage neighborhoods had a higher risk of ADRD compared with those in low-disadvantage neighborhoods.

LIMITATIONS: ZIP codes as a proxy for neighborhoods.

CONCLUSIONS: Older patients with kidney failure residing in high-disadvantage neighborhoods, particularly Black patients and those in suburban, rural, or small-town areas, had a higher risk of ADRD compared with those in low-disadvantage neighborhoods. Multifaceted interventions (eg, cognitive screening, collaborative care) are needed to mitigate structural barriers associated with neighborhood disadvantage and preserve cognitive function in this population.},
}

@article {pmid42819534,
year = {2026},
author = {Stone, J and Johnstone, DM and Mason, RS and Mitrofanis, J and Robinson, SR},
title = {The evolutionary origins of dementia.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261470053},
pmid = {42819534},
issn = {2542-4823},
abstract = {Evidence has grown that the core pathology of age-related dementias, including Alzheimer's disease, is microvascular-small, symptomless bleeds from cerebral capillaries, accelerated by the hypertension of age. Each such bleed, this evidence suggests, damages a patch of brain, causing the death of neurons. This review asks how this vulnerability of the brain emerged from evolution, to cause age-related dementia? And has the vulnerability spurred the evolution of mitigating mechanisms? It is argued that seven features of human evolution contribute to the cause of dementia: the dependence of our tissues, especially the brain, on oxygen; the toxicity of the molecule (heme) that binds to oxygen to enable its transport; the pulsatility of the heart; the danger of glutamate as an excitatory neurotransmitter; the irreparability of elastin; the low level of adult neurogenesis in humans; and the breakdown, in late life, of the blood-brain barrier. Also discussed are mechanisms that have evolved to counter these threats to the brain, including the generation of a reserve of brain tissue. We argue that the vulnerabilities of the brain to damage that accumulates throughout life, and leads to dementia in the aged, were established early in the evolution of vertebrates. Several can be understood as unavoidable yet damaging outcomes of highly advantageous steps in evolution. Human cognition fails when and because, with age, the damage that results from these vulnerabilities overwhelms the evolved protections and exhausts any reserve of brain tissue. Implications of these vulnerabilities for the delay and management of dementia are discussed.},
}

@article {pmid42819539,
year = {2026},
author = {Takahashi, R and Kashibayashi, T and Fujita, J and Yoshida, K and Hashiramoto, A and Kowa, H and Mizuta, E},
title = {Baseline CSF tau and short-term clinical change during lecanemab therapy: A prospective real-world cohort study in Japan.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70487},
pmid = {42819539},
issn = {2352-8729},
abstract = {INTRODUCTION: Real-world prognostic evidence for cerebrospinal fluid (CSF) biomarkers during lecanemab therapy remains limited. We examined whether baseline CSF phosphorylated tau 181 (pTau181), total tau, and amyloid beta (Aβ) 42/Aβ40 were associated with 6-month clinical change.

METHODS: This prospective single-center cohort included 50 patients with early Alzheimer's disease spectrum treated with lecanemab. CSF biomarkers were measured using the Lumipulse G system. The primary outcome was 6-month change in Clinical Dementia Rating Sum of Boxes (CDR-SB). Models were adjusted for age, sex, and baseline Mini-Mental State Examination; sensitivity analyses included APOE ε4 status.

RESULTS: CDR-SB worsening occurred in 19 participants (38.0%). Higher pTau181 (β per SD = 0.408; 95% CI: 0.106 to 0.709; p = 0.0091) and total tau (β = 0.341; 95% CI: 0.032 to 0.651; p = 0.0314) were associated with worsening. Aβ42/Aβ40 was not.

DISCUSSION: Baseline CSF pTau181 and total tau were associated with 6-month clinical trajectories, supporting cautious cohort-level risk stratification.},
}

@article {pmid42819642,
year = {2026},
author = {Yang, X and Hu, P and Han, W and Dong, L and Zhang, H and Wang, J and Chen, H},
title = {Research advances in red ginseng polysaccharides: preparation, structural characteristics and immunomodulatory effect.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1929729},
pmid = {42819642},
issn = {1663-9812},
abstract = {Red ginseng is a processed product of ginseng through steaming. Its polysaccharides differ in structure and biological activity from those of ginseng. Red ginseng polysaccharides are mostly acidic polysaccharides and have various biological activities. It is worth noting that its immunomodulatory effect has become an important area of research. Pharmacological studies have shown that polysaccharides from red ginseng can enhance immunity through various pathways, such as affecting immune cell activity, regulating cytokine levels, promoting immune organ development, and regulating gut microbiota. In addition, red ginseng polysaccharide has other pharmacological effects, such as anti-diabetic effect, anti-Alzheimer's disease effect, health benefits for the skin, anticancer effect, and cardioprotective effect. This article reviews the extraction, purification, structural characterization, and biological activity of polysaccharides from red ginseng to elucidate their pharmacological effects and potential molecular mechanisms. In addition, this review also discusses the current research status of red ginseng polysaccharides, pointed out the existing gaps, and proposed innovative perspectives for better development of red ginseng polysaccharides.},
}

@article {pmid42819698,
year = {2026},
author = {Khawar, M and Bakthavatchalam, P},
title = {The Promise of Blood-Based Biomarkers in Early Detection and Care of Alzheimer's Disease.},
journal = {Nepal journal of epidemiology},
volume = {16},
number = {2},
pages = {1436-1437},
pmid = {42819698},
issn = {2091-0800},
}

@article {pmid42820100,
year = {2026},
author = {Le, LNN and Wheeler, GJ and Blockley, NP and Fletcher, E and Jung, Y and Farias, SET and Gavett, B and DeCarli, C and Fan, AP},
title = {Oxygen extraction fraction mapping between normal cognition and mild cognitive impairment in older adults using quantitative BOLD.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {42820100},
issn = {2837-6056},
support = {P30 AG072972/AG/NIA NIH HHS/United States ; R01 AG031563/AG/NIA NIH HHS/United States ; R01 NS128179/NS/NINDS NIH HHS/United States ; U19 NS120384/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/metabolism/physiopathology ; *Magnetic Resonance Imaging/methods ; *Oxygen/metabolism/blood ; Aged ; Female ; *Cognition/physiology ; Male ; *Brain/diagnostic imaging/metabolism ; *Aging/physiology/metabolism ; Brain Mapping/methods ; Bayes Theorem ; Aged, 80 and over ; },
abstract = {Oxygen extraction fraction (OEF) represents the proportion of oxygen utilized by the brain from the blood and is a sensitive biomarker in understanding the vascular interplay between oxygen supply and demand. Alterations in OEF are increasingly recognized in normal aging and the pathophysiology of many neurological disorders, including Alzheimer's disease and cognitive impairment. Here, we aimed to assess regional OEF MRI in older adults and investigate its relationship with mild cognitive impairment (MCI) and normal aging using a Variational Bayesian quantitative BOLD (qBOLD) framework. The qBOLD model leverages a biophysical relationship between OEF, deoxygenated blood volume (DBV), and the reversible transverse relaxation rate (R2 [']) to extract parameter values from asymmetric spin echo (ASE) MRI scans. The reliability of these parameter estimates was enhanced by Variational Bayesian inference, which incorporates prior distributions that we optimized in numerical simulation. We then applied this model to a cohort of older adults (N = 70) from the Alzheimer's Disease Research Center (ADRC) at the University of California, Davis, including 58 cognitively normal (CN) and 12 amnestic mild cognitive impaired (MCI) participants. Our findings revealed a trend of elevated OEF across many cortical brain regions in the MCI group. Additionally, we identified regional positive associations between OEF and age in the MCI group, significantly in the left inferior parietal region (β = 0.88 ± 0.23 , T = 3.75 , P = 0.0004). Furthermore, the relationship between OEF and episodic memory in the right parahippocampal region differed significantly between two diagnostic groups (negative for CN and positive for MCI) (β = 0.09 ± 0.02 , T = 3.77 , P = 0.0004). This work adopts a novel qBOLD MRI framework for studying OEF changes in cognitive impairment as a potential biomarker for monitoring pathophysiology in aging and dementia.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/metabolism/physiopathology
*Magnetic Resonance Imaging/methods
*Oxygen/metabolism/blood
Aged
Female
*Cognition/physiology
Male
*Brain/diagnostic imaging/metabolism
*Aging/physiology/metabolism
Brain Mapping/methods
Bayes Theorem
Aged, 80 and over

@article {pmid42820135,
year = {2026},
author = {Zaraska, M},
title = {Our Tears Can Help Diagnose Cancer, Parkinson's, and Alzheimer's.},
journal = {ACS central science},
volume = {12},
number = {9},
pages = {1273-1276},
doi = {10.1021/acscentsci.6c01440},
pmid = {42820135},
issn = {2374-7943},
abstract = {Eye swabs, bioassays, and even smart contact lenses can "pick up" biomarkers for various conditions.},
}

@article {pmid42820145,
year = {2026},
author = {Weng, Q and Goldstein, BA and Engelhard, MM},
title = {Censoring-Aware Reinforcement Learning to Optimize Early Risk Alerts from Longitudinal Clinical Data.},
journal = {Proceedings of machine learning research},
volume = {340},
number = {},
pages = {2151-2174},
pmid = {42820145},
issn = {2640-3498},
support = {K01 MH127309/MH/NIMH NIH HHS/United States ; P50 HD093074/HD/NICHD NIH HHS/United States ; },
abstract = {Early recognition of chronic conditions is critical to ensure patients receive timely interventions and support. Passive surveillance of routine electronic health records (EHRs) provides information about longitudinal health trajectories that can support prompt recognition and inform associated early actions. However, relevant information is acquired at a different rate for each patient, and there is an inherent trade-off between the earliness versus the specificity of diagnosis and related actions. Therefore, determining when to alert providers about a likely chronic condition requires us to weigh the predicted risk at the given time against the anticipated value of future information. To address this challenge, we analyze the optimal timing of early alerts using a Partially Observable Markov Decision Process (POMDP) with asymmetric reward. To learn an optimal alerting policy, we then propose a model-free reinforcement learning (RL) framework tailored to long-term clinical event surveillance from EHRs. Our proposed framework overcomes the pervasive issue of right-censoring in offline EHRs by leveraging a pseudo-label imputation approach. We also analytically demonstrate that entropy-regularized RL enables post-hoc threshold calibration to adapt the learned policy to specific preferences regarding the importance of earliness versus specificity without retraining. Systematic evaluations in synthetic data reveal that the advantage of RL-based look-ahead planning is maximized when diagnostic evidence emerges in predictable information bursts. Finally, real-world validations on two clinical cohorts show that our policy achieves an actionable lead time of 20.9 months prior to Alzheimer's disease diagnosis and 8.7 months prior to autism diagnosis in a pediatric cohort, both at 90% specificity. Our method and results provide a generalizable blueprint for optimal surveillance of chronic disease processes.},
}

@article {pmid42820327,
year = {2026},
author = {Lin, Y and Cho, I and Zhu, X and Wang, K and Zhu, L and Wong, W and Murray, M and Zhou, F},
title = {Potential of Ginkgo biloba Extract to Intervene in Chronic Inflammation-Related Diseases.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70467},
pmid = {42820327},
issn = {1099-1573},
support = {//USYD-Wepon and Faculty of Health and Medicine Scholarship of the University of Sydney/ ; },
abstract = {Chronic inflammation is a pathological mechanism of central importance that underpins a wide range of diseases, including neurodegenerative, cardiovascular, respiratory, gastrointestinal, and dermatological disorders. Ginkgo biloba extract (GBE), a standardized formulation derived from Ginkgo biloba leaves, has attracted growing attention due to its anti-inflammatory, antioxidant, and neuroprotective properties. This review comprehensively summarizes the current preclinical and clinical evidence regarding the therapeutic potential of GBE and its active constituents in inflammation-related diseases. GBE has been shown to attenuate pro-inflammatory cytokine production, suppress nuclear factor kappa B (NF-κB) activation, restore redox homeostasis, and modulate disease-relevant pathways in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, atherosclerosis, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, inflammatory skin conditions and rheumatoid arthritis. While these findings highlight the promising multi-targeted anti-inflammatory actions of GBE, limitations remain regarding the identification of specific active compounds, standardization of formulations, and the availability of robust clinical evidence. Further research is warranted to clarify the mechanisms of action and optimize delivery of GBE, and to validate the efficacy and safety of GBE in large-scale clinical trials.},
}

@article {pmid42820818,
year = {2026},
author = {Dillon, EC and Bailey, C and Alsamawi, A and Aasaavari, A and Fabian, T and Robison, J},
title = {"I Wanted to Get Back Out There": In-depth Interviews With Older Adults and Family Caregivers About Moving Out of Nursing Homes Using Medicaid's Money Follows the Person Program and How Dementia Influences Transitions.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648261491313},
doi = {10.1177/07334648261491313},
pmid = {42820818},
issn = {1552-4523},
support = {R01 AG083100/AG/NIA NIH HHS/United States ; },
abstract = {Medicaid's Money Follows the Person (MFP) Program enables nursing home residents to return to community living, yet people living with dementia (PLWD) less often transition to the community through MFP, for unclear reasons. To understand mechanisms underlying this disparity, we conducted in-depth interviews with 44 older adults in Connecticut eligible for MFP and 44 family caregivers (41% PLWD/PLWD family members). Desire to move, program awareness, ability to self-advocate, personal care needs, family support, housing and home and community-based services (HCBS) resources all influenced moves. PLWD less often desired to move, typically required more assistance to move, were less able to self-advocate and manage logistics, had higher personal care needs, needed more family/informal support, and had additional safety and supervision needs. Better support for PLWD is needed in transition and HCBS programs as the population grows, nursing homes beds decrease, and the desire to live in the community persists.},
}

@article {pmid42820819,
year = {2026},
author = {Zhang, Q and Yu, J and Zhai, X and Zhang, L and Peng, J and Deng, C and Liu, Y and Zhou, Q and Niu, T and Luo, F and Chen, C},
title = {Mosaic Loss of the Y Chromosome: Mechanisms and Diseases.},
journal = {Protein & cell},
volume = {},
number = {},
pages = {},
doi = {10.1093/procel/pwag073},
pmid = {42820819},
issn = {1674-8018},
abstract = {Mosaic loss of the Y chromosome (mLOY) is a male‑specific somatic loss of the Y chromosome that is predominantly observed in peripheral blood leukocytes, but can also be found in other tissue types. It represents one of the most common male-specific somatic mutations, particularly prevalent in aging individuals. Accumulating evidence shows that mLOY markedly increases the incidence, progression, and adverse prognosis of multiple diseases, including, but not limited to, myocardial fibrosis, lung and bladder cancers, and Alzheimer's disease. Mechanistically, for extrinsic effects of mLOY, hematopoietic mLOY affect other cell populations, thereby promoting disease initiation and progression. From an intrinsic effects, mLOY within cells reprograms autosomal gene expression and reshapes interactions with the immune microenvironment, jointly driving malignant evolution. In this review, we summarize the current understanding of both intrinsic and extrinsic mLOY effects on immune regulation and disease pathogenesis, highlighting its multifaceted roles across cancer, cardiovascular disorders, infections, and other mLOY-associated conditions.},
}

@article {pmid42821427,
year = {2026},
author = {Lévesque, M and Akzam-Ouellette, MA and Joubert, S and Arguin, M},
title = {Altered temporal features of visual processing in subjective cognitive decline.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001128},
pmid = {42821427},
issn = {1931-1559},
support = {//Hope for Dementia/ ; },
abstract = {OBJECTIVE: Subjective cognitive decline (SCD) is possibly the earliest known stage of Alzheimer's disease. Individuals with SCD report perceiving a decline in their cognitive functioning and express concern about it. However, when assessed with standard neuropsychological tests, they perform within normal limits.

METHOD: The present study focuses on the temporal features of visual processing in SCD using the random temporal sampling technique. This method reveals the perceptual oscillations which occur during a visual task by presenting stimuli with randomly varying signal-to-noise ratio through time. Fourteen individuals with SCD and 15 others without (i.e., controls), aged between 60 and 85 years old, took part in the study.

RESULTS: Participants with SCD performed within normal limits on neuropsychological tasks, as did the control group. In the experimental task, participants had to recognize briefly presented five-letter French words. The results take the form of classification images, which depict how visual processing efficiency fluctuates over time and across different frequency bands of signal-to-noise ratio oscillations. The classification images reveal significant differences between groups on the temporal patterns of visual processing. A machine learning classifier was used to categorize the data of individual participants according to group membership. The classifier achieved 79.3% classification accuracy using 18.0% of the available features.

CONCLUSIONS: Even though SCD individuals show no detectable cognitive impairment in neuropsychological testing, random temporal sampling can reveal anomalies in their perceptual function. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42821606,
year = {2026},
author = {Xu, MY and Bai, YD and Zeng, XQ and Tan, CR and Lai, YJ and Wang, YJ},
title = {Bazedoxifene restores myelin changes and attenuates cognitive deficits in a mouse model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490479},
doi = {10.1177/13872877261490479},
pmid = {42821606},
issn = {1875-8908},
abstract = {BackgroundDemyelination and remyelination are critical processes in the pathogenesis of Alzheimer's disease (AD). The selective estrogen receptor modulator bazedoxifene (BZA) has been shown to promote remyelination, suggesting its potential therapeutic efficacy.ObjectiveThis study aimed to evaluate the therapeutic efficacy of BZA in addressing demyelination and associated cognitive deficits in a mouse model of AD.MethodsThe changes in myelin and oligodendrocyte-related indicators in the brains of APP/PS1 mice were assessed via immunostaining. 5 × FAD transgenic mice received oral administration of BZA or vehicle for 3 months. The therapeutic outcomes were evaluated through behavioral tests, immunostaining and western blotting.ResultsAD mice exhibited pronounced myelin loss and oligodendrocytes depletion. BZA treatment attenuated cognitive decline, restored myelin changes and mitigated neurodegeneration in the brain. These effects were observed independently of alterations in amyloid-β deposition.ConclusionsThese findings provide compelling evidence supporting the involvement of demyelination in AD and suggest that BZA may represent a promising therapeutic agent for AD by targeting myelin repair mechanisms.},
}

@article {pmid42821639,
year = {2026},
author = {Schwaninger, I and Ighanian, P and Borga, L and Giraitis, M and Hoogendoorn, P and Klucken, J},
title = {Value in app store metadata and user reviews: A dual perspective on quality of Parkinson's and dementia apps.},
journal = {PLOS digital health},
volume = {5},
number = {10},
pages = {e0001730},
pmid = {42821639},
issn = {2767-3170},
abstract = {App stores provide a range of health applications for people living with Alzheimer's disease (AD) and Parkinson's disease (PD). Users like patients can access information from both manufacturer-provided app descriptions and metadata, as well as from user reviews. However, navigating this information to identify value-generating apps of high quality remains challenging. From a health technology assessment (HTA) standpoint, quality is defined by evidence-based medicine, safety, and user-centeredness. To explore the potential value of app store information available to patients, we conducted a descriptive, mixed-methods analysis of unstructured app metadata and user feedback from the Apple App Store and Google Play Store (as of May 2024). We analyzed 1,237 AD/PD-related apps which included 50 duplicates (resulting in 1,187 apps), utilizing descriptive statistics, content analysis, large language model-supported exploratory classification, and a topic modeling approach. In total, only about 2% of the apps claimed to be certified medical devices. Moreover, 24% of Apple apps and 14% of Google apps were in the "Medical" app store genre, among which we found that 63% of Apple and 54% of Google apps were patient-facing. We manually categorized patient-facing apps predominantly under "Care Support," followed by "Health & Wellness" and "Patient Monitoring." Importantly, user feedback provided exploratory, potentially valuable patient-reported outcome and experience information but is derived from personal opinions on "user experience," "health improvement," and "costs." As quality information on DHTs could be identified in unstructured app metadata, this information should be improved in trustworthiness and more accessible to users like patients, supporting the public to find high-quality health apps. Furthermore, as user opinions contained information with potential value for patients, these should be explored as complementary value-generating indicators of health apps in future work.},
}

@article {pmid42821808,
year = {2026},
author = {Costa, N and Marcélo Fleuret, C and Gombault, E and Soto Martin, M and De Mauleon, A},
title = {Longitudinal Impact of Agitation and Aggression Symptoms on Societal Costs in Alzheimer's Disease: A Focus on Informal Care and Socioeconomic Disparities.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {10},
pages = {e70257},
pmid = {42821808},
issn = {1099-1166},
support = {//Ethypharm/ ; //Center Hospitalier Universitaire de Toulouse/ ; },
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/economics/psychology ; Aged ; *Psychomotor Agitation/economics ; *Aggression/psychology ; France ; Longitudinal Studies ; Prospective Studies ; Aged, 80 and over ; Caregivers/economics ; *Cost of Illness ; Middle Aged ; *Health Care Costs/statistics & numerical data ; Socioeconomic Disparities in Health ; *Patient Care/economics ; Long-Term Care/economics ; },
abstract = {BACKGROUND: To date, no longitudinal study has assessed the effect of agitation on societal costs-particularly informal care costs-over time in Alzheimer's Disease (AD) patients with Agitation and Aggression (A/A) symptoms.

OBJECTIVES: This study estimates the impact of A/A symptoms evolution on longitudinal care costs including informal care costs in moderate-to-severe AD, considering patient and caregiver socioeconomic characteristics.

DESIGN: A longitudinal trajectory clustering method was used on this longitudinal, prospective, multicenter observational cohort study.

SETTING AND PARTICIPANTS: 262 community-dwelling and long-term care facility (LTCF) patients of both sexes, aged 60 years and older, with clinically significant A/A symptoms were recruited from memory centers in southwest France.

METHODS: Patients were followed for 12 months. A/A data was recorded by clinicians using the Neuropsychiatric Inventory (NPI-c). Costs were estimated from a societal perspective, including healthcare and informal care, using the RUD questionnaire. K-means longitudinal method identified A/A evolution profiles. Cost differences across A/A evolution profiles were analyzed using Generalized Linear Models.

RESULTS: Two A/A evolution profiles were identified: mild symptoms at baseline with improvement (A) and moderate symptoms at baseline with limited improvement or stability (B). Annual costs were €22,959 in group A and €23,625 in group B excluding supervision, and €52,111 and €56,149, respectively, including supervision. In LTCF residents, higher A/A severity was associated with increased medical visits and medication costs, though overall cost differences were smaller. Informal care neared 70% of total costs for community-dwelling patients, with supervision covering the majority of these costs.

CONCLUSIONS: Evolution of A/A symptoms significantly increases both healthcare and informal care costs, particularly in at-home settings. Integrating systematic monitoring of behavioral symptoms into routine care would enable personalized, cost-effective strategies. Informal care costs, often undervalued and overlooked in economic analyzes, underscores the need for improvement in resource allocation and quality of life, for both patients and caregivers.

CLINICAL TRIAL NUMBER: NCT03554226.},
}

Humans
Female
Male
*Alzheimer Disease/economics/psychology
Aged
*Psychomotor Agitation/economics
*Aggression/psychology
France
Longitudinal Studies
Prospective Studies
Aged, 80 and over
Caregivers/economics
*Cost of Illness
Middle Aged
*Health Care Costs/statistics & numerical data
Socioeconomic Disparities in Health
*Patient Care/economics
Long-Term Care/economics

@article {pmid42821845,
year = {2026},
author = {Shir, D and Algeciras-Schimnich, A and Piura, YD and Bornhorst, JA and Figdore, DJ and Elgenidi, A and Lachner, C and Graff-Radford, NR and Day, GS},
title = {Clinical Factors Associated With Discordant Plasma P-Tau217 and Established Alzheimer Disease Biomarkers.},
journal = {Neurology},
volume = {107},
number = {8},
pages = {e218591},
pmid = {42821845},
issn = {1526-632X},
support = {R01 AG041851/AG/NIA NIH HHS/United States ; RF1 AG069052/AG/NIA NIH HHS/United States ; R01 AG089380/AG/NIA NIH HHS/United States ; R01 AG075802/AG/NIA NIH HHS/United States ; UF1 NS125417/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R37 AG011378/AG/NIA NIH HHS/United States ; RF1 AG061900/AG/NIA NIH HHS/United States ; R01 AG056366/AG/NIA NIH HHS/United States ; UH2 AG083186/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; U01 NS120901/NS/NINDS NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/blood/diagnosis ; Female ; Biomarkers/blood ; Male ; Retrospective Studies ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Aged, 80 and over ; Middle Aged ; Phosphorylation ; Positron-Emission Tomography ; },
abstract = {BACKGROUND AND OBJECTIVES: Plasma phosphorylated tau (p-tau) 217 is increasingly used for Alzheimer disease (AD) diagnosis and treatment decisions but may be discordant with established AD biomarkers. False-positive (FP) plasma results may lead to overtreatment and false-negative (FN) results to missed or delayed disease-modifying therapies. We evaluated factors associated with discordant results.

METHODS: This retrospective study included participants enrolled in memory and aging studies at Mayo Clinic with "positive" (>0.324 pg/mL) or "negative" (<0.186 pg/mL) plasma p-tau217 results and confirmatory AD biomarkers. Plasma results were classified as true positive (TP), true negative (TN), FP, or FN, referencing amyloid-PET and CSF p-tau181/β-amyloid (Aβ) 42. Clinical and laboratory variables were compared using univariate analyses; multivariable logistic regression evaluated independent associations with discordance.

RESULTS: Among 706 participants (median 70.0 [interquartile range 15.8] years; 54% male), 60 (8.5%) had discordant plasma p-tau217 results. FN results (5.6%) were more frequent than FP results (2.8%; p = 0.007). Discordance was associated with older age (odds ratio [OR] 1.61 per decade, 95% CI 1.23-2.14) and obstructive sleep apnea (OR 1.94, 95% CI 1.08-3.49). FN (vs TP) results were associated with milder clinical stage (global Clinical Dementia Rating [CDR] ≤0.5 vs CDR ≥1; p < 0.001), higher Mini-Mental State Examination scores (OR 1.20 per point, 95% CI 1.05-1.36), obstructive sleep apnea (OR 2.01, 95% CI 1.01-4.3), higher body mass index (OR 1.11/kg/m[2], 95% CI 1.03-1.20), and higher estimated glomerular filtration rate (eGFR: OR 1.33/10 mL/min/1.73 m[2], 95% CI 1.05-1.69). In age-adjusted models, body mass index (OR 1.14, 95% CI 1.03-1.25), eGFR (OR 1.63/10 mL/min/1.73 m[2], 95% CI 1.22-2.16), and earlier clinical stage (CDR ≤0.5) were independently associated with FN results. FP (vs TN) results were associated with older age (OR 2.37, 95% CI 1.36-4.09), thyroid disease (OR 4.41, 95% CI 1.36-14.3), lower eGFR (OR 0.48/10 mL/min/1.73 m[2], 95% CI 0.31-0.66), and advanced disease stage (CDR ≥1). In age-adjusted models, eGFR (OR 0.54/10 mL/min/1.73 m[2], 95% CI 0.35-0.82) and advanced disease stage (CDR ≥ 1 vs CDR 0: OR 11.11, 95% CI 2.0-50.0; vs CDR 0.5: OR 4.55, 95% CI 1.12-16.67) were independently associated with FP results.

DISCUSSION: Plasma p-tau217 results and established AD biomarkers were discordant in 8.5% of participants. Clinical stage and factors related to brain amyloid clearance, renal clearance, and volume of distribution were associated with discordant results. These insights may inform mechanisms of discordance and identify patients requiring confirmatory biomarker measures.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/blood/diagnosis
Female
Biomarkers/blood
Male
Retrospective Studies
Aged
Amyloid beta-Peptides/cerebrospinal fluid/blood
Aged, 80 and over
Middle Aged
Phosphorylation
Positron-Emission Tomography

@article {pmid42821881,
year = {2026},
author = {Güntert, L and Taeymans, J and Baur, H and Van Dyck, M and Lutz, N},
title = {Physical inactivity attributable burden of disease on morbidity and mortality across Swiss language regions: a population-based modelling study.},
journal = {Swiss medical weekly},
volume = {156},
number = {},
pages = {5162},
doi = {10.57187/5162},
pmid = {42821881},
issn = {1424-3997},
mesh = {Humans ; Switzerland/epidemiology ; Female ; *Sedentary Behavior ; Male ; Middle Aged ; Aged ; Adult ; *Cost of Illness ; Prevalence ; Language ; Risk Factors ; *Noncommunicable Diseases/epidemiology ; Morbidity ; Exercise ; },
abstract = {UNLABELLED: BACKGROUND: Physical inactivity is a major risk factor for noncommunicable diseases, contributing to both substantial morbidity and premature mortality. In Switzerland, the prevalence of physical inactivity varies across language regions. This study aimed to quantify differences across Swiss language regions in the physical inactivity-attributable burden of disease, expressed as Years Lived with Disability (YLD) and Years of Life Lost (YLL) for 2022. The analysis focuses on YLD and YLL attributable to physical inactivity across 15 physical inactivity-associated diseases.

METHODS: This study employed the Population Attributable Fraction approach to estimate the proportion of YLD and YLL attributable to physical inactivity in Switzerland. The analysis included individuals aged >20 years and was stratified by disease, age, sex and language region (German-, French- and Italian-speaking). Physical inactivity was defined according to WHO guidelines as not meeting at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week. Prevalence data on physical inactivity were derived from the 2022 Swiss Health Survey. Prevalences were combined with relative risks (RR) of corresponding diseases, identified through a systematic literature search to derive Population Attributable Fractions. Estimates of YLD and YLL for Switzerland for 2022 were derived from the Global Burden of Disease study. YLD and YLL estimates attributable to physical inactivity are presented as rates per 100,000 people aged >20 years. Uncertainty was assessed using parametric bootstrapping.

RESULTS: Overall, the physical inactivity-attributable burden of disease was estimated at 227.08 (95% CI: 214.74-240.08) YLD and 424.23 (95% CI: 383.15-479.23) YLL per 100,000 people aged >20 years. This corresponds to approximately 2% of total DALYs in Switzerland in 2022. Clear regional differences were observed. Estimated physical inactivity-attributable YLD rates were highest in the Italian-speaking region (134.90; 95% CI: 122.04-148.25) followed by the French-speaking region (130.72; 95% CI: 120.78-141.50) and German-speaking region (96.26; 95% CI: 88.81-104.01). Similarly, estimated YLL rates attributable to physical inactivity were highest in the Italian-speaking region (287.74; 95% CI: 245.82-349.99), followed by the French-speaking region (221.56; 95% CI: 192.54-264.55) and German-speaking region (186.67; 95% CI: 162.64-222.27). Disease-specific analysis indicated that depression (93.38; 95% CI: 85.46-101.80) and low back pain (52.01; 95% CI: 45.90-58.47) contributed most to physical inactivity-attributable YLD rates, whereas coronary heart disease (132.12; 95% CI: 115.60-149.55) and Alzheimer's disease and dementia (83.61; 95% CI: 51.90-134.97) were the main contributors to physical inactivity-attributable YLL rates. Women showed consistently higher burden of disease than men, with physical inactivity-attributable YLD rates of 286.06 (95% CI: 264.58-308.90) versus 166.32 (95% CI: 155.06-178.44) and physical inactivity-attributable YLL rates of 475.23 (95% CI: 404.85-577.64) versus 371.69 (95% CI: 337.50-414.96).

CONCLUSION: Results of this analysis suggest that physical inactivity significantly contributes to YLD and YLL rates in Switzerland, with pronounced regional and sex-specific disparities. The higher burden of disease observed in the Italian- and French-speaking regions highlights the need for regionally tailored prevention strategies that address cultural and contextual differences.},
}

Humans
Switzerland/epidemiology
Female
*Sedentary Behavior
Male
Middle Aged
Aged
Adult
*Cost of Illness
Prevalence
Language
Risk Factors
*Noncommunicable Diseases/epidemiology
Morbidity
Exercise

@article {pmid42822260,
year = {2026},
author = {d'Orsi, G},
title = {Epilepsy phenotypes and Alzheimer's disease biomarkers in adults with down syndrome: beyond diagnostic codes.},
journal = {Seizure},
volume = {143},
number = {},
pages = {39-40},
doi = {10.1016/j.seizure.2026.09.024},
pmid = {42822260},
issn = {1532-2688},
}

@article {pmid42822579,
year = {2026},
author = {Zhang, X and Tao, T and Liu, W and Xie, A and Liang, Y and Zhu, X},
title = {Mitochondria and associated complexes as therapeutic targets in aging: From biomacromolecular structure-function insights to clinical translation.},
journal = {Mitochondrion},
volume = {92},
number = {},
pages = {102221},
doi = {10.1016/j.mito.2026.102221},
pmid = {42822579},
issn = {1872-8278},
abstract = {Mitochondria and their biomacromolecular complexes-such as the electron transport chain (ETC), mitochondrial permeability transition pore (mPTP), and protein quality control systems-play pivotal roles in aging and age-related diseases. This review integrates recent insights into how structural and functional disruptions of these complexes drive cellular senescence and systemic decline. We outline the architecture of mitochondrial assemblies (e.g., oxidative phosphorylation (OXPHOS) complexes, mtDNA-protein interactions) essential for energy production and organelle stability. Age-related alterations in stoichiometry, conformational states (e.g., mPTP opening), and post-translational modifications (e.g., SIRT3-mediated acetylation) compromise mitochondrial integrity, fueling metabolic dysfunction and chronic inflammation ("inflammaging"). Therapeutic strategies include small-molecule stabilizers of ETC supercomplexes, peptide-based mPTP inhibitors, and CRISPR-mediated correction of mtDNA-protein mismatches. Tissue-specific models (e.g., Complex I in skin aging, Bcl-2 protein imbalance in ovarian aging) exemplify the clinical relevance. We also categorize nine age-associated diseases-neurodegenerative, cardiovascular, and cancer types-based on their dependence on distinct mitochondrial complexes, such as ATP synthase in cancer resistance and the TIM/TOM import machinery in Alzheimer's disease. By linking structural findings (e.g., cryo-EM studies) with therapeutic innovation, this review offers a framework for targeting mitochondrial complexes to mitigate aging and its related pathologies.},
}

@article {pmid42822589,
year = {2027},
author = {Saleki, S and Wabant, C and Loriot, A and Stanga, S and Masquelier, J and Muccioli, GG and Suelves, N and Kienlen-Campard, P},
title = {Alzheimer's disease-associated presenilin 2 N141I mutation impairs neuronal lipid homeostasis and mitochondrial dynamics through selective downregulation of the Golgi exchange factor Gbf1.},
journal = {Experimental neurology},
volume = {407},
number = {},
pages = {116045},
doi = {10.1016/j.expneurol.2026.116045},
pmid = {42822589},
issn = {1090-2430},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism ; Mice ; *Neurons/metabolism ; Homeostasis/physiology ; *Lipid Metabolism/genetics/physiology ; Down-Regulation/physiology ; Mutation/genetics ; *Presenilin-2/genetics ; *Mitochondrial Dynamics/physiology/genetics ; *Guanine Nucleotide Exchange Factors/genetics/metabolism/biosynthesis ; Cells, Cultured ; Mitochondria/metabolism ; Mice, Inbred C57BL ; Golgi Apparatus/metabolism ; },
abstract = {Presenilin 2 (PS2) mutations cause familial Alzheimer's disease, yet their effects beyond amyloid processing remain poorly understood. Here, we investigated how PS2 deletion and the N141I mutation affect neuronal lipid homeostasis and mitochondrial dynamics in mouse primary neurons. Both PS2 deletion and N141I mutation reduced neuronal lipid content. However, exogenous lipid supplementation rescued this deficit only in N141I-expressing neurons, indicating a partial loss-of-function effect. N141I neurons also displayed reduced OPA1, a mitochondrial fusion regulator, restored by lipid supplementation. RNA-sequencing identified Gbf1, a Golgi-specific guanine nucleotide exchange factor, as selectively downregulated in N141I but not knockout tissue, which was confirmed at the protein level in mouse brain and primary neurons. Gbf1 knockdown in mouse embryonic fibroblasts (MEFs) recapitulated the N141I lipid profile. Together, these findings reveal a PS2-GBF1-lipid-mitochondria axis disrupted specifically by the N141I mutation, suggesting an amyloid-independent pathway contributing to neurodegeneration and identifying potential therapeutic targets for familial Alzheimer's disease.},
}

Animals
*Alzheimer Disease/genetics/metabolism
Mice
*Neurons/metabolism
Homeostasis/physiology
*Lipid Metabolism/genetics/physiology
Down-Regulation/physiology
Mutation/genetics
*Presenilin-2/genetics
*Mitochondrial Dynamics/physiology/genetics
*Guanine Nucleotide Exchange Factors/genetics/metabolism/biosynthesis
Cells, Cultured
Mitochondria/metabolism
Mice, Inbred C57BL
Golgi Apparatus/metabolism

@article {pmid42822590,
year = {2026},
author = {Yagihara, H and Saito, Y and Takeuchi, T and Seki, K and Minakawa, EN},
title = {Fluid amyloid-β (Aβ) biomarkers reflect early β-sheet-rich Aβ deposition during the preclinical stage in Alzheimer's disease model 5XFAD mice.},
journal = {Experimental neurology},
volume = {408},
number = {},
pages = {116044},
doi = {10.1016/j.expneurol.2026.116044},
pmid = {42822590},
issn = {1090-2430},
abstract = {Early detection of disease progression using clinically-relevant biomarkers in animal models is important for mechanistic studies and for developing therapeutics in neurodegenerative diseases including Alzheimer's disease (AD). The preclinical stage of AD, when amyloid-β (Aβ) starts to accumulate before cognitive decline, provides a critical window for disease modification. In humans, decreases in cerebrospinal fluid (CSF) Aβ42 and the Aβ42/Aβ40 ratio in preclinical AD are considered to reflect the preferential sequestration of aggregation-prone Aβ42 into β-sheet-rich deposition in the brain, with corresponding changes being detectable in plasma. However, the extent to which these biomarker-pathology relationships are recapitulated in AD model mice remains incompletely defined. Here we show that CSF and plasma Aβ42 and the Aβ42/Aβ40 ratio decline with age in parallel with the progression of β-sheet-rich Aβ deposition in preclinical 5XFAD mice, one of the most widely used AD mouse models, as assessed through monthly profiling of these biomarkers. Notably, the CSF Aβ42/Aβ40 ratio showed a negative correlation with β-sheet-rich Aβ deposition in the brain, whereas CSF Aβ40 did not show a comparable association. In addition, the plasma Aβ42/Aβ40 ratio showed a positive correlation with the CSF Aβ42/Aβ40 ratio, suggesting that the plasma Aβ42/Aβ40 ratio may also reflect brain Aβ deposition in this model. The strength of these correlations differed by sex, suggesting that sex-dependent differences in the Aβ kinetics in this model may influence how closely fluid biomarkers reflect pathological progression. These findings support the potential utility of fluid Aβ as a pathology-linked, translatable biomarker in preclinical 5XFAD mice.},
}

@article {pmid42822610,
year = {2026},
author = {Arayesh, MJ and Ataellahi, F and Masoudi, R},
title = {Differential effects of amyloid-β and tau on UCH gene expression in Drosophila models of Alzheimer's disease.},
journal = {Gene},
volume = {1016},
number = {},
pages = {150431},
doi = {10.1016/j.gene.2026.150431},
pmid = {42822610},
issn = {1879-0038},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive impairments in learning and memory. Substantial evidence indicates that dysfunction of the ubiquitin-proteasome system (UPS) in the AD brain leads to aberrant protein aggregation, ultimately resulting in synaptic dysfunction and neuronal loss. In this study, we investigated the effects of pan-neuronal expression of Tau[WT] or Aβ42-key pathological hallmarks of AD-on the expression of UCH, a critical UPS component, in Drosophila melanogaster at three time points: 5, 15, and 25 days after eclosion.

METHODS AND RESULTS: UCH mRNA levels were quantified using real-time RT-PCR. UCH expression showed an age-dependent downregulation in Aβ42 transgenic flies over all three post-eclosion intervals. While UCH transcription witnessed no significant change in 5-day-old Tau[WT] transgenic flies, there was a considerable decline in UCH mRNA levels in 15- and 25-day-old flies. Notably, Aβ42 had a more prominent impact on UCH gene expression than Tau[WT] across all three time points.

CONCLUSION: Tau[WT] and Aβ42 exert independent adverse effects on UCH expression. An apparent age-related trend was observed in the fly models, whereby Aβ42 showed a relatively stronger influence on UCH transcription compared with Tau[WT]. Accordingly, therapeutic strategies that target both Tau and amyloid-β may warrant consideration.},
}

@article {pmid42822752,
year = {2026},
author = {Xuan, Z and Rahman, MU and Ilyas, M and Alioui, Y and Xin, Y and Cao, X and Ullah, H},
title = {Gut bacterial isolates from individuals with Alzheimer's disease induce strain-specific intestinal, inflammatory, and neurobehavioral phenotypes in mice.},
journal = {Brain research},
volume = {1893},
number = {},
pages = {150569},
doi = {10.1016/j.brainres.2026.150569},
pmid = {42822752},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which alterations in the microbiota-gut-brain axis has been increasingly investigated. However, the effects of individual cultivable bacterial isolates recovered from individuals with AD on host intestinal and neurobehavioral phenotypes remain insufficiently characterized. In this study, three bacterial isolates, Escherichia coli, Klebsiella pneumoniae, and Citrobacter pasteurii, were recovered from fecal samples collected from individuals diagnosed with AD and evaluated in healthy BALB/c mice following long-term oral administration. The effects of the isolates on physiological parameters, intestinal morphology and barrier-associated markers, inflammatory responses, gut microbial community composition, and neurobehavioral outcomes were assessed. The three isolates produced strain-specific effects, with C. pasteurii producing the most pronounced overall phenotype. Mice receiving C. pasteurii showed reduced body weight gain, increased spleen index, and shortened colon length, accompanied by elevated circulating inflammatory cytokines. Alterations in goblet cells, MUC2 expression, and tight-junction-associated proteins, including ZO-1 and claudin-1, were also observed, indicating alterations in intestinal barrier-associated structures. Gut microbiota analysis revealed strain-specific changes in microbial diversity and community composition, with the most pronounced alterations observed in the C. pasteurii group. In addition, C. pasteurii administration was associated with increased hippocampal inflammatory responses and astrocytic activation, whereas no apparent hippocampal neuronal loss was detected. Neurobehavioral testing revealed reduced locomotor activity and altered exploratory and behavioral responses, particularly in the C. pasteurii group. However, because reduced locomotor activity may influence performance in the novel object recognition and tail suspension tests, these findings should be interpreted cautiously. K. pneumoniae produced intermediate effects, whereas E. coli showed comparatively milder effects under the experimental conditions used. Collectively, these findings indicate that the tested bacterial isolates recovered from individuals with AD can produce strain-specific intestinal, inflammatory, microbial, and neurobehavioral alterations in healthy mice, with C. pasteurii producing the strongest overall phenotype. Importantly, the observed changes in gut microbial composition do not establish specific bacterial functions or pathogenicity, as microbial functional activity was not directly assessed. The present study does not establish that these bacteria are specifically associated with AD or that they cause AD progression; rather, it provides experimental evidence that individual cultivable bacterial isolates recovered from individuals with AD may differentially influence host phenotypes relevant to processes implicated in neurodegenerative disease. Further studies using larger human cohorts with appropriate healthy controls, validated AD models, and direct functional and mechanistic investigations are required to clarify the relevance of these observations to AD pathophysiology.},
}

@article {pmid42823347,
year = {2026},
author = {Bravo-Risi, F and Alburquerque Orta, G and Kim, PJ and Wylie-Young, H and Stimming, TH and Soto, P and Estrada, L and Jankowsky, JL and Morales, R},
title = {The Progression of Prion Diseases Is Not Altered in the Absence of TMEM106B.},
journal = {eNeuro},
volume = {13},
number = {10},
pages = {},
pmid = {42823347},
issn = {2373-2822},
support = {P01 AG066606/AG/NIA NIH HHS/United States ; P01 AI077774/AI/NIAID NIH HHS/United States ; R01 AG072491/AG/NIA NIH HHS/United States ; R01 AI132695/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; *Membrane Proteins/genetics/deficiency/metabolism ; Female ; *Nerve Tissue Proteins/genetics/deficiency/metabolism ; Male ; Disease Progression ; *Prion Diseases/pathology/metabolism/genetics ; Disease Models, Animal ; Prions/metabolism ; Mice, Knockout ; Brain/pathology/metabolism ; Mice, Inbred C57BL ; Mice ; },
abstract = {Transmembrane protein 106B (TMEM106B) is a type II transmembrane glycoprotein localized in late endosomes and lysosomes. This protein has been attributed to relevant roles in disease risk and progression of multiple neurodegenerative disorders. In experimental models, TMEM106B has been linked with the prion-like spread of misfolded tau proteins responsible for Alzheimer's disease and other tauopathies. The role of this protein in the spread of other misfolded proteins, like prions, has not been explored. Here, we tested whether the removal of TMEM106B altered the progression of prion diseases using animal mouse models (male and female). This was carefully tested using different prion dosages, strains, and routes of administration. Our results demonstrate that the absence of TMEM106B does not alter the progression of prion diseases in any of the tested conditions. This data provides supportive evidence on the specificity of TMEM106B in neurodegenerative conditions.},
}

Animals
*Membrane Proteins/genetics/deficiency/metabolism
Female
*Nerve Tissue Proteins/genetics/deficiency/metabolism
Male
Disease Progression
*Prion Diseases/pathology/metabolism/genetics
Disease Models, Animal
Prions/metabolism
Mice, Knockout
Brain/pathology/metabolism
Mice, Inbred C57BL
Mice

@article {pmid42823476,
year = {2026},
author = {Rittmo, J and Franzmeier, N and Strandberg, O and Chauveau, L and Satterthwaite, TD and Wisse, LEM and Spotorno, N and Behjat, HH and Dehsarvi, A and van Westen, D and Anijärv, TE and , and Landau, SM and Palmqvist, S and Janelidze, S and Stomrud, E and Ossenkoppele, R and Mattsson-Carlgren, N and Hansson, O and Vogel, JW},
title = {Different functional connectivity gradients reflect aging and Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42823476},
issn = {1546-1726},
support = {KAW 2020.0239//Science for Life Laboratory (SciLifeLab)/ ; KAW 2020.0239//Science for Life Laboratory (SciLifeLab)/ ; 2024-03642//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2022-00775, 2021-02219//Vetenskapsrådet (Swedish Research Council)/ ; 2024-03642//Vetenskapsrådet (Swedish Research Council)/ ; 23074CB//Alzheimer Forschung Initiative (Alzheimer Forschung Initiative e.V.)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; 2022-0231//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; FO2021-0293, FO2023-0163//Hjärnfonden (Swedish Brain Foundation)/ ; },
abstract = {Aging and Alzheimer's disease (AD) are accompanied by alterations to large-scale communication patterns in the brain, which can be tracked in vivo using functional connectivity. The location, direction and relevance of these changes remain widely debated, although they are rarely studied in the context of whole-cortex communication dynamics. Here, in two independent cohorts (BioFINDER-2, N = 973; Alzheimer's Disease Neuroimaging Initiative, N = 129), we show that functional connectivity changes associated with aging and AD are strongly aligned with separate fundamental axes of hierarchical brain communication. Early accumulation of AD pathology and subsequent cognitive decline are both linked to functional change along the sensory-association axis. Meanwhile, age-related functional changes occur along the representation-executive axis consistently throughout the adult lifespan. These findings together suggest that both AD and aging alter major but orthogonal functional pathways in the brain. More broadly, our findings position whole-brain connectivity dynamics as a unifying framework for interpreting functional changes across the adult lifespan.},
}

@article {pmid42823573,
year = {2026},
author = {Nguyen, N and Yuan, M and Wang, Y},
title = {From Design to Bedside: Brain-Targeted Engineered Nanoparticles and Predictive Modeling for Neurodegenerative Diseases Therapeutics.},
journal = {Pharmaceutical research},
volume = {},
number = {},
pages = {},
pmid = {42823573},
issn = {1573-904X},
support = {CMMI 1851635//National Science Foundation/ ; ECCS 2021081//National Science Foundation/ ; },
abstract = {Nanoparticle (NP)-based drug delivery systems offer promising solutions for neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, which have no cure due to the brain's structural complexity and the restrictive nature of the blood-brain barrier (BBB). Conventional therapeutics, despite strong in vitro efficacy, often fail clinically due to poor brain penetration. Recent advances in NP engineering, including optimization of size (10-100 nm), surface charge (-10 to -20 mV), and targeted ligand decoration, have improved BBB crossing and reduced premature clearance. In parallel, predictive in silico approaches, such as physiologically based pharmacokinetic (PBPK) modeling, computational fluid dynamics, and machine learning models, enable quantitative prediction of NP biodistribution, residence times, and region-specific uptake. By simulating key determinants, including blood flow dynamics, vasculature heterogeneity, permeability, and retention, these computational tools accelerate lead selection, reduce experimental burden, and inform design before in vivo testing. This review integrates recent progress in NP design with advanced computational modeling, highlighting how their convergence provides a rational framework for developing next-generation brain-targeted therapeutics. We further discuss regulatory and translational challenges, including safety, biocompatibility, and the need for humanized preclinical benchmarks. Together, these innovations offer a roadmap for advancing NP-based strategies toward clinical impact in neurodegenerative disease.},
}

@article {pmid42823667,
year = {2026},
author = {Kavlak, Y and Yıldız, S and Yıldız, P and Kar, F},
title = {Effects of an eight-week combined exercise program on functional and sarcopenia-related outcomes in institutionalized older adults with and without Alzheimer's disease: a comparative intervention study.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {42823667},
issn = {1471-2318},
mesh = {Humans ; *Sarcopenia/therapy/physiopathology/psychology/diagnosis/epidemiology ; Aged ; Female ; Male ; *Alzheimer Disease/therapy/psychology/physiopathology/diagnosis/epidemiology ; Aged, 80 and over ; Muscle Strength/physiology ; *Exercise Therapy/methods ; Treatment Outcome ; *Institutionalization/trends/methods ; Activities of Daily Living/psychology ; Time Factors ; Nutritional Status ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a major cause of disability in older adults and is frequently accompanied by sarcopenia and functional decline, contributing to loss of independence. To investigate the effects of an eight-week combined exercise program on physical and cognitive function, sarcopenia-related outcomes and nutritional status in institutionalized older adults with and without AD.

METHODS: Twenty-three participants aged ≥ 65 years (12 with moderate AD and 11 cognitively healthy controls) completed supervised combined aerobic and resistance exercise three times per week for eight weeks. Muscle strength, physical performance, nutritional status, cognition, and activities of daily living were assessed before and after the intervention. Sarcopenia status was classified according to Working Group on Sarcopenia in Older People 2018 (EWGSOP2) criteria using strength and gait speed measures.

RESULTS: Comparison of quadriceps muscle strength before and after exercise showed significant improvement in both Alzheimer's patients (p = 0.013) and the healthy group (p < 0.001). Significant improvement was found in MNA values ​​after exercise in Alzheimer's patients (p = 0.021) and in instrumental activities of daily living in healthy individuals (p = 0.002). After the intervention, quadriceps strength improved significantly in both groups (p < 0.001). When the relationships between parameters were examined, it was found that the relationships between physical function and daily living activities were significant in individuals with Alzheimer's disease (p < 0.05).

CONCLUSIONS: Short-term combined exercise is a versatile intervention method applicable to improve muscle strength, mobility, and nutritional status in older adults living in institutions, including those with Alzheimer's disease.},
}

Humans
*Sarcopenia/therapy/physiopathology/psychology/diagnosis/epidemiology
Aged
Female
Male
*Alzheimer Disease/therapy/psychology/physiopathology/diagnosis/epidemiology
Aged, 80 and over
Muscle Strength/physiology
*Exercise Therapy/methods
Treatment Outcome
*Institutionalization/trends/methods
Activities of Daily Living/psychology
Time Factors
Nutritional Status

@article {pmid42823730,
year = {2026},
author = {Rotter, J and Kirmann, T and Brendler, J and Anthofer, L and Wilpert, NM and Hallermann, S and Biebermann, H and Bechmann, I},
title = {Multiscale characterization and distribution of the thyroid hormone transporter MCT8 in the adult and aged human brain.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42823730},
issn = {2051-5960},
mesh = {Humans ; *Monocarboxylic Acid Transporters/metabolism/genetics ; Symporters ; Aged ; *Brain/metabolism/pathology ; Female ; Male ; Adult ; Middle Aged ; *Aging/metabolism/pathology ; *Thyroid Hormones/metabolism ; Aged, 80 and over ; },
abstract = {The local availability of thyroid hormones (TH) depends on TH transporters such as monocarboxylate transporter 8 (MCT8, encoded by SLC16A2). Mutations of SLC16A2 cause Allan-Herndon-Dudley syndrome (AHDS), a disorder characterized by severe neurodevelopmental and motor deficits. While MCT8's importance in foetal brain development is well-established, its precise topographical, cellular, and subcellular distribution in the adult human brain has remained largely uncharacterized, limiting our understanding of which structures depend on MCT8-mediated TH transport throughout life and whether neurodegenerative processes such as Alzheimer's disease (AD) affect local transporter availability. In this study, we systematically mapped MCT8 expression across eight functionally distinct brain regions from 14 aged human body donors. Our multiscale approach combined immunostaining, automated whole-slide image analysis of over 13 million cells, multiplex RNAscope in situ hybridization, stimulated emission depletion (STED) microscopy, and single-nucleus RNA sequencing data analysis. We additionally applied standardized Braak staging to investigate whether AD progression correlates with alterations in MCT8 expression. We demonstrate robust MCT8 expression across brain barriers, glial cells, and in distinct neuronal populations. RNAscope confirmed a strong concordance between SLC16A2 mRNA presence and MCT8 immunoreactivity. STED and confocal microscopy localized MCT8 to plasma membranes, perinuclear regions, and axonal/dendritic compartments, indicating roles in both trans- and intracellular TH transport. MCT8 expression was preserved across Braak stages, with no significant difference between donors with varying degrees of neurofibrillary pathology. Our findings establish a comprehensive cellular and regional framework for MCT8-mediated transport in the human brain, mapping its specific anatomical distribution across regions crucial for motor control and cognitive processing. Stable MCT8 expression across Braak stages suggests that cerebral TH dysregulation in AD likely reflects altered hormone metabolism rather than transporter loss.},
}

Humans
*Monocarboxylic Acid Transporters/metabolism/genetics
Symporters
Aged
*Brain/metabolism/pathology
Female
Male
Adult
Middle Aged
*Aging/metabolism/pathology
*Thyroid Hormones/metabolism
Aged, 80 and over

@article {pmid42823800,
year = {2026},
author = {Kharitonova, EV and Chen, B and Sun, Q and Ockerman, F and Chen, C and Zhou, LY and Tian, S and Cao, H and Ober, C and Cox, NJ and Tao, R and Li, Y},
title = {EndoPRS-SS: Summary-statistic based incorporation of endophenotypes to improve risk prediction.},
journal = {HGG advances},
volume = {},
number = {},
pages = {100677},
doi = {10.1016/j.xhgg.2026.100677},
pmid = {42823800},
issn = {2666-2477},
abstract = {Endophenotypes are critical biological markers with genetic links to disease progression. We previously developed endoPRS, a multi-trait polygenic risk score (PRS) method that leverages endophenotype data to improve disease risk prediction. However, endoPRS requires individual-level genotype-phenotype data for model fitting, restricting its broader use. To address this, we introduce endoPRS-SS, an extension which enables PRS inference using genome-wide association study (GWAS) summary statistics and LD reference panels. Through simulation and real data analysis, we demonstrate that endoPRS-SS maintains the predictive accuracy of endoPRS, while increasing computational efficiency up to 90-fold. We also extend the endoPRS framework to support the incorporation of multiple endophenotypes simultaneously and find that multi-endophenotype PRS outperform single-endophenotype PRS. Notably, incorporating both monocyte count and executive function scores significantly improves Alzheimer's disease prediction for Europeans in the UK Biobank cohort. These extensions expand the scope of endoPRS and strengthen its utility for large-scale genetic risk assessment.},
}

@article {pmid42823958,
year = {2026},
author = {Lanata, S and Windon, C and Tee, BL and de Leon, J and Aguirre, GA and Jackson, AJ and Lieu, K and Diaz, V and Escudero, SP and Hill-Jarrett, TG and Weng, A and Adewale, K and Amiuri, A and Archila, J and Calderon, LM and Chen, A and Chen, Y and Ching, A and Colverson, A and Lopera, CC and Dorsman, K and Fuentes-Juarez, B and Garcia, A and Guevarra, A and Joo, YM and Kaczmarska, M and Erismas, KR and Klein, J and Kornhuber, A and Lay, S and Leng, F and Light, SW and Li, K and Lopez, L and Macri, D and Mamuyac, E and Martinez Roman, L and Mei, D and Caipa, MP and Prioleau, C and Dionisio Reyes, RJ and Robles-Archila, O and Rodriguez, D and Shibiru, I and Suntay, JM and Thomas, K and Tucker, M and Wang, YT and Wu, J and Zhao, X and Smith, K and Gorno-Tempini, ML and Seeley, WW and Rosen, HJ and Valcour, V and Kramer, JH and Possin, K and Rabinovici, G and Miller, BL},
title = {From neighborhoods to brain health: an outreach model linking health literacy, cognitive care, research, and the arts, in San Francisco.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1930344},
pmid = {42823958},
issn = {2296-2565},
support = {R01 AG075775/AG/NIA NIH HHS/United States ; R21 AG068757/AG/NIA NIH HHS/United States ; U19 AG079774/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 NS050915/NS/NINDS NIH HHS/United States ; U01 NS128913/NS/NINDS NIH HHS/United States ; K24 DC015544/DC/NIDCD NIH HHS/United States ; R01 AG058233/AG/NIA NIH HHS/United States ; R01 AG080469/AG/NIA NIH HHS/United States ; R01 AG083840/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; RF1 NS050915/NS/NINDS NIH HHS/United States ; R01 NS100440/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; San Francisco ; *Health Literacy ; *Community-Institutional Relations ; *Residence Characteristics ; Aged ; *Brain ; Cognition ; Aging ; },
abstract = {Traditional community outreach, research recruitment, and engagement strategies in aging neuroscience often fail to target and capture the diversity of structural and environmental conditions that shape the risk of age-related neurocognitive disorders (NCDs), including Alzheimer's disease. In this manuscript, we describe the rationale, implementation, and outcomes of the Community Outreach Program (COP) of the UCSF Fein Memory and Aging Center (MAC), emphasizing its neighborhood-based initiative designed to engage vulnerable populations to improve brain health literacy, access to cognitive care, and research inclusion among older adults living in underserved San Francisco neighborhoods. Guided by a social and environmental determinants of brain health framework, the program used neighborhood-level vulnerability and research representation mapping to identify neighborhoods with high vulnerability and low engagement in research, then implemented a multilingual, community-engaged model centered on four pillars: brain health education, arts- and movement-based programming, community-based cognitive clinics, and multilingual media outreach. Delivered in partnership with community organizations and safety-net providers in Mandarin, Cantonese, Spanish, Tagalog, and English, this model has generated durable partnerships across vulnerable neighborhoods, expanded access to culturally responsive cognitive care, improved inclusion in brain aging and NCDs research, and fostered innovative research projects. From 2019 to 2025, representation of individuals from vulnerable and underrepresented San Francisco neighborhoods in UCSF Fein MAC observational research increased substantially compared to previous years. These findings support place-based, multilingual, and reciprocity-centered community engagement as a promising framework for reducing and studying disparities in brain health.},
}

Humans
San Francisco
*Health Literacy
*Community-Institutional Relations
*Residence Characteristics
Aged
*Brain
Cognition
Aging

@article {pmid42824080,
year = {2026},
author = {Privšek, E and Marseglia, A and Košutić, I and Rosenberg, A and Granberg, T and Kramberger, MG and Kivipelto, M and Westman, E},
title = {Cerebral microbleed assessment on MRI in a memory clinic: Reliability, prevalence, and implications for anti-amyloid therapy.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70472},
pmid = {42824080},
issn = {2352-8729},
abstract = {INTRODUCTION: Cerebral microbleeds (CMBs) represent an important magnetic resonance imaging (MRI) marker of cerebral small vessel pathology in memory-clinic populations, where vascular and neurodegenerative pathologies frequently overlap.

METHODS: This cross-sectional study included 747 patients from a Swedish memory clinic who underwent 3T MRI with susceptibility-weighted imaging. Two readers assessed CMBs using standardized criteria. Inter- and intra-observer agreement were evaluated before and after protocol refinement. CMB prevalence and burden were analyzed across diagnostic groups and by cerebrospinal fluid amyloid status.

RESULTS: CMBs were present in 28.6% of patients and frequently observed in subjects with mild cognitive impairment or dementia. Inter-observer agreement improved from κ = 0.71 to κ = 0.82 after protocol refinement. Among amyloid-positive patients with cognitive impairment, 11.2% exceeded proposed CMB thresholds for anti-amyloid therapy eligibility.

DISCUSSION: Standardized CMB assessment improves reliability in memory-clinic populations. Given its growing impact on treatment eligibility and safety, consistent evaluation is essential for patient management.},
}

@article {pmid42824090,
year = {2026},
author = {Schwartz, NU and Ellingson, T and Nguyen, H and Lin, Z and Ashton, NJ and Dage, JL and Deniz, K and Dietz, CD and Ljubenkov, PA and Miller, BL and Nael, K and Possin, K and Rojas, JC and Rosen, HJ and Saloner, R and Soleimani-Meigooni, DN and Staffaroni, AM and Stephens, ML and Tammewar, G and Wang, Y and La Joie, R and Rabinovici, GD and Boxer, AL and VandeVrede, L},
title = {Evaluation of plasma neurofilament and glial fibrillary acidic protein to predict or detect amyloid related imaging abnormalities.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70446},
pmid = {42824090},
issn = {2352-8729},
support = {K23 AG073514/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; T32 AG023481/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Amyloid-targeting therapies (ATT) require frequent magnetic resonance imaging monitoring to detect vasogenic edema and hemorrhage, i.e., amyloid-related imaging abnormalities (ARIA). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are potential blood-based biomarkers (BBM) of ARIA.

METHODS: Plasma NfL and GFAP were longitudinally collected in an ATT clinic and natural log transformed. Baseline, pre-ARIA, and trajectories were compared between patients with (N = 15) and without (N = 45) ARIA.

RESULTS: Baseline NfL and GFAP did not differ between patients with or without ARIA (ln[NfL] ECLIA 1.24 ± 0.38 pg/mL vs 1.25 ± 0.40 pg/mL, p = 0.77; ln[NfL] Simoa 2.87 ± 0.47 pg/mL vs 2.98 ± 0.40 pg/mL, p = 0.30, ln[GFAP] ECLIA 4.95 ± 0.36 pg/mL vs 4.88 ± 0.47 pg/mL, p = 0.69). No significant changes were seen at the timepoint preceding ARIA, and ARIA incidence made no detectable impact on biomarker trajectories.

DISCUSSION: Biobanking in treatment clinics can evaluate clinical utility of BBMs as monitoring tools. These findings do not support a strong association between NfL or GFAP and ARIA in the ATT clinic.},
}

@article {pmid42824337,
year = {2026},
author = {Beltrán, ÓG and Angarita-Rodríguez, A and González, J and Hernández, ED and Pinzón, A},
title = {Gut microbiota signatures in mild cognitive impairment: a scoping review of microbial taxa and clinical implications.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1895237},
pmid = {42824337},
issn = {1664-302X},
abstract = {OBJECTIVE: To identify systematically the typical gut microbiota in mild cognitive impairment patients and its association in disease progression. Systematically identify microbial taxa consistently associated with Mild Cognitive Impairment.

DESIGN: A scoping review was performed according to the guidelines of the Joanna Briggs Institute using CoCoPop design.

STUDY SELECTION: Several studies about gut microbiota sequencing in mild cognitive impairment diagnosed patients compared against healthy controls.

METHODS: Searches in PubMed, Embase, Scopus, and Web of Science using MeSH and DeCS terms, were performed up to December 2025. Two reviewers independently screened titles and abstracts. Then, the full texts were reviewed to select documents to be included. When there were disagreements in papers selection, those were resolved after discussions among the reviewers. Relevant data information from selected publications was extracted, and a descriptive analysis was made.

RESULTS: The documents do not show drastic changes in the alpha or beta diversity of the microbiota, but they do identify consistent alterations in the relative abundance of specific taxa that allow patients with MCI to be distinguished from healthy controls. Among the most relevant findings is the decrease in SCFA-producing genera, such as Ruminococcus and Lachnospira, whose reduction is directly associated with the deterioration of key brain functions, including synaptic processes and neuronal oxidative metabolism. On the other hand, there is an increase in proinflammatory taxa such as Bacteroides, a pattern that is similar to that observed in patients with Alzheimer's disease, although generally less pronounced.

CONCLUSION: The results highlight that alterations in the abundance of specific bacteria, characterized by the loss of protective taxa and an increase in proinflammatory bacteria, serve as early biomarkers for detecting and predicting Mild Cognitive Impairment (MCI). This pattern of proinflammatory dysbiosis can be identified even in preclinical stages, and it has been proposed as a potential noninvasive tool for early diagnosis and therapeutic intervention before dementia progresses.},
}

@article {pmid42824359,
year = {2026},
author = {Aversi, MTM and Freitas, PM and Aversi-Ferreira, TA},
title = {New Alzheimer's disease diagnostics and psychological clinical perspectives.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1866853},
pmid = {42824359},
issn = {1664-1078},
abstract = {Recent advances in blood-based biomarkers have transformed the early diagnosis of Alzheimer's disease (AD), enabling the identification of biological risk at preclinical and presymptomatic stages in a noninvasive and accessible manner. Despite this diagnostic progress, the expansion of psychological clinical services in dementia care has not kept pace, representing a critical gap in the current management of AD. This theoretical paper critically discusses the role of psychological clinical practice in the prevention and management of AD in light of these diagnostic advances, particularly from the perspective of the International Working Group (IWG), which defines AD as a clinical-biological entity and recommends that cognitively normal individuals with positive biomarkers be considered at risk rather than diagnosed. Based on this framework and on evidence from the 2024 Lancet Commission on dementia prevention, we propose a three-phase roadmap for the integration of psychological care into multidisciplinary AD management. Phase 1 encompasses universal prevention through psychoeducation, cognitive reserve promotion, and emotional education. Phase 2 targets at-risk individuals with elevated biomarker profiles, focusing on neuropsychological evaluation, risk disclosure support, and early cognitive intervention. Phase 3 addresses individuals with established AD through cognitive rehabilitation and caregiver support. We further argue that government policies must integrate psychologists into multidisciplinary neurological and geriatric teams, and that psychology training programs must be updated to prepare professionals for preventive roles. More research on standardized psychological protocols for pre-dementia contexts is urgently needed.},
}

@article {pmid42824632,
year = {2026},
author = {Miao, J and Xue, C and Yan, X and Gu, J and Chu, D and Sun, H},
title = {From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1927017},
pmid = {42824632},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly, pathologically defined by extracellular amyloid-β plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. The Braak staging system established that tau pathology spreads in a stereotypical pattern across the brain, supporting the "prion-like" hypothesis: misfolded tau aggregates serve as seeds, inducing the misfolding and aggregation of normal tau, and thereby driving disease progression along neuroanatomical pathways. In the past 5 years (2021-2026), substantial advances have elucidated the molecular mechanisms underlying tau seeding activity. This review summarizes recent progress in tau seeding research, highlighting both intrinsic and extrinsic regulators of tau prion-like activity. Intrinsic factors include the structural basis of tau strains, MAPT mutations, alternative splicing (3R/4R isoforms), post-translational modifications, and liquid-liquid phase separation. Extrinsic factors encompass cofactors, molecular chaperones, non-coding RNAs, epigenetic mechanisms, environmental exposures, and the emerging concept of trans-seeding by heterologous protein fibrils. We also review therapeutic strategies targeting tau pathology, focusing on their mechanisms and clinical development. Integrating these mechanistic insights and therapeutic advances will inform future research and clinical strategies for AD and related tauopathies.},
}

@article {pmid42824777,
year = {2026},
author = {Taherkhani, AM and Şenol, H and Valizadeh, Y and Ghafouri, SN and Dastyafteh, N and Aktaş, A and Sadeghian, N and Moradkhani, F and Larijani, B and Biglar, M and Taslimi, P and Mohammadi-Khanaposhtani, M and Mahdavi, M},
title = {Design and synthesis of carbazole-acrylamide-pyridinium hybrids as dual acetylcholinesterase/butyrylcholinesterase inhibitors and evaluation of their cytotoxic profile on SH-SY5Y and HEK293 cell lines.},
journal = {RSC medicinal chemistry},
volume = {17},
number = {10},
pages = {5017-5033},
pmid = {42824777},
issn = {2632-8682},
abstract = {A novel series of seventeen carbazole-acrylamide-pyridinium-N-phenylacetamide hybrids (12a-q) was designed and synthesized as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for potential Alzheimer's disease therapy. Their inhibitory activity was evaluated against both enzymes using tacrine and galantamine as reference standards. Tacrine exhibited IC50 values of 58.34 nM against AChE and 160.50 nM against BChE, while galantamine showed 124.72 nM and 216.23 nM, respectively. The synthesized derivatives demonstrated IC50 values ranging from 6.41 to 74.93 nM against AChE and from 38.05 to 191.96 nM against BChE. All compounds were more potent than galantamine, and most outperformed tacrine as well. Compound 12i was the most potent AChE inhibitor (IC50 = 6.41 nM), showing 9.1-fold and 19.5-fold higher potency than tacrine and galantamine, respectively. Compound 12g was the strongest BChE inhibitor (IC50 = 38.05 nM), with 4.2-fold and 5.7-fold higher activity than tacrine and galantamine. Kinetic analysis revealed that all of the most potent compounds act as competitive inhibitors. Cytotoxicity evaluation revealed that compounds 12i and 12g exhibited lower toxicity toward HEK293 cells than sorafenib, with favorable selectivity toward SH-SY5Y cells. These results establish the carbazole-acrylamide-pyridinium scaffold as a promising lead for developing safer cholinesterase inhibitors for Alzheimer's disease.},
}

@article {pmid42824999,
year = {2026},
author = {Bai, Y and Zhao, J and Zhang, S and Yan, C and Chen, Y and Du, G and Liu, A},
title = {Machine Learning-Guided Discovery of Natural BACE1 Inhibitors with Enzymatic and Cellular Validation.},
journal = {ACS omega},
volume = {11},
number = {38},
pages = {58100-58111},
pmid = {42824999},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by excessive accumulation of β-amyloid (Aβ) peptides in the brain. Beta-secretase 1 (BACE1), the rate-limiting enzyme in the amyloidogenic processing pathway of amyloid precursor protein (APP), has been widely recognized as an important therapeutic target for reducing Aβ production. In the present study, nine machine learning-based predictive models for BACE1 inhibitors were constructed using Naïve Bayes (NB) and Recursive Partitioning (RP) algorithms. Subsequently, internal and external validations were conducted to evaluate predictive performance. The optimized models were subsequently applied to screen an in-house natural product library containing 452 compounds. Based on consensus prediction criteria, 171 compounds were identified as potential BACE1 inhibitors and subjected to fluorescence resonance energy transfer (FRET)-based enzymatic assays. Among them, 33 compounds exhibited inhibitory rates greater than 50% at an initial concentration of 50 μg/mL. Further dose-response evaluation identified five compounds with IC50 values below 50 μM, including Theaflavin-3,3'-digallate, γ-mangostin, Licoagrochalcone B, Chicoric acid, and Resveratrol. Cell-based validation using APPswe-HEK293T cells demonstrated that Theaflavin-3,3'-digallate significantly reduced extracellular Aβ1-42 secretion. Molecular docking analysis further revealed that Theaflavin-3,3'-digallate could stably bind to BACE1 through multiple hydrogen-bond and hydrophobic interactions. Collectively, this study demonstrates that integrating machine learning-assisted virtual screening with natural product libraries is an effective strategy for discovering novel BACE1 inhibitors. Theaflavin-3,3'-digallate was identified as a promising natural BACE1 inhibitor with both enzymatic and cellular activities. This research provides new technology and potential lead compound for the development of future anti-Alzheimer's disease drug.},
}

@article {pmid42825043,
year = {2026},
author = {Wu, M and Cao, Y and Wu, X and Wang, Y and Deng, Z and Zhao, Y and Lu, G and Qu, X and Zhu, F and Cheng, Y and Wang, P and Zhong, L},
title = {Comprehensive metabolite profiling in fruits of different Prunus cultivars.},
journal = {Food chemistry: X},
volume = {39},
number = {},
pages = {104431},
pmid = {42825043},
issn = {2590-1575},
abstract = {Variations in metabolite profiles among Prunus cultivars shape fruit flavor and overall quality, and ultimately determine consumer preference. To comprehensively evaluate the metabolic quality of various Prunus cultivars, we adopted an integrated extraction strategy to obtain distinct metabolite fractions from identical samples. In this work, seven predominant Prunus cultivars from Xinjiang, China were investigated, 382 volatile metabolites and 417 non-volatile metabolites were identified, where phenols were detected as the dominant secondary metabolites and esters were abundant volatile metabolites. 'Black' displayed greater antioxidant activity relative to other cultivars, due to its more than four-fold higher content of pyroglutamic acid, glutamine, and γ-dodecalactone. Additionally, network pharmacology analysis confirmed that the metabolites maybe associated with diabetes, cancer, and Alzheimer's disease. Collectively, this study for the first time elucidates the full metabolite profile in Prunus, and provides practical guidance for consumer choices as well as a solid theoretical foundation for selective breeding of Prunus.},
}

@article {pmid42825245,
year = {2026},
author = {Jia, M and Yang, R and Xu, Y and Wu, Z and Lu, J and Li, Z and Yan, Q and Fan, G and Gui, Y},
title = {Oral microbiome-metabolome axis links glycerophospholipid dysregulation to Alzheimer's disease.},
journal = {Journal of oral microbiology},
volume = {18},
number = {1},
pages = {2732297},
pmid = {42825245},
issn = {2000-2297},
abstract = {INTRODUCTION: This study aimed to evaluate the feasibility of using tongue biofilm as a non-invasive, patient-friendly, and cost-effective biomarker source for identifying early microbial and metabolic disturbances associated with Alzheimer's disease (AD).

MATERIALS AND METHODS: A total of 62 outpatients were enrolled (31 with AD and 31 cognitively normal controls). Tongue biofilm samples were analyzed using 16S rRNA sequencing and untargeted metabolomics via UPLC-Q/TOF-MS. Additionally, cerebrospinal fluid (CSF) samples from 36 individuals (18 per group) were examined under identical untargeted metabolomics processing protocols to validate the metabolomic findings.

RESULTS AND DISCUSSION: Microbiome analysis revealed an increased relative abundance of Proteobacteria in the AD group, while Firmicutes and Bacteroidetes were enriched in controls. Metabolomic profiling identified 88 significantly different metabolites between groups, 64 of which achieved area under the curve (AUC) values > 0.90 in the ROC analysis. Glycerophospholipid metabolism has emerged as a key dysregulated pathway in AD, a finding further corroborated by CSF metabolomic analysis. Tongue biofilm represents a non-invasive, cost-effective, and accessible biomarker source, offering potential for AD diagnosis and research when coupled with microbiome and metabolomic analyses. Moreover, the role of glycerophospholipid metabolism in AD pathogenesis warrants further investigation.},
}

@article {pmid42825350,
year = {2026},
author = {Chen, J and Long, Z and Li, Y and Luo, M and Luo, S and He, G},
title = {[Corrigendum] Alteration of the Wnt/GSK3β/β‑catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer's disease model.},
journal = {International journal of molecular medicine},
volume = {58},
number = {5},
pages = {},
doi = {10.3892/ijmm.2026.6003},
pmid = {42825350},
issn = {1791-244X},
abstract = {Following the publication of the above article, a concerned author drew to the authors' attention that they had apparently used an inappropriate antibody in their study: In the Materials and methods section, the authors had reported the use of Abcam's recombinant antibody against plant homeodomain (PHD) finger protein 1 (a.k.a. PHF1; cat. no. ab184951) to probe for the unrelated protein, tau paired helical filaments (PHFs). Based on their search of previous literature, the authors acknowledged that they had made a methodological error in selecting the incorrect antibody; therefore, the western blot assay results shown in Fig. 4A on p. 317 for protein PHF1 should be considered to be invalid. Given that this issue has come to light, the authors have now purchased the correct and specific antibody targeting phosphorylated tau (p‑tau‑S404) from ABclonal Viotech Co., Ltd (cat. no. AP1378) and completely repeated the relevant experiments, in strict accordance with the original experimental protocols and conditions. In addition, the authors provided the Editorial Office with the raw data from the repeated experiments, and also proof of purchase of the correct antibody. The corrected version of Fig. 4, now showing the revised data for the PHF1 blots in Fig. 4A together with re‑quantified bar charts for these data shown in Fig. 4B, is featured on the next page. Additional changes to the text should also be noted: The text in the Materials and methods section, 'Western blot analysis' subsection, on p. 315 (left-hand column, lines 14-15), should read as follows (changes highlighted in bold): '...rabbit anti insulin degrading enzyme (IDE) antibody (ab133561), rabbit anti‑PHF‑1 antibody (ab184951), mouse anti‑GSK3β antibody (ab93926)...'. In addition, revisions have also been made to the legend for Fig. 4. The authors confirm that the error made in performing these experiments has not had a significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 44: 313‑323, 2019; DOI: 10.3892/ijmm.2019.4198].},
}

@article {pmid42825390,
year = {2026},
author = {Vanderlip, CR and Hartley, SL and Krinsky-McHale, S and Hom, C and Brickman, AM and Petersen, ME and Head, E and Stark, CEL and , },
title = {Memory and Plasma pTau217 Refine Prognosis in Down Syndrome.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78366},
pmid = {42825390},
issn = {1531-8249},
abstract = {Individuals with Down syndrome (DS) are at high risk for Alzheimer's disease (AD), yet accessible tools for routine clinical screening of AD in individuals with DS remain limited. Using data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS), we show that integrating plasma pTau217 with performance on the modified cued recall task identifies a subgroup of cognitively stable individuals at markedly elevated risk of developing clinical impairment in the next 7 years. This low-burden, multimodal framework improves prognosis, supports more informed clinical management and efficient trial enrichment in Down syndrome. ANN NEUROL 2026.},
}

@article {pmid42825454,
year = {2026},
author = {Varshney, H and Siddique, YH},
title = {Molecular and genetic basis of alzheimer's disease and emerging treatment Modalities.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/17582024.2026.2739332},
pmid = {42825454},
issn = {1758-2032},
abstract = {BACKGROUND: Alzheimer's disease (AD) is linked to various causes and pathological processes. It represents a major global health challenge due to its increasing prevalence in aging populations. AD involves multifactorial pathological mechanisms. Two different forms of AD defined by changes in specific genes like APOE4, CLU, TREM2, PICALM, BIN1, MS4A, CR1, ABCA7 and APH1B. Apart from specific genetic mutations, there are multiple risk factors such as aging, obesity, lifestyle, head injury, drinking, smoking and environmental factors that further influence disease risk and its progression.

METHODS: The literature of this review article was taken from different search engines viz. Pubmed, Google Scholar and Scopus, explaining modifiable contributing factors and prognostic markers, including the genetics of AD and overall, this review analyzes literature published between 2000 to 2025 to summarizes the current status of disease, highlighting its importance for improving diagnosis, prognosis, and the development of targeted therapeutic strategies.

RESULT: There are multiple contributing factors in both the disease mechanism and development of AD, apart from amyloid hypothesis and neurofibrillary tangles.

DISCUSSION: A strategic analysis and targeted treatment of these contributing factors could help mitigate the progression of AD and offer potential protective benefits.},
}

@article {pmid42825521,
year = {2026},
author = {Nicol, NI and Li, T and Su, Q and Suhocki, A and Dunlap, E and Zhou, X and Jester, HM and Swift, NA and Underwood, E and Lee, J and Cervera-Juanes, R and Ma, T},
title = {AMPK Activator MK-8722 Improves Spatial Memory Deficit and Alters Metabolome in APP/PS1 AD Mouse Model.},
journal = {Journal of neurochemistry},
volume = {170},
number = {10},
pages = {e70563},
doi = {10.1111/jnc.70563},
pmid = {42825521},
issn = {1471-4159},
support = {R01 AG073823/AG/NIA NIH HHS/United States ; R01 AG082388/AG/NIA NIH HHS/United States ; RF1 AG082388/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Metabolome/drug effects/physiology ; Mice ; Mice, Transgenic ; *AMP-Activated Protein Kinases/metabolism ; Presenilin-1/genetics ; *Amyloid beta-Protein Precursor/genetics ; *Memory Disorders/drug therapy/metabolism/genetics ; Disease Models, Animal ; Male ; Hippocampus/drug effects/metabolism ; *Spatial Memory/drug effects/physiology ; },
abstract = {Alzheimer's disease (AD) involves early synaptic vulnerability and systemic metabolic dysfunction, yet the impact of peripheral metabolic state on brain function remains unclear. Previous studies indicate a link between AMP-activated protein kinase (AMPK) signaling dysregulation and AD pathophysiology. Here we tested whether systemic treatment of a potent pan-AMPK activator MK-8722 influences cognitive function, synaptic plasticity, and circulating metabolic profiles in APP/PS1 AD model mice at the age of 6-8 months. MK-8722 was well tolerated and activated AMPK in the liver but not in the hippocampus. Our findings revealed that MK-8722 selectively improved AD-associated hippocampal-dependent spatial memory deficits and enhanced dendritic spine maturation in the hippocampus of APP/PS1 mice. In contrast, MK-8722 did not alter hippocampal long-term potentiation (LTP). In-depth analysis of plasma lipidomics and metabolomics revealed coordinated disruptions in glycerophosphatidylcholine species, glutathione cycling, carnitine-dependent fatty acid transport, and the kynurenine pathway in APP/PS1 mice, which were partially normalized by MK-8722 treatment. These findings suggest that peripheral AMPK activation can remodel systemic metabolic networks and improve certain aspects of cognitive and synaptic outcomes in early AD, supporting a model in which metabolic interventions outside the brain influence neuronal resilience.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/genetics
*Metabolome/drug effects/physiology
Mice
Mice, Transgenic
*AMP-Activated Protein Kinases/metabolism
Presenilin-1/genetics
*Amyloid beta-Protein Precursor/genetics
*Memory Disorders/drug therapy/metabolism/genetics
Disease Models, Animal
Male
Hippocampus/drug effects/metabolism
*Spatial Memory/drug effects/physiology

@article {pmid42825683,
year = {2026},
author = {Shin, J and García, AM and Scimeca, M and Kiran, S and Sung, JE},
title = {Culture-Agnostic and Culture-Specific Analyses of Semantic Fluency in Korean and English Speakers With Alzheimer's Disease.},
journal = {American journal of speech-language pathology},
volume = {35},
number = {5S},
pages = {2754-2767},
pmid = {42825683},
issn = {1558-9110},
mesh = {Humans ; *Alzheimer Disease/psychology/ethnology/diagnosis/physiopathology ; Female ; Aged ; Male ; *Semantics ; *Cross-Cultural Comparison ; Aged, 80 and over ; Republic of Korea ; Animals ; Neuropsychological Tests ; Cognition ; Language ; },
abstract = {PURPOSE: This study investigated cross-linguistic and cultural influences on semantic fluency in monolingual Korean- and English-speaking individuals with Alzheimer's disease (AD) by contrasting culture-agnostic and culture-specific analytic frameworks. We focused on how culturally grounded schemas, such as the East Asian zodiac, shape clustering and switching patterns and on their associations with global cognition.

METHOD: We analyzed semantic fluency in 36 individuals with AD and 30 language-matched older adults using culture-agnostic and culture-specific frameworks. We examined total and first-response proportions of exemplars and compared clustering and switching patterns based on Troyer's taxonomy and a culture-specific scheme that included zodiac animals. All fluency measures were correlated with global cognition.

RESULTS: In Korean-speaking individuals with AD, animal fluency was shaped by culture-specific schemas, with zodiac animals frequently produced early and in clusters. This pattern-marked by greater clustering-was unique to the Korean group and was not detected using culture-agnostic analyses, which showed no group differences. Only the Korean group showed positive correlations between fluency and Mini-Mental State Examination scores.

CONCLUSIONS: The present findings suggest that culturally grounded schemas may influence both word generation and the organization of clustering and switching in semantic fluency. In Korean-speaking individuals with AD, zodiac animals formed structured clusters and switches that uniquely correlated with global cognition, highlighting the need for culturally informed norms in cross-linguistic neuropsychological assessment.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.33989638.},
}

Humans
*Alzheimer Disease/psychology/ethnology/diagnosis/physiopathology
Female
Aged
Male
*Semantics
*Cross-Cultural Comparison
Aged, 80 and over
Republic of Korea
Animals
Neuropsychological Tests
Cognition
Language

@article {pmid42825842,
year = {2026},
author = {Martinez Holst, MA and Sierra Valiente, AM and Garcia-Becerra, CA},
title = {Incidence, severity, and associated risk factors for amyloid-related imaging abnormalities in anti-amyloid monoclonal antibody therapy for early Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42825842},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/epidemiology/genetics ; *Amyloid beta-Peptides ; *Antibodies, Monoclonal/therapeutic use ; Incidence ; Risk Factors ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are the most concerning side effect of the treatment for early Alzheimer's disease (AD) with anti-amyloid monoclonal antibodies (mAbs).

OBJECTIVE: This study systematically evaluates the incidence, severity, and associated risk factors of ARIA in patients with early AD receiving anti-amyloid mAbs therapy.

METHODS: A comprehensive systematic review and meta-analysis were conducted following PRISMA guidelines. Assessed outcomes included ARIA incidence, symptomatic cases and severity, radiographic severity, and risk factors. Pooled incidences and odds ratios were estimated with a random effects model using the R software (version 4.5.2).

RESULTS: The systematic search yielded a total of 20 articles, representing 21 phase 3 randomized controlled trials that involved 12,610 AD patients. Pooled incidence was 5.4% for ARIA-E and 10.27% for ARIA-H. Most cases being asymptomatic and radiographically mild to moderate. Risk factor analysis revealed that ApoE 4 homozygotes carriers (OR = 5.12), ApoE 4 heterozygotes carriers (OR = 1.91), higher mAb dosage (OR = 2.0) and baseline microhemorrhages (OR = 1.43) had a major influence on ARIA-E occurrence, as for ARIA-H incidence was higher in ApoE 4 heterozygous (OR = 1.65) and homozygotes carriers (OR = 4.65). Moreover, ApoE 4 heterozygous and homozygotic carriers were associated with symptomatic (OR = 1.52;3.68) and severe radiographic (OR = 2.11;6.31) ARIA-E.

DISCUSSION: ARIA remains a significant safety concern in anti-amyloid mAb therapy, with incidence and severity influenced by genetic, neuroimaging, and treatment-related factors. Future research should focus on refining risk stratification and understanding long-term consequences of ARIA.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/epidemiology/genetics
*Amyloid beta-Peptides
*Antibodies, Monoclonal/therapeutic use
Incidence
Risk Factors

@article {pmid42825974,
year = {2026},
author = {Wu, J and Wang, Y and Zhao, M and Liu, J and Zhao, W},
title = {Bisphenol A Exposure Perturbs the Immune Microenvironment in Alzheimer's Disease: Insights from Network Toxicology and Single-Cell Transcriptomics.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42825974},
issn = {1559-1166},
mesh = {*Phenols/toxicity ; *Benzhydryl Compounds/toxicity ; *Alzheimer Disease/genetics/immunology/metabolism ; Bisphenol A Compounds ; Humans ; *Transcriptome ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Single-Cell Analysis ; *Endocrine Disruptors/toxicity ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which exposure to environmental endocrine-disrupting chemicals may contribute to disease susceptibility. Here, we integrated network toxicology, bulk transcriptomics, machine learning, immune deconvolution, single-nucleus transcriptomics, competing endogenous RNA (ceRNA) analysis, molecular docking, and 100-ns molecular dynamics (MD) simulations to investigate the potential molecular links between bisphenol A (BPA) exposure and AD. Cross-database integration identified 248 shared BPA-AD targets, from which 47 network-central genes and 19 differentially expressed genes were prioritized. Five genes-GSK3B, BCL2, EGFR, APP, and PPARD-were subsequently retained as a candidate gene signature. Although the resulting model showed strong discriminatory performance in the discovery cohort, substantially lower performance in validation cohorts indicated limited generalizability and potential overfitting. Functional analyses implicated neuroinflammatory signaling, mitochondrial apoptosis, amyloid-related processes, and lipid and metabolic dysregulation in the molecular association between BPA and AD. LM22-based CIBERSORT analysis revealed alterations in peripheral leukocyte-like immune signatures, which were interpreted cautiously because this reference matrix does not directly represent resident brain immune populations. Single-nucleus transcriptomic analysis of GSE163577 further localized key genes across biologically plausible cerebrovascular and neuroimmune cell populations. CeRNA analysis suggested potential post-transcriptional regulatory relationships associated with the identified hub genes, while molecular docking identified putative interactions between BPA and candidate target proteins. Subsequent 100-ns MD simulations further characterized the dynamic behavior and conformational stability of the selected BPA-protein complexes, providing complementary evidence for the docking-derived structural hypotheses. Collectively, these findings suggest that BPA-related molecular targets may converge on immune, vascular, metabolic, and neurodegenerative processes relevant to AD. However, the present findings remain primarily computational and hypothesis-generating, and experimental studies are required to establish causal and mechanistic relationships.},
}

*Phenols/toxicity
*Benzhydryl Compounds/toxicity
*Alzheimer Disease/genetics/immunology/metabolism
Bisphenol A Compounds
Humans
*Transcriptome
Molecular Docking Simulation
Molecular Dynamics Simulation
Single-Cell Analysis
*Endocrine Disruptors/toxicity

@article {pmid42826098,
year = {2026},
author = {Lin, W and Phanse, S and van der Spek, SJF and Lampl, N and Stephens, MC and Wang, Z and Nigro, JT and Ortiz, AR and Hekman, R and Cruz, ALF and Roberts, R and Jiang, L and Botas, J and Emili, A and Wolozin, B},
title = {Progressive remodeling of global protein interaction networks in a mouse model of tauopathy.},
journal = {Cell reports},
volume = {45},
number = {10},
pages = {118084},
doi = {10.1016/j.celrep.2026.118084},
pmid = {42826098},
issn = {2211-1247},
abstract = {Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present a temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This interactomic atlas serves as a resource to investigate functional assemblies, including MAPT-Dpysl2 and Cyfip1-actin, as well as ptk2b-Kars/Dars and ptk2b-Msn-Farsb-complexes, that modulate early disease phenotypes in vivo. Notably, it captures the composition, dynamics, and regulatory state of protein complexes at scale. By revealing how phosphorylation tunes macromolecular complex architecture and function, this work highlights dynamic network instability that develops over the course of tauopathy, and establishes a generalizable framework for mechanistic dissection of functional complexes in neurodegeneration.},
}

@article {pmid42826267,
year = {2026},
author = {Amouzad-Lichahi, M and Petkov, I and Smerat, A and Alsarhan, HW and Letafatkar, N and Abbasnejad-Ardehroudkenari, M and Mohammadi, S and Jafari, M and Ghodous, S and Amini-Salehi, E},
title = {Prevalence of metabolic syndrome among patients with Alzheimer disease: A systematic review and meta-analysis.},
journal = {Medicine},
volume = {105},
number = {40},
pages = {e50670},
pmid = {42826267},
issn = {1536-5964},
mesh = {*Metabolic Syndrome/epidemiology ; Humans ; *Alzheimer Disease/epidemiology/complications ; Prevalence ; },
abstract = {BACKGROUND: The relationship between metabolic syndrome (MetS) and Alzheimer disease (AD) has gained increasing attention in recent years, reflecting the growing recognition of metabolic factors in neurodegenerative conditions. The present study aims to estimate the prevalence of MetS in patients with AD.

METHODS: A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search of PubMed, Scopus, and Web of Science was performed. Observational studies reporting the prevalence of MetS among patients with AD and/or providing comparative data with control groups were included. Pooled prevalence and odds ratios with 95% confidence intervals (CIs) were calculated using a random-effects model, and heterogeneity was assessed using the I2 statistic. Subgroup and meta-regression analyses were also performed.

RESULTS: Nine studies were included. The pooled prevalence of MetS among patients with AD was 46.7% (95% CI: 28.0%-65.8%; I2 = 97.11%). In subgroup analysis by continent, the prevalence was 26.1% (95% CI: 11.1%-44.4%) in Asia (I2 = 84.42%) and 52.8% (95% CI: 25.2%-79.5%) in Europe (I2 = 97.05%), while the estimate from North America was 72.2% (95% CI: 62.5%-81.0%) based on a single study. The comparative analysis showed an odds ratio of 1.64 (95% CI: 0.75-3.57), with no statistically significant association between AD and MetS. Meta-regression identified glucose as significantly associated with MetS prevalence (β = 0.022; P = .021).

CONCLUSION: MetS was frequently observed among patients with AD; however, the pooled prevalence estimate should be interpreted cautiously because of substantial between-study heterogeneity. The comparative analysis did not demonstrate a statistically significant association between AD and MetS. Further studies using standardized definitions and more homogeneous populations are needed to clarify this relationship and the sources of heterogeneity.},
}

*Metabolic Syndrome/epidemiology
Humans
*Alzheimer Disease/epidemiology/complications
Prevalence

@article {pmid42826310,
year = {2026},
author = {Lwere, K and Nakasujja, N and Muwonge, H and Sendagire, H and Gumikiriza-Onoria, JL and Buwembo, D and Buwembo, W and Kabwigu, S and Mukasa, JK and Kirya, F and Nazziwa, A and Othieno, E and Nassanga, R and Nakimbugwe, R and Munabi, IG and Sajatovic, M and Kaddumukasa, M},
title = {Systemic inflammation, gut microbiome composition, and cognitive performance among older Ugandans with Alzheimer's disease and related dementias: A cross-sectional study.},
journal = {Medicine},
volume = {105},
number = {40},
pages = {e50956},
pmid = {42826310},
issn = {1536-5964},
support = {D43 NS118560/NS/NINDS NIH HHS/United States ; R56 DE032217/DE/NIDCR NIH HHS/United States ; },
mesh = {Humans ; Cross-Sectional Studies ; Female ; Male ; *Gastrointestinal Microbiome/physiology ; *Alzheimer Disease/microbiology ; C-Reactive Protein/analysis/metabolism ; *Inflammation/blood ; Aged ; Uganda/epidemiology ; *Cognition/physiology ; *Cognitive Dysfunction ; Biomarkers/blood ; Aged, 80 and over ; East African People ; },
abstract = {Systemic inflammation is implicated in neurodegeneration; however, evidence linking circulating inflammatory biomarkers to cognitive decline remains inconsistent, particularly in low- and middle-income countries. High-sensitivity C-reactive protein (hs-CRP) is a standard systemic inflammatory marker; however, its relationship with cognitive performance and gut microbiome composition in sub-Saharan Africa remains underexplored. We investigated the association between hs-CRP and cognitive performance across older Ugandans diagnosed with Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitively intact controls and examined whether gut microbial composition modified this relationship. We conducted a cross-sectional study of community-dwelling older adults in Wakiso District, Uganda. Cognitive performance was assessed using the Education-Adjusted Montreal Cognitive Assessment (MoCA). Systemic inflammation was quantified using plasma hs-CRP, and gut microbial profiles were generated via full-length 16S rRNA gene sequencing. Multivariable linear regression models were used to evaluate the associations between log-transformed hs-CRP concentrations and MoCA scores, adjusting for age, sex, and body mass index. Linear regression assumptions were formally tested. Exploratory analyses examined taxon-level differential abundance across diagnostic categories, hs-CRP-microbiome correlations, and hs-CRP × taxon interaction terms on MoCA scores, with multiple-testing adjustment using the false discovery rate. The analytic cohort comprised 85 participants (mean age 77.5 ± 9.2 years; 67 AD, 10 MCI, and 8 controls). Median hs-CRP was higher in AD (1.96 [0.25-3.75] mg/L) than in MCI (0.25 [0.25-2.73] mg/L) and controls (0.25 [0.25-0.84] mg/L). Higher hs-CRP showed a modest inverse trend with MoCA scores that was not statistically significant after adjustment for age, sex, and body mass index (standardized ,). Advancing age was independently associated with poorer cognitive performance (standardized ,). Several microbial genera exhibited nominal differences across diagnostic groups and hs-CRP levels; however, no individual taxon-level associations or hs-CRP × microbiome interaction terms survived false discovery rate correction (). Circulating hs-CRP was not independently associated with global cognitive performance in this cohort of older Ugandans. Genus-level microbiome analyses yielded exploratory, hypothesis-generating patterns that warrant validation in larger longitudinal cohorts investigating gut-brain axis interactions in African populations.},
}

Humans
Cross-Sectional Studies
Female
Male
*Gastrointestinal Microbiome/physiology
*Alzheimer Disease/microbiology
C-Reactive Protein/analysis/metabolism
*Inflammation/blood
Aged
Uganda/epidemiology
*Cognition/physiology
*Cognitive Dysfunction
Biomarkers/blood
Aged, 80 and over
East African People

@article {pmid42826326,
year = {2026},
author = {Zeng, Z and Shao, S and Deng, T and Zhou, S},
title = {Multiple chronic conditions and intrinsic capacity among middle-aged and older adults: Evidence from CHARLS.},
journal = {Medicine},
volume = {105},
number = {40},
pages = {e50947},
pmid = {42826326},
issn = {1536-5964},
support = {SXJYB2529//Sichuan Research Center for Sexology and Sex Education/ ; YF22-Q20//Sichuan Medical Law Research Center/ ; 2025RWY29//Humanities and Social Sciences Research Project of Sichuan Nursing Vocational College/ ; 2024SZS218//Deyang Science and Technology Program/ ; },
mesh = {Humans ; Aged ; Male ; China/epidemiology ; Female ; Middle Aged ; Longitudinal Studies ; *Multiple Chronic Conditions/epidemiology ; *Aging/physiology ; Cross-Sectional Studies ; Socioeconomic Factors ; Socioeconomic Disparities in Health ; },
abstract = {With the accelerating global aging process, maintaining intrinsic capacity (IC) among middle-aged and older adults has become a major public health priority. Multiple chronic conditions (MCC) are highly prevalent in later life and may contribute to declines in physical and mental functioning. However, evidence regarding the association between MCC and IC, as well as variations across disease types and socioeconomic contexts, remains limited. This study aimed to examine the association between MCC and IC among middle-aged and older adults and to explore heterogeneity across chronic disease categories, regional contexts, and individual characteristics. Data were obtained from the 2011, 2015, and 2018 waves of the China Health and Retirement Longitudinal Study. Using 28,613 pooled repeated cross-sectional person-wave observations, regression models incorporating survey-year and regional fixed effects were applied to examine the association between MCC and IC. Respondent-level cluster-robust standard errors were used to account for the nonindependence of repeated observations. Robustness analyses, instrumental variable estimation, and propensity score matching were conducted to assess the stability of the findings. Subgroup analyses were performed across macro-level (urban/rural residence and regional economic zones) and micro-level (sex, education, and household income) characteristics. MCC was significantly associated with lower IC (β = -0.076, P < .01). Disease-specific analyses showed that neurodegenerative diseases, including Parkinson disease and Alzheimer disease, demonstrated the strongest negative association with IC (β = -0.587, P < .01), followed by cardiovascular diseases (β = -0.135, P < .01). The negative association between MCC and IC was stronger among individuals living in rural areas and western regions, as well as among men, individuals with lower educational attainment, and those with lower household income. Robustness analyses, instrumental variable estimation, and propensity score matching yielded findings that were directionally consistent with the main analysis. MCC is significantly associated with reduced IC among middle-aged and older adults, with substantial heterogeneity across disease types and socioeconomic contexts. These findings highlight the importance of integrated chronic disease management, IC assessment, and targeted interventions for vulnerable populations, particularly those in socioeconomically disadvantaged regions, to promote healthy aging.},
}

Humans
Aged
Male
China/epidemiology
Female
Middle Aged
Longitudinal Studies
*Multiple Chronic Conditions/epidemiology
*Aging/physiology
Cross-Sectional Studies
Socioeconomic Factors
Socioeconomic Disparities in Health

@article {pmid42826335,
year = {2026},
author = {Xiong, Y and Wei, K and Fang, J},
title = {The association between Naples prognostic score and cognitive function in older adults: A cross-sectional study of NHANES 2011 to 2014.},
journal = {Medicine},
volume = {105},
number = {40},
pages = {e51026},
pmid = {42826335},
issn = {1536-5964},
mesh = {Humans ; Cross-Sectional Studies ; Female ; Male ; Aged ; *Cognition/physiology ; Nutrition Surveys ; Prognosis ; Neuropsychological Tests ; Middle Aged ; Alzheimer Disease/diagnosis ; United States/epidemiology ; Logistic Models ; },
abstract = {The purpose of this study was to examine the association between the Naples prognostic score (NPS) and cognitive function in older adults. This cross-sectional study analyzed data from 2759 participants aged 60 years and older, with a mean age of 69.2 ± 6.6 years, from the National Health and Nutrition Examination Survey 2011 to 2014 data. Participants were categorized into 2 groups based on NPS: Group 1 (NPS = 0-2) and Group 2 (NPS = 3-4). Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest, Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). A global composite z-score was also calculated. Multivariable linear and logistic regression models were used to examine the associations between NPS and cognitive outcomes, with adjustments for sociodemographic and health-related confounders. In the fully adjusted models, a higher NPS was associated with lower AFT, DSST, and composite z-scores, whereas no significant association was observed with the Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest score. Compared with the low-NPS group, the high-NPS group had significantly lower AFT scores (β = -1.39, 95% confidence interval [CI]: -1.89 to -0.88), DSST scores (β = -1.82, 95% CI: -3.11 to -0.53), and composite z-scores (β = -0.43, 95% CI: -0.62 to -0.24), all with P < .05. Logistic regression further showed that the high-NPS group had higher odds of cognitive impairment according to the AFT (odds ratio = 1.41, 95% CI: 1.04-1.92) and DSST (odds ratio = 1.47, 95% CI: 1.00-2.14), both with P < .05. No statistically significant interactions were detected in the subgroup analyses (all P for interaction > .05). This study revealed the possible association between a high NPS and poorer cognitive performance, especially in terms of verbal fluency and processing speed. These findings suggest that the NPS may provide supplementary information for identifying individuals with poorer cognitive performance. However, the cross-sectional design precludes temporal or causal inference.},
}

Humans
Cross-Sectional Studies
Female
Male
Aged
*Cognition/physiology
Nutrition Surveys
Prognosis
Neuropsychological Tests
Middle Aged
Alzheimer Disease/diagnosis
United States/epidemiology
Logistic Models

@article {pmid42826355,
year = {2026},
author = {Bevilacqua, R and Maranesi, E and Felici, E and Marziali, RA and Margaritini, A and Sgolastra, A and Paciaroni, L and Raccichini, A and Pelliccioni, G and Grassi, L and Recchiuto, CT and Lattanzio, F and Sgorbissa, A and Amabili, G},
title = {Technology-Assisted Cognitive Support for Older Adults With Mild Cognitive Impairment: Study Protocol for the DHEAL-COM COGNITIVE Quasi-Experimental Pilot Study.},
journal = {JMIR research protocols},
volume = {15},
number = {},
pages = {e80233},
pmid = {42826355},
issn = {1929-0748},
mesh = {Humans ; Pilot Projects ; *Cognitive Dysfunction/therapy/psychology ; Aged ; Cognitive Training/methods ; Feasibility Studies ; Single-Blind Method ; Female ; Male ; Cognitive Enhancement ; Aged, 80 and over ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents a transitional phase between normal aging and dementia. While no pharmacological treatments have proven effective, nonpharmacological interventions, such as cognitive stimulation and psychosocial support, have shown promise. Integrating digital tools and socially assistive robotics may improve engagement, personalization, and access to care, contributing to the preservation of cognitive function and overall well-being in older adults.

OBJECTIVE: The DHEAL-COM COGNITIVE pilot study aims to evaluate the feasibility, acceptability, and preliminary efficacy of a sociotechnological intervention that combines digital cognitive stimulation, social robot interaction, and group training in digital and health literacy to counteract cognitive decline.

METHODS: This is a single-blind, quasi-experimental feasibility trial involving 60 older adults with MCI, recruited from the Neurology and Alzheimer Units of IRCCS INRCA (INRCA - IRCCS Istituto Nazionale di Ricovero e Cura per Anziani). Participants were allocated into 2 groups: the experimental group received home-based cognitive training via the Brainer app, a month-long interaction with the NAO social robot, and weekly group sessions on eHealth literacy and cognitive stimulation; the control group received a well-being booklet with optional activities. Assessments were conducted at baseline, postintervention after 12 weeks, and follow-up after 3 months, using validated instruments, such as the Montreal Cognitive Assessment, the EQ-5D-5L, the Italian version of the eHealth Literacy Scale, the System Usability Scale, the unified theory of acceptance and use of technology, and the Psychological Well-Being Scale. Descriptive statistics will be used to summarize feasibility, usability, and acceptability outcomes, while preliminary differences over time will be explored using appropriate inferential analyses, acknowledging that the study is not powered to detect effectiveness.

RESULTS: Patient recruitment began in March 2025 and continued through September 2025. As of April 2026, 36 patients have been recruited, with 18 participants per group. The trial started in May 2025 and ran throughout the year. Results will focus on changes in cognitive performance, psychological well-being, quality of life, eHealth literacy, and user acceptability and usability of the technologies. Findings will be analyzed quantitatively and qualitatively and are expected to be published by the end of 2026.

CONCLUSIONS: The DHEAL-COM COGNITIVE study proposes an innovative, integrated intervention for older adults with MCI, using digital platforms and social robotics to support cognitive health and autonomy. This pilot study represents a promising step toward a more integrated and technology-supported model of care for older adults with MCI.},
}

Humans
Pilot Projects
*Cognitive Dysfunction/therapy/psychology
Aged
Cognitive Training/methods
Feasibility Studies
Single-Blind Method
Female
Male
Cognitive Enhancement
Aged, 80 and over

@article {pmid42826515,
year = {2026},
author = {Das, B and Baidya, AT and Chouhan, D and Gupta, HK and Thakur, B and Darreh-Shori, T and Chen, G and Tiwari, V and Kumar, R},
title = {Rational design, synthesis, and biological evaluation of indole-piperazine based α-ketoamide derivatives as dual Aβ and tau aggregation modulators for Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {320},
number = {},
pages = {119353},
doi = {10.1016/j.ejmech.2026.119353},
pmid = {42826515},
issn = {1768-3254},
mesh = {*Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Design ; Humans ; *tau Proteins/metabolism/antagonists & inhibitors ; Animals ; *Indoles/chemistry/pharmacology ; Structure-Activity Relationship ; *Piperazines/chemistry/pharmacology ; *Amides/chemistry/pharmacology/chemical synthesis ; Protein Aggregates/drug effects ; Mice ; Molecular Structure ; Dose-Response Relationship, Drug ; *Neuroprotective Agents/chemical synthesis/pharmacology/chemistry ; Peptide Fragments/metabolism/antagonists & inhibitors ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological aggregation of amyloid-β (Aβ) and tau proteins, representing two major hallmarks of disease progression. Targeting both aggregation pathways simultaneously offers a promising therapeutic strategy. Building upon our previous identification of the α-ketoamide derivative BD23 as a dual aggregation modulator, we report the rational design, synthesis, and biological evaluation of a new series of indole-piperazine based α-ketoamide moiety. A focused library of twenty-four compounds was synthesized and characterized using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS). These compounds were evaluated for modulation of Aβ42 aggregation using the thioflavin T fluorescence assay. Several derivatives significantly altered fibrillization kinetics, with MD03, MD07, MD08, and MD10 emerging as the most active candidates. Among them, MD08 exhibited optimal aqueous solubility (0.037 ± 0.0035 mg/mL) along with moderate blood-brain barrier permeability (Pe = 3.42 ± 0.33 × 10[-6] cm/s). Further evaluation demonstrated that MD08 inhibited heparin-induced tau aggregation in vitro, without cytotoxicity in human neuroblastoma (SH-SY5Y) cells. In vivo studies in an Aβ-induced cognitive decline mouse model revealed significant cognitive improvement in a dose-dependent manner (2, 5, and 10 mg/kg), with the highest dose showing efficacy comparable to the standard drug donepezil. Complementary in silico studies, including molecular docking and molecular dynamics simulations, supported stable interactions with Aβ and tau. Collectively, these findings identify MD08 as a promising dual aggregation modulator for AD, warranting further preclinical investigation.},
}

*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Alzheimer Disease/drug therapy/metabolism
*Drug Design
Humans
*tau Proteins/metabolism/antagonists & inhibitors
Animals
*Indoles/chemistry/pharmacology
Structure-Activity Relationship
*Piperazines/chemistry/pharmacology
*Amides/chemistry/pharmacology/chemical synthesis
Protein Aggregates/drug effects
Mice
Molecular Structure
Dose-Response Relationship, Drug
*Neuroprotective Agents/chemical synthesis/pharmacology/chemistry
Peptide Fragments/metabolism/antagonists & inhibitors

@article {pmid42826575,
year = {2026},
author = {Tripathi, A and Yadav, AK and Kumar, N},
title = {AI-driven transcriptomics for neurodegenerative disease research: A systematic review.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 1},
pages = {109448},
doi = {10.1016/j.compbiolchem.2026.109448},
pmid = {42826575},
issn = {1476-928X},
abstract = {BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS), present a growing global health challenge, with traditional diagnostic and therapeutic approaches facing significant limitations in early detection and mechanistic resolution.

OBJECTIVES: Innovations in transcriptomic technologies-spanning bulk RNA sequencing, single-cell RNA-seq (scRNA-seq), and spatially resolved transcriptomics-provide unprecedented insights into cellular heterogeneity and microenvironmental dysregulation. This systematic review synthesizes recent applications of artificial intelligence (AI), machine learning (ML), and deep learning (DL) across transcriptomic tiers to benchmark computational models for biomarker identification, disease diagnosis, patient subtyping, and drug repurposing.

METHODS & ELIGIBILITY: Following PRISMA 2020 guidelines for qualitative systematic reviews, literature published between 2016 and 2025 was systematically searched across PubMed/MEDLINE, IEEE Xplore, Google Scholar, and bioRxiv/medRxiv. Of 1058 records identified, 19 core empirical studies met all eligibility criteria and were synthesized in depth alongside contextual reference benchmarks.

SYNTHESIS & KEY FINDINGS: Traditional ML algorithms (SVM, RF, Elastic Net) demonstrate high diagnostic accuracy (AUC 0.72-0.98) in blood-based biomarker selection, while deep architectures (autoencoders, LSTMs, and Graph Neural Networks) excel at modeling continuous disease trajectories and resolving spatial transcriptomic niches (e.g., STAGATE, SpaGCN, cell2location). Emerging spatial deep learning models successfully localize disease-associated microglia (DAM) around amyloid plaques and trace axonal degeneration pathways.

LIMITATIONS & CONCLUSIONS: Key translational hurdles include data scarcity in rare NDD subtypes, lack of cross-platform spatial benchmarks, and the black-box nature of deep neural networks. Integrating explainable AI (XAI) and prospective multi-modal cohorts is essential for translating computational transcriptomics into clinical diagnostics and targeted therapeutics.},
}

@article {pmid42826598,
year = {2026},
author = {Rava, A and Di Trapano, M and Tse, C and Ji, L and Bid, HK and Trezza, V},
title = {Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107005},
doi = {10.1016/j.neubiorev.2026.107005},
pmid = {42826598},
issn = {1873-7528},
mesh = {Humans ; *Cannabinoids/pharmacology/therapeutic use/chemistry ; Animals ; *Brain Diseases/drug therapy/metabolism ; Neurodegenerative Diseases/drug therapy ; },
abstract = {Acidic cannabinoids, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and related biosynthetic precursors, represent the predominant phytocannabinoid forms naturally produced by Cannabis sativa. Long considered pharmacologically inactive intermediates, these compounds are now increasingly recognized as bioactive molecules with potential therapeutic relevance for brain disorders. Compared with their decarboxylated counterparts, acidic cannabinoids exhibit distinct physicochemical, pharmacokinetic, and pharmacodynamic properties that may confer reduced psychotropic liability together with unique neurobiological effects. Emerging preclinical evidence indicates that acidic cannabinoids modulate multiple processes implicated in neurological and psychiatric disorders, including serotonergic and endocannabinoid signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, calcium dyshomeostasis, and synaptic transmission. In this review, we critically examine current knowledge regarding acidic cannabinoids in the context of brain disorders. We first summarize their biosynthesis, chemical stability, pharmacokinetic characteristics, and pharmacological differences from neutral cannabinoids. We then examine preclinical evidence supporting their potential therapeutic effects in epilepsy, anxiety, depression, psychosis-related conditions, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We also discuss how artificial intelligence and computational approaches may support target identification, formulation optimization, pharmacokinetic modeling, and the development of personalized cannabinoid-based interventions. Finally, we highlight key methodological and translational challenges limiting the field and outline priorities for future research. Overall, acidic cannabinoids emerge as promising but still underexplored multitarget compounds with potential relevance for the treatment of brain disorders.},
}

Humans
*Cannabinoids/pharmacology/therapeutic use/chemistry
Animals
*Brain Diseases/drug therapy/metabolism
Neurodegenerative Diseases/drug therapy

@article {pmid42826610,
year = {2026},
author = {Rodriguez, S and Wetmore, JB and Diaz Caro, D and Cabán, M and Uhlmann, WR and Roberts, JS and Siegel, K and Ottman, R},
title = {Numeracy and recall of Alzheimer's disease risk information: Effects of risk format in a Latino community.},
journal = {Patient education and counseling},
volume = {154},
number = {},
pages = {110330},
pmid = {42826610},
issn = {1873-5134},
support = {R01 AG062528/AG/NIA NIH HHS/United States ; R01 AG072474/AG/NIA NIH HHS/United States ; RF1 AG066107/AG/NIA NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; },
abstract = {PURPOSE: Accurate recall of risk information is essential for informed decision-making, yet the influence of numeracy on risk recall among Latinos is unknown. We examined the relations of numeracy to recall of Alzheimer's disease (AD) risk and APOE genotypes among Latino participants in the IDEAL Study.

METHODS: Latinos aged 40-64 (N = 310) randomized to receive AD risk estimates to age 85 with or without APOE genotype information completed five numeracy items before risk disclosure. Risk estimates were delivered by genetic counselors in two formats: percentage and number out-of-20. Six weeks after disclosure, participants reported recall of risks in both formats, risk relative to other Latinos in their community, APOE-ε4 carrier status, and APOE genotype. Logistic regression was used to assess associations of numeracy with recall accuracy, adjusting for sociodemographic factors.

RESULTS: Numeracy was increased among men, participants of Mexican descent, and those who had higher education, higher income, or greater identification with non-Latinos. Among all participants, 40% correctly recalled their exact risk percentage and 37% correctly recalled their exact risk estimate out-of-20. Among participants told their APOE genotype, 75% correctly recalled their APOE-ε4 carrier status, but only 24% their specific genotype. Higher numeracy was associated with better recall of risk estimates presented out-of-20, but not with recall of genotype, percentage-based risk estimates, or risk relative to others.

CONCLUSIONS: Numeracy was associated with recall of some, but not all, forms of AD risk information. Percentage-based risk estimates were recalled somewhat better overall, and recall of risk presented out-of-20 was dependent on numeracy.

PRACTICE IMPLICATIONS: Selection of risk formats that minimize cognitive burden may improve retention of risk information, particularly among persons with lower numeracy. Use of simplified numeric formats and supportive communication strategies may enhance the effectiveness of AD risk disclosure in diverse populations.},
}

@article {pmid42826647,
year = {2026},
author = {Esmaeili, H and Das, S and Rytel, K and Sidransky, E and Chen, Y},
title = {CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.},
journal = {Molecular genetics and metabolism},
volume = {149},
number = {3},
pages = {110265},
pmid = {42826647},
issn = {1096-7206},
abstract = {Growing genetic and mechanistic evidence has highlighted substantial convergence between neurodegenerative disorders and lysosomal biology. Variants in lysosomal protein-encoding genes associated with lysosomal storage disorders (LSDs) have been implicated in common neurodegenerative diseases, suggesting that perturbations of lysosomal function represent a shared pathogenic mechanism. However, the low penetrance of neurodegenerative diseases in individuals carrying variants in these lysosomal genes suggests that additional genetic modifiers are involved as well. Advances in functional genomics, particularly clustered regularly interspaced short palindromic repeat (CRISPR)-based high-throughput screens, have opened new avenues to identify such modifiers and elucidate disease-associated pathways. These unbiased approaches have accelerated the discovery of molecular mechanisms underlying neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although to date few studies have applied CRISPR-based functional screens directly to LSDs, findings from neurodegenerative disease models provide a valuable framework for investigating lysosomal pathways and identifying genetic factors that influence phenotypic variability. In this review, we summarize recent advances in in vitro CRISPR-based screening approaches in neurodegenerative disorders and discuss their implications for understanding lysosomal biology and LSD-related mechanisms.},
}

@article {pmid42826663,
year = {2026},
author = {Paparella, M and Leuci, R and Cerini, M and Simic, S and Chaves, S and Carrieri, A and Loiodice, F and Tortorella, P and Laghezza, A and Wackerlig-Damle, J and Santos, MA and Piemontese, L},
title = {Structural optimization of donepezil-like hybrids toward an improved multi-target and ADME-related profile.},
journal = {Bioorganic chemistry},
volume = {183},
number = {},
pages = {110599},
doi = {10.1016/j.bioorg.2026.110599},
pmid = {42826663},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving mainly cholinergic dysfunction, protein misfolding, and metal dyshomeostasis. Considering the complexity of the pathology, multi-target approaches represent a valuable alternative to current approved mono-target treatments. In this study, starting from two previously identified lead compounds, fifteen new derivatives were designed. Various functional groups were introduced to evaluate their impact on cholinesterases (ChEs) and fatty-acid amide hydrolase (FAAH) and in some cases potent selective human acetylcholinesterase inhibition was observed (IC50 up to 9 ± 1 nM for compound 1 and 3). Among the series, the amine-based derivatives (9 and 11) were further evaluated for Fe[3+], Cu[2+], and Zn[2+] chelation ability, under a metal targeted strategy, showing high selectivity (pFe[3+] = 16.1, pCu[2+] = 11.0 and pZn[2+] = 6.03 for compound 11) and a metal-binding pattern suitable for anti-AD activity. Additionally, these molecules exhibited noteworthy antioxidant properties (IC50 = 17-45 μM for compounds 9-11), thus potentially beneficial in overcoming ROS overproduction typical of the disease. Finally, the whole series was subjected to an extensive in vitro ADME-related profiling, showing promising experimental ADME-related properties.},
}

@article {pmid42826681,
year = {2026},
author = {Xu, F and Li, H and Yan, Y and Chen, L and Sheng, Z and Dou, B and Yan, C and Zhu, X and Xu, Y},
title = {Cyclic nucleotide signaling through phosphodiesterase 1 inhibition and its interaction with the competing endogenous RNA network regulates cognition.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {204},
number = {},
pages = {119963},
doi = {10.1016/j.biopha.2026.119963},
pmid = {42826681},
issn = {1950-6007},
abstract = {BACKGROUND: Phosphodiesterase 1 (PDE1) has been demonstrated to be a potential drug target for a variety of diseases, ranging from peripheral system disease (PSD) to central nervous system disorders (CNSD). However, how cyclic nucleotide signaling, regulated by PDE1, particularly its isoform PDE1A, regulates the pathology of neurodegenerative disorders, including Alzheimer's disease (AD), remains unclarified.

METHOD: The Gene Expression Omnibus (GEO) database, a public gene expression repository, was used to analyze the role of PDE1 dysfunction in AD pathology. The mRNA and long non-coding RNA (lncRNA) were analyzed by comparing their differences in the GENCODE data resource V22. The relationship between PDE1, particularly PDE1A, and competing endogenous RNA (ceRNA) was validated by a dual-luciferase assay and reverse transcription-quantitative PCR (RT-qPCR), suggesting a potential ceRNA relationship among XIST, miR-338-3p, and PDE1A. Further cell-based assay and behavioral tests were conducted to determine the neuroprotective and memory-enhancing effects of PDE1 inhibition in cell and mouse models of AD.

RESULTS: A total of 11,781 differentially expressed genes (DEGs) were identified as AD- related genes. Approximately 1131 genes were identified as mitochondrial dysfunction-related by Venn plot analysis and were closely associated with AD pathology. PDE1, especially PDE1A, interacts with the lncRNA-microRNA network to promote cellular infiltration. These bioinformatic analyses were further supported by cell-based assays and behavioral studies, which demonstrated that treatment with the PDE1 inhibitor vinpocetine and PDE1A knockout ameliorated mitochondrial morphological abnormalities, restored immune function, and enhanced memory in a mouse model of AD.

CONCLUSION: These findings demonstrate that PDE1, particularly PDE1A activity, plays critical roles in AD progression by modulating mitochondrial morphology, immunity, and neuronal function, ultimately contributing to cognitive deficits.},
}

@article {pmid42826718,
year = {2026},
author = {Cha, Y and Kim, KS},
title = {From patient cells to patient therapy: Twenty years of iPSC-based translation in neurodegenerative disease.},
journal = {Cell reports. Medicine},
volume = {7},
number = {10},
pages = {103104},
doi = {10.1016/j.xcrm.2026.103104},
pmid = {42826718},
issn = {2666-3791},
mesh = {Humans ; *Induced Pluripotent Stem Cells/cytology/transplantation/metabolism ; *Neurodegenerative Diseases/therapy/pathology ; *Translational Research, Biomedical ; *Cell- and Tissue-Based Therapy/methods ; Stem Cell Transplantation ; Regenerative Medicine/methods ; Animals ; },
abstract = {Twenty years after the discovery of induced pluripotent stem cells, the field has progressed from patient-specific disease modeling toward cell-based therapies for neurodegenerative disorders. Parkinson's disease has emerged as the leading model for neuronal replacement, whereas Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis require distinct combinations of circuit reconstruction, cellular support, immune modulation, and engineered therapeutic delivery. We discuss key determinants of clinical translation, including cell source, product identity, graft composition, graft-host interactions, manufacturing reproducibility, genomic integrity, and clinical evaluation. We propose that the interval between cell transplantation and long-term engraftment constitutes a biological "black box" in which graft fate and therapeutic outcome are determined. As regenerative medicine enters its third decade, future progress will depend not only on generating therapeutic cells but also on elucidating and engineering the biological processes that determine their fate after transplantation, marking a conceptual transition from stem cell biology toward transplantation biology.},
}

Humans
*Induced Pluripotent Stem Cells/cytology/transplantation/metabolism
*Neurodegenerative Diseases/therapy/pathology
*Translational Research, Biomedical
*Cell- and Tissue-Based Therapy/methods
Stem Cell Transplantation
Regenerative Medicine/methods
Animals

@article {pmid42826722,
year = {2026},
author = {Murata, K and Mizushina, Y and Izawa, D and Matsui, Y and Wakabayashi, T and Hashimoto, T and Iwatsubo, T and Matsushima, Y},
title = {Ruscus aculeatus Extract Inhibits Amyloid Beta Production and Upregulates the Active form of ADAM10 in Human Neural Progenitor Cells.},
journal = {Planta medica},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2943-8874},
pmid = {42826722},
issn = {1439-0221},
abstract = {Alzheimer's disease is characterized by the accumulation of cerebral amyloid beta (Aβ) peptides, making the inhibition of Aβ production a key therapeutic strategy. We screened a plant extract library for Aβ42 inhibitors using human neural progenitor cells and identified a Ruscus aculeatus extract as a potential candidate. Although rhizome extracts of R. aculeatus exhibit vasotonic, and anti-inflammatory properties, their effects on amyloid-β precursor protein (APP) processing have not been investigated. We aimed to elucidate how R. aculeatus extract influences Aβ production and its underlying mechanisms. R. aculeatus extract significantly reduced Aβ40 and Aβ42 production and the pathogenic Aβ42/Aβ40 ratio in both human neural progenitor (ReNcell VM) and mouse neuroblastoma (Neuro2a) cells in concentration-dependent manner. The extract enhanced non-amyloidogenic APP pathway processing, evidenced by increased levels of ADAM10 active form, soluble APPα and C-terminal fragment α levels. Despite increasing BACE1 protein levels, the extract reduced soluble APPβ production, suggesting inhibition of BACE1-mediated APP cleavage. RNA-seq analysis revealed Notch signaling pathway downregulation, implying γ-secretase activity modulation. In conclusion, the R. aculeatus extract suppresses Aβ production by modulating multiple APP processing pathways, primarily through enhancing non-amyloidogenic pathway via ADAM10 activation. By reducing amyloidogenic peptides levels, R. aculeatus extract may contribute to decreased amyloid plaques formation. These findings identify R. aculeatus extract as a modulator of APP metabolism.},
}

@article {pmid42826818,
year = {2026},
author = {Chaudhari, A and Goyal, S},
title = {Microglial GPR56 in synaptic pruning: mechanisms, comparative receptor biology, and context-dependent roles in brain disorders.},
journal = {Biochimica et biophysica acta. Molecular cell research},
volume = {1874},
number = {1},
pages = {120231},
doi = {10.1016/j.bbamcr.2026.120231},
pmid = {42826818},
issn = {1879-2596},
abstract = {Microglia regulate synaptic remodelling, eliminating weakened and dysfunctional synapses to maintain circuit development and homeostasis. Adhesion G protein-coupled receptor G1 (ADGRG1/GPR56) has emerged as a distinctive regulator integrating phosphatidylserine recognition, mechano-transduction, and G-protein signalling. This review synthesises the molecular, cellular and disease-level evidence, distinguishing throughout between direct experimental findings, associations, and proposed mechanisms. We discuss its structural organisation, the microglia-enriched splice variant 4 (S4), and how phosphatidylserine-exposing synapses are recognised and engulfed. The Gα12/13-RhoA cascade placed downstream of microglial GPR56 was defined in neural progenitor cells and has not been perturbed in microglia; it is presented as proposed rather than established. Comparison with CR3, CX3CR1, TREM2, MERTK, MEGF10 and BAI1, identifies microglia-enriched alternative splicing, direct coupling of phosphatidylserine recognition to G-protein signalling, and mechanosensitivity as distinguishing features. We then evaluate evidence linking GPR56 to traumatic brain injury, major depressive disorder, maternal immune activation models, and Alzheimer's disease. In every context the causal evidence is loss-of-function: removing the receptor worsens the phenotype, including in Alzheimer's disease, where microglial ADGRG1 is increased yet deletion aggravates amyloid pathology and cognitive decline. The evidence supports a protective receptor that, when lost, produces different outputs in different settings, not one that switches between protective and pathological roles. The four disease outcomes are different from each other and from developmental pruning. The idea that they all involve a single S4-dependent mechanism remains a hypothesis, not a confirmed fact. We conclude by discussing therapeutic and biomarker opportunities and translational challenges.},
}

@article {pmid42827109,
year = {2026},
author = {Song, J and Lee, SJ and Mook-Jung, I},
title = {Golgi dysfunction in Alzheimer disease: from human multiomic signatures to therapeutic targets.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42827109},
issn = {2092-6413},
abstract = {Deciphering the intricate pathogenesis of Alzheimer disease (AD) has been a highly demanding task for researchers for decades. Evidence from from human multiomic studies provides critical insights into complex disease mechanisms and drives novel findings. However, the data are often selectively comprehended, leaving a few notable factors underappreciated in the research field. We focus on the Golgi apparatus, one of the most undervalued organelles in AD research, to demonstrate its multidimensional contribution to the pathogenesis. Given the importance of Golgi in modulating intracellular protein and lipid homeostasis, implication of Golgi in AD pathogenesis deserves thorough investigation. In this review, we describe changes in Golgi morphology and function in AD, and summarize specific Golgi-related factors discovered by genomic, transcriptomic, proteomic, and lipidomic data using human samples. Based on the findings, we demonstrate mechanistic link of Golgi-related factors to AD pathogenesis and highlight potential therapeutic strategies to modify Golgi-mediated pathogenesis. Overall, Golgi dysfunction may serve as a notable mechanistic hub of AD pathogenesis, making it a promising target for development of novel therapeutic strategies.},
}

@article {pmid42827268,
year = {2026},
author = {Abdulhameed, N and Babin, A and Hansen, K and Weaver, R and Banks, WA and Talbot, K and Rhea, EM},
title = {Correction: Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {42827268},
issn = {1758-9193},
}

@article {pmid42827376,
year = {2026},
author = {Carvalho, LB and Yamada, AK and Furtado, LA and Feltran, GDS and de Lima, ER and Paiva, A and Canineo, D and Bernardi, MM and Fernandes, CJDC and da Silva, RAF},
title = {REST in the Central Nervous System: Context-Dependent Regulation of Neuronal Homeostasis and Disease.},
journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience},
volume = {86},
number = {6},
pages = {e70186},
doi = {10.1002/jdn.70186},
pmid = {42827376},
issn = {1873-474X},
support = {301498/2022-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 88887.827837/2023-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {Humans ; RE1-Silencing Transcription Factor ; *Homeostasis/physiology ; Animals ; *Neurons/metabolism ; *Repressor Proteins/metabolism/genetics ; *Central Nervous System/metabolism ; },
abstract = {The RE1-silencing transcription factor (REST), also known as neuron-restrictive silencer factor (NRSF), is a zinc-finger domain-containing transcriptional regulator involved in coordinating gene expression programmes in the nervous system. Initially characterized as a repressor of neuronal genes in nonneuronal cells, REST also exerts context-dependent functions during neurodevelopment, neuronal maturation, homeostasis and brain ageing. Its activity involves the recruitment of multiple regulatory complexes, including Sin3A/HDACs and CoREST/LSD1, as well as interactions with mechanisms associated with DNA methylation and hydroxymethylation. REST also integrates regulatory networks involving noncoding RNAs. MicroRNAs such as miR-9, miR-124 and miR-132 participate in networks that interact with REST, contributing to the regulation of neuronal differentiation, maturation and function, whereas interactions with long noncoding RNAs remain less well characterized. Alterations in REST expression, subcellular localization or activity have been associated with various neurological and neurodegenerative conditions. In specific neuronal populations during ageing, nuclear REST has been associated with the regulation of genes involved in stress responses and neuronal resilience, whereas alterations in REST activity have been observed in diseases such as Alzheimer's and Huntington's disease. In addition, mechanistic evidence indicates that cellular metabolic state, particularly alterations in glycolysis and the NADH/NAD[+] ratio, may influence REST-regulated pathways. In contrast, associations between REST and factors such as physical exercise and creatine availability remain predominantly indirect or hypothetical. In this review, we synthesize the evidence regarding the transcriptional and epigenetic regulatory mechanisms associated with REST, its interactions with noncoding RNA networks and its functions during neuronal development, homeostasis and ageing. We also discuss the interfaces between REST, metabolism and environmental factors, highlighting differences in the strength of the available evidence, current limitations and mechanistic gaps that warrant further investigation.},
}

Humans
RE1-Silencing Transcription Factor
*Homeostasis/physiology
Animals
*Neurons/metabolism
*Repressor Proteins/metabolism/genetics
*Central Nervous System/metabolism

@article {pmid42827801,
year = {2026},
author = {Bressler, SG and Blacher, C and Harpaz, KA and Grunhaus, D and Rüdiger, SGD and Hurevich, M and Shalev, DE and Miller, Y and Friedler, A},
title = {Site-specific phosphorylation of Ser352 drives aggregation of Tau R4 under acidosis conditions.},
journal = {Chemical science},
volume = {},
number = {},
pages = {},
pmid = {42827801},
issn = {2041-6520},
abstract = {In Alzheimer's disease, neurons undergo acidosis as their pH drops from ∼7.1 to ∼6.5. Here we elucidate the molecular mechanism of specific Tau aggregation only at this lower pH. We show that a specific phosphorylation event in the Tau R4 domain is coupled to this pH drop to drive a defined phase transition from condensates to fibrils. Using a combination of experimental and computational studies, our results demonstrate that site-specific phosphorylation of Ser352 is the molecular switch that induces aggregation of Tau only at the more acidic, disease-related pH. We designed and synthesized a phosphopeptide library covering all phosphorylation patterns of the Tau-R4 domain and tested its response to controlled acidification using an array of complementary biophysical methods. This revealed that only a single phosphorylation of Ser352 led to acid-driven aggregation of Tau-R4. At neutral pH, Tau-R4 with a phosphorylation on Ser352 formed liquid condensates. These condensates converted irreversibly into amyloid filaments as the pH gradually decreased towards the level associated with pathological acidosis. Using a combination of [31]P- and [1]H-NMR, MD simulations and microscopy studies, we show that the mechanism by which the phosphorylation of Ser352 Tau R4 exerts its effects is based on the unique position of this residue within the protein structure. pSer352 is located at the inside of the tip of a β-hairpin, pointing into the hydrophobic core of the amyloid fold. This buried position increases its effective pK a, resulting in compacting of the hairpin following pSer352 protonation upon acidification. This shortens the inter-sheet distance at this position and tightens the filament. We conclude that this single protonation event of the pSer352 phosphate is responsible for the macroscopic phase transition from condensates to aggregates. Our results provide the molecular explanation for the specific aggregation of Tau under the pathologically relevant acidic pH, which is substantially different from its behavior at neutral pH.},
}

@article {pmid42827967,
year = {2026},
author = {Ling, Z and Huang, S and Cheng, Y and Liu, X and Xu, X and Chen, Y and Hu, P and Wu, L and Cai, G},
title = {Short-chain fatty acid-producing commensals: Key modulators of AD neuroinflammation via the microbiota-gut-brain axis.},
journal = {Current research in microbial sciences},
volume = {11},
number = {},
pages = {100660},
pmid = {42827967},
issn = {2666-5174},
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapies. Neuroinflammation has emerged as a central driver of AD pathogenesis, and the gut-brain axis represents a key modulator of neuroimmune responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are microbial metabolites that bridge gut homeostasis with brain function. This review synthesizes current evidence on the functional depletion of SCFA-producing gut bacteria in AD, the journey of SCFAs from the gut to the brain, and their pleiotropic actions on neuroinflammatory cell states. SCFAs regulate microglial and astrocytic phenotypes, suppress NLRP3 inflammasome activation, and promote peripheral immune tolerance via GPCR signaling, HDAC inhibition, and metabolic reprogramming. They also modulate amyloid-β deposition, tau pathology, and synaptic integrity. Translational strategies, including dietary interventions, next-generation probiotics, postbiotics, and fecal microbiota transplantation, are critically evaluated. We further discuss challenges such as causal evidence gaps, host heterogeneity, and stage-dependent therapeutic windows, and propose a pharmacomicrobiomics framework for biomarker-guided trial design. Restoring SCFA-mediated regulatory networks holds promise as a first-line disease-modifying strategy for AD, but clinical translation will require rigorous mechanistic dissection and personalized approaches.},
}

@article {pmid42828019,
year = {2026},
author = {Kucukbagriacik, Y and Saribas, GS and Ates, K and Ozturk, C and Kahyaoglu, E and Kislal, S and Akgul, CC and Karacalioglu, AO and Goksoy, C and Kantarcioglu, M},
title = {Exploratory effects of coffee-derived exosome-like nanoparticles in a fibrillar amyloid-beta 1-42-induced neurodegenerative rat model: evidence from fluorodeoxyglucose positron emission tomography and phosphorylated tau/amyloid precursor protein expression.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21739},
pmid = {42828019},
issn = {2167-8359},
mesh = {Animals ; Male ; *Amyloid beta-Peptides/metabolism ; Rats, Sprague-Dawley ; *tau Proteins/metabolism ; *Nanoparticles/chemistry/administration & dosage ; *Exosomes/chemistry ; Peptide Fragments ; Rats ; Phosphorylation ; Disease Models, Animal ; *Coffee/chemistry ; Fluorodeoxyglucose F18 ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta 1-42 (Aβ1-42) accumulation, tau pathology, and metabolic dysfunction. This exploratory study evaluated the effects of coffee-derived exosome-like nanoparticles (CELNs) on selected metabolic and histopathological endpoints in a fibrillar Aβ1-42-induced neurodegenerative rat model.

METHODS: Fifty male Sprague-Dawley rats were randomly divided into five groups (N = 10 each): Control (C), sham (SF), a fibrillar Aβ1-42-induced neurodegenerative rat model (AD), AD treated with a low dose of CELNs (AD + LE, 10 mg/kg/day), and AD treated with a high dose of CELNs (AD + HE, 20 mg/kg/day) for 14 days. CELNs were quantified and characterized using the bicinchoninic acid method, scanning electron microscopy, and nanoparticle tracking analysis (NTA). Micro-positron emission tomography/computed tomography fluorodeoxyglucose (MicroPET/CT FDG) imaging of the central nervous system was performed in all groups at the end of treatment. Subsequently, all animals were sacrificed, and hippocampal tissues were subjected to histopathological analysis.

RESULTS: MicroPET imaging demonstrated a significant, dose-dependent increase in cerebral glucose metabolism in AD rats treated with CELNs compared with the untreated AD group. Histopathological evaluations were consistent with the imaging data: in AD groups receiving CELNs, phospho-tau and beta-amyloid precursor protein expression were significantly reduced in the hippocampal cornu ammonis 2 (CA2) and dentate gyrus regions compared with the untreated AD group.

CONCLUSIONS: In this exploratory fibrillar Aβ1-42-induced neurodegenerative rat model, oral CELN administration was associated with dose-dependent partial improvements in cerebral glucose metabolism and region-specific reductions in hippocampal phosphorylated tau (p-Tau) and amyloid precursor protein (APP) immunoreactivity. However, these are preliminary biomarker-level findings that support further investigation of CELNs; definitive confirmation of functional and cognitive benefits requires additional behavioral, biodistribution, and experimental validation.},
}

Animals
Male
*Amyloid beta-Peptides/metabolism
Rats, Sprague-Dawley
*tau Proteins/metabolism
*Nanoparticles/chemistry/administration & dosage
*Exosomes/chemistry
Peptide Fragments
Rats
Phosphorylation
Disease Models, Animal
*Coffee/chemistry
Fluorodeoxyglucose F18
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Amyloid beta-Protein Precursor/metabolism
Positron-Emission Tomography

@article {pmid42828025,
year = {2025},
author = {Zhang, S and Wang, Z and Kharrazi, H},
title = {RaiLED-AD: Rationale-Guided Knowledge Transfer for Alzheimer's Disease Prediction from Electronic Health Records.},
journal = {Proceedings. IEEE International Conference on Bioinformatics and Biomedicine},
volume = {2025},
number = {},
pages = {7673-7680},
pmid = {42828025},
issn = {2156-1125},
support = {R01 AG068002/AG/NIA NIH HHS/United States ; },
abstract = {In Alzheimer's Disease and Related Dementia (ADRD) prediction, Electronic Health Records (EHRs) provide rich but fragmented information. Without a coherent clinical narrative, models tend to rely on a few dominant signals (e.g., age-related patterns) rather than capturing the underlying clinical mechanisms. Such reliance becomes problematic in younger-onset cases, where these signals are less informative. To address this challenge, we propose RaiLED-AD, a dual-encoder teacher-student framework where the student learns from serialized EHR data and the teacher leverages LLM-generated narratives that capture temporal and relational patterns. A hybrid objective with soft-label supervision and hierarchical contrastive alignment transfers these reasoning signals to the student, which operates independently at inference. On a real-world EHR cohort, RaiLED-AD consistently improves ADRD prediction over baselines and achieves substantial gains in the challenging younger-onset subgroup (index age <65). These results highlight the potential of integrating LLM-derived reasoning signals with structured EHR models for early-stage ADRD risk prediction.},
}

@article {pmid42828275,
year = {2026},
author = {Law, KW and Engstrom, AC and Lohman, T and Quiring, M and Kapoor, A and Alitin, JPM and Wang, DJJ and Gaubert, A and Rodgers, K and Head, E and Valencia, CI and Joyce, JL and Ferrer, F and Nation, DA},
title = {Older adults in more disadvantaged neighborhoods exhibit brain vascular dysfunction.},
journal = {Cerebral circulation - cognition and behavior},
volume = {11},
number = {},
pages = {100562},
pmid = {42828275},
issn = {2666-2450},
support = {P01 AG052350/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG064228/AG/NIA NIH HHS/United States ; R01 AG082073/AG/NIA NIH HHS/United States ; },
abstract = {Neighborhood disadvantage is a risk factor for dementia, but the mechanisms involved are not well understood. In this study, we explored the relationship between neighborhood deprivation and whole-brain cerebrovascular reactivity (CVR) in 132 older adults without a history of clinical stroke or dementia. Participants underwent brain MRI and venipuncture. Relative neighborhood deprivation was quantified using the Area Deprivation Index. Spontaneous CVR was calculated as the percent change in resting cerebral blood flow per unit change in end-tidal CO2. Greater neighborhood deprivation was associated with lower whole-brain CVR when adjusted for age and sex (p = 0.027). Further adjustment for APOE ε4 carrier status, vascular risk factors, and plasma Alzheimer's disease (AD) biomarker p-tau217 did not alter the results. These findings show that older adults in more disadvantaged environments exhibit reduced cerebrovascular function, independent of traditional vascular risk and AD-related pathology. However, further investigation with more diverse samples and a life-course model is warranted to better understand these microvascular differences.},
}

@article {pmid42828354,
year = {2026},
author = {Dacey, R and Durape, S and Wang, M and Hwang, PH and Gurnani, AS and Ang, TFA and Devine, SA and Choi, SE and Lee, M and Scollard, P and Mukherjee, S and Trittschuh, E and Sherva, R and Dumitrescu, L and Hohman, TJ and Cuccaro, ML and Saykin, AJ and Crane, PK and Li, Y and Levy, D and Ma, J and Liu, C and Lunetta, KL and Au, R and Farrer, LA and Mez, J},
title = {Epigenetic Age and Resilience in the Framingham Heart Study.},
journal = {Neurology open access},
volume = {2},
number = {2},
pages = {},
pmid = {42828354},
issn = {2998-7601},
support = {U01 AG058654/AG/NIA NIH HHS/United States ; R01 AG016495/AG/NIA NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; R01 AG008122/AG/NIA NIH HHS/United States ; N01 HC025195/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; U01 AG062602/AG/NIA NIH HHS/United States ; U01 AG081230/AG/NIA NIH HHS/United States ; U19 AG068753/AG/NIA NIH HHS/United States ; RF1 AG054156/AG/NIA NIH HHS/United States ; R01 AG061028/AG/NIA NIH HHS/United States ; RF1 AG062109/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; R01 AA028263/AA/NIAAA NIH HHS/United States ; R01 AG033040/AG/NIA NIH HHS/United States ; R01 AG048927/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVES: Growing evidence suggests that decreased epigenetic age relative to chronological age may be protective against late-life cognitive decline and dementia, but the mechanism leading to this resilience is unknown.

METHODS: DNA methylation (DNAm), plasma total tau (t-tau), MRI total cerebral brain volume (TCBV), and neuropsychological (NP) data were obtained from Framingham Heart Study Offspring cohort participants. Three epigenetic age measures, DunedinPACE, PCPhenoAge, and PCGrimAge, were estimated from DNAm data. DunedinPACE and residuals from regressing PCPhenoAge and PCGrimAge on chronological age were standardized for analysis. Longitudinal NP factor scores were previously derived for memory, language, and executive function (EF) using confirmatory factor analysis. We tested the association of epigenetic age with cognitive trajectories using linear mixed-effects models and with time to mild cognitive impairment (MCI), Alzheimer disease dementia (AD), and all-cause dementia using Cox proportional hazard models and whether t-tau and TCBV moderated the observed relationships.

RESULTS: At baseline (Exam 8, 2005-2008), the sample included 2,606 participants [mean age: 66 (SD = 9) years, 55% female, mean education: 16 (SD = 3) years]. Epigenetic age measures were weakly but significantly (p < 0.001) correlated with t-tau (r: 0.08-0.12) and TCBV (r: -0.05 to -0.24). All epigenetic age measures were associated with worse baseline EF (DunedinPACE: β = -0.040, 95% CI [-0.067 to -0.012], padj = 0.01; PCPhenoAge: β = -0.036, 95% CI [-0.062 to -0.011], padj = 0.01; PCGrimAge: β = -0.049, 95% CI [-0.080 to -0.018], padj = 0.01). PCPhenoAge also was associated with worse baseline memory (β = -0.034, 95% CI [-0.058 to -0.010], padj = 0.01) and language (β = -0.032, 95% CI [-0.058 to -0.006], padj = 0.03). DunedinPACE was associated with time to MCI (hazard ratio [HR] = 1.16, 95% CI [1.04-1.30], padj = 0.04) and all-cause dementia (HR = 1.30, 95% CI [1.10-1.54], padj = 0.03). Epigenetic age measures were not associated with the rate of decline. Magnitudes of association for epigenetic age measures remained similar after adjustment for TCBV and t-tau. TCBV and t-tau had similar magnitudes of association in analyses stratified by median epigenetic age.

DISCUSSION: Independent of t-tau and TCBV, epigenetic age measures were associated with time to MCI, AD, and all-cause dementia and baseline cognition, but not with cognitive trajectories. The results support epigenetic age measures as markers of resilience through brain reserve. The findings may have important implications regarding use of epigenetic age measures as biomarkers to track the success of interventions targeting resilience.},
}

@article {pmid42828458,
year = {2026},
author = {Megari, K and Keramida, MM},
title = {Indications and pathways of Type 2 diabetes mellitus as a predictor of neurocognitive decline and dementia: Clinical implications and management.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/23279095.2026.2741894},
pmid = {42828458},
issn = {2327-9109},
abstract = {Type 2 diabetes mellitus (T2DM) is a metabolic disease, one of the most common chronic conditions globally. Studies suggest that T2DM can increase the risk of mild cognitive impairment (MCI), Alzheimer's disease (AD) and other types of dementia; T2DM has been associated with decline in memory, verbal fluency, executive function and processing speed. It seems that T2DM and AD share common biological mechanisms. Multiple studies have investigated them, suggesting that insulin resistance, hyperglycemia and neuroinflammation are some potential factors which can increase risk of dementia in patients with T2DM. Thus, it is suggested that cognitive screening in the early stages of T2DM can be beneficial to prognose disease progression. Despite the current data regarding T2DM and dementia, there is a research gap on interventions focusing on the cognitive and psychological aspects of diabetes. Therefore, future studies should focus on creating tailored interventions for diabetic patients and identify possible biomarkers for the early prediction of cognitive deficits on T2DM. With a deeper understanding, researchers can help prevent or delay cognitive impairment in patients with T2DM contributing to patient's quality of life and the broader landscape of public health.},
}

@article {pmid42828470,
year = {2026},
author = {Sabahizadeh, A and Askarinejad, A and Ahmadzadeh, K and Mirjalili, SR and Farshid, K and Serio, L and Tartaglia, E and Proietti, R and Davies, R and Lip, GYH},
title = {Delirium in Patients With Traumatic Brain Injury and Long-Term Cognitive Decline: A Global Federated Real World Data Analysis.},
journal = {European journal of clinical investigation},
volume = {56},
number = {10},
pages = {e70262},
pmid = {42828470},
issn = {1365-2362},
mesh = {Humans ; Female ; *Brain Injuries, Traumatic/epidemiology/complications ; *Delirium/epidemiology/etiology ; Aged ; Retrospective Studies ; Male ; Middle Aged ; *Cognitive Dysfunction/epidemiology/etiology ; Alzheimer Disease/epidemiology ; Adult ; *Dementia/epidemiology ; Dementia, Vascular/epidemiology ; Aged, 80 and over ; Propensity Score ; },
abstract = {BACKGROUND AND OBJECTIVE: Delirium may occur in patients with traumatic brain injury (TBI), but this may be a marker for subsequent cognitive decline post-TBI. We aimed to compare cognitive outcomes and all-cause mortality between TBI patients with and without delirium.

METHODS: We conducted a retrospective cohort study using the TriNetX global federated research network. We compared TBI patients who developed delirium within 14 days of TBI diagnosis with those who did not. The primary outcome was the 2-year composite risk of dementia, vascular dementia and Alzheimer's disease. Secondary outcomes included dementia, vascular dementia, Alzheimer's disease and all-cause mortality. Pre-specified subgroup analyses were performed in female patients, older adults (≥ 75 years), and individuals with substance use.

RESULTS: TBI patients with delirium (n = 2564; mean age, 66.6 ± 19.4 years; 59.4% male), when compared with TBI patients without delirium (n = 667,950; mean age, 48.0 ± 25.1 years; 60.3% male), had more baseline comorbidities, including psychiatric disease, cerebrovascular disease and ischemic heart disease. After propensity score matching, TBI patients with delirium, compared with those without delirium, had a higher 2-year risk of the primary composite outcome (HR, 2.47; 95% CI, 1.84-3.31), as well as dementia (HR, 2.63; 95% CI, 1.92-3.60), vascular dementia (HR, 2.76; 95% CI, 1.45-5.24) and Alzheimer's disease (HR, 2.23; 95% CI, 1.21-4.09).

CONCLUSION: Delirium following TBI is associated with an increased risk of dementia and Alzheimer's disease. Delirium post-TBI may be a marker or a contributing factor to long-term cognitive decline in TBI patients.},
}

Humans
Female
*Brain Injuries, Traumatic/epidemiology/complications
*Delirium/epidemiology/etiology
Aged
Retrospective Studies
Male
Middle Aged
*Cognitive Dysfunction/epidemiology/etiology
Alzheimer Disease/epidemiology
Adult
*Dementia/epidemiology
Dementia, Vascular/epidemiology
Aged, 80 and over
Propensity Score

@article {pmid42828479,
year = {2026},
author = {Riga, MS and Pérez-Fernández, M and Andrade-Talavera, Y and Domínguez-Velasco, B and Rodríguez-Moreno, A and Álvarez-Dolado, M},
title = {Scn1a-mediated developmental regulation of prefrontal cortex plasticity and cognition.},
journal = {Epilepsia},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi.70484},
pmid = {42828479},
issn = {1528-1167},
support = {//Asociación Apoyo Dravet/ ; RH-0048-2020//Ministry of Health and Consumer of the Andalusian Government/ ; PID2021-127044OB-I00//Ministerio de Ciencia y Universidades/Agencia Estatal de investigacion/Fondos Europeos de Desarrollo Regional (MCIU/AEI/FEDER), UE/ ; PID2022-136597NB-I00//Ministerio de Ciencia y Universidades/Agencia Estatal de investigacion/Fondos Europeos de Desarrollo Regional (MCIU/AEI/FEDER), UE/ ; PID2024-162613OB-I00//Ministerio de Ciencia y Universidades/Agencia Estatal de investigacion/Fondos Europeos de Desarrollo Regional (MCIU/AEI/FEDER), UE/ ; GA_10106117//Skłodowska-Curie Fellowship/ ; },
abstract = {OBJECTIVE: The voltage-gated sodium channel Nav1.1, encoded by Scn1a, is essential for γ-aminobutyric acid (GABA)ergic function, and its alteration is associated with neurological disorders such as Dravet syndrome and Alzheimer's disease. We previously demonstrated that local Nav1.1 dysfunction in the medial prefrontal cortex (mPFC) during adolescence causes epilepsy, cognitive deficits, and depressive-like behaviors. Here, to investigate putative developmental differences, we analyzed whether Nav1.1 dysfunction in the adult mPFC produces comparable phenotypic outcomes.

METHODS: Nav1.1 dysfunction was selectively induced in the adult mPFC via conditional expression of a mutant human SCN1A variant. We then analyzed PFC-related cognitive tasks and depressive-like behaviors; epileptic and oscillatory activity using in vivo electroencephalography (EEG) recordings; and ex vivo synaptic plasticity in mPFC circuits.

RESULTS: As observed after adolescent Nav1.1 dysfunction, adult manipulation induced epileptic activity and depressive-like phenotypes. However, mPFC-dependent cognitive functions remained intact, unlike adolescent mice, which showed impaired working memory and fear extinction. Electrophysiological recordings revealed distinct mPFC oscillatory patterns. Adult Nav1.1 dysfunction reduced sleep-related delta mPFC power and dorsal hippocampus (dHPC)-mPFC coherence, mimicking adolescent patterns. In contrast, no alteration in mPFC oscillatory activity was observed during wakefulness, differing from adolescent mice. IN addition, synaptic plasticity analyses showed that adolescent-but not adult-Nav1.1 dysfunction impaired long-term potentiation (LTP) at cortical L2/3-L2/3 prelimbic synapses. Moreover, LTP was sensitive to Nav1.1 pharmacological activation only in adolescent mice.

SIGNIFICANCE: These findings reveal a developmental role for Nav1.1 activity in mPFC plasticity and cognition, whereas in adulthood, it remains critical for regulating network stability and depressive-like behaviors.},
}

@article {pmid42828568,
year = {2026},
author = {Bernetti, C and Calandrelli, R and Pilato, F and Di Lazzaro, V and Zobel, BB and D'Amelio, M and Mallio, CA},
title = {Exploring the role of glymphatic system in Alzheimer's disease with insights from MRI-based studies: a systematic review.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42828568},
issn = {1432-1920},
abstract = {BACKGROUND: The glymphatic constitutes a crucial neurophysiological mechanism for the clearance of interstitial solutes and neurotoxic metabolites from the central nervous system. Dysfunction within this pathway is increasingly implicated in the etiopathogenesis of neurodegenerative diseases, notably Alzheimer's disease (AD). Advanced magnetic resonance imaging (MRI) modalities, such as diffusion tensor image analysis along the perivascular space (DTI-ALPS), have emerged as non-invasive, in vivo approaches quantifying glymphatic transport efficacy and its association with cognitive decline and AD progression.

METHODS: This systematic review was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. and systematic literature retrieval was executed across PubMed, Cochrane, and Scopus databases, targeting studies that employed MRI-based metrics to assess glymphatic functionality in the context of AD.

RESULTS: A total of 35 studies fulfilled the inclusion criteria. AD patients exhibited significantly reduced DTI-ALPS indices, correlating with elevated enlarged perivascular space (ePVS) volumes, neurocognitive deterioration, and cerebral atrophy. Notably ePVSs enlargement emerged as a surrogate marker of glymphatic dysfunction and a predictor of MCI-to-AD conversion. However, amyloid PET correlations exhibited inter-study heterogeneity.

CONCLUSIONS: MRI derived biomarkers, particularly DTI-ALPS index and ePVSs analysis, demonstrate high potential as surrogate indicators of glymphatic impairment in AD. These findings underscore their diagnostic and prognostic value, warranting harmonization of imaging protocols and longitudinal investigations to establish their translational utility in clinical biomarker frameworks.

CLINICAL RELEVANCE STATEMENT: MRI biomarkers of glymphatic dysfunction provide valuable insights into Alzheimer's disease pathophysiology and progression. These imaging markers may enhance early diagnosis, monitor disease progression, and evaluate treatment efficacy in AD.},
}

@article {pmid42828605,
year = {2026},
author = {Przywara, D and Petniak, A and Gil-Kulik, P},
title = {The Therapeutic Potential of MicroRNAs Delivered By Mesenchymal Stem Cells in Parkinson's Disease, Alzheimer's Disease, and Stroke: A Systematic Review of Preclinical Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42828605},
issn = {1559-1182},
mesh = {*MicroRNAs/administration & dosage/genetics/therapeutic use ; Animals ; Humans ; *Alzheimer Disease/therapy/genetics ; *Stroke/therapy/genetics ; *Mesenchymal Stem Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Parkinson Disease/therapy/genetics ; },
abstract = {Population aging has led to a substantial increase in the prevalence of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and stroke. As current therapeutic strategies are largely limited to symptomatic management, the identification of disease-modifying treatments remains a major unmet clinical need. Mesenchymal stem cells (MSCs) and MSCs-derived microRNAs (miRNAs) have emerged as promising therapeutic candidates for these conditions. A systematic literature search was conducted in the PubMed and Scopus databases in accordance with the PRISMA guidelines. The aim was to synthesize the available evidence regarding the effects of MSCs-derived miRNAs on cellular processes, including apoptosis, proliferation, inflammation, oxidative stress, and motor function in experimental models of PD, AD, and stroke. Risk of bias was assessed using the SYRCLE Risk of Bias tool for animal intervention studies and the modified OHAT Risk of Bias Rating Tool (mOHAT). A total of 37 preclinical studies were included in the review: 9 focused on PD, 10 on AD, and 18 on stroke. The synthesized evidence indicates that specific MSCs-derived miRNAs, particularly miR-133b, miR-146a, miR-17-92, and miR-223, exert significant neuroprotective effects. These miRNAs actively modulate gene expression, attenuate neuroinflammation and apoptosis, and reduce the accumulation of disease-specific pathological markers, including α-synuclein and amyloid-β (Aβ). Furthermore, targeted delivery of these miRNAs was associated with improved motor and cognitive outcomes across the evaluated animal models. MSCs-derived miRNAs demonstrate considerable therapeutic potential for the treatment of neurodegenerative diseases and stroke through the modulation of multiple pathological pathways. However, as the current evidence is derived exclusively from in vitro and animal studies, future research should focus on the development of safe, standardized, and reproducible protocols to facilitate the translation of these findings into human clinical trials. The review was registered in the Open Science Framework (OSF): https://osf.io/cxt9b .},
}

*MicroRNAs/administration & dosage/genetics/therapeutic use
Animals
Humans
*Alzheimer Disease/therapy/genetics
*Stroke/therapy/genetics
*Mesenchymal Stem Cells/metabolism
*Mesenchymal Stem Cell Transplantation/methods
*Parkinson Disease/therapy/genetics