IMPORTANCE: The long-term efficacy of amyloid-targeting therapies hinges on their ability to slow downstream neuropathologic change, but little is known about the influence of amyloid clearance on tau pathology and neurodegeneration. OBJECTIVE: To determine the postmortem and in vivo association between amyloid levels and downstream neuropathology after treatment with aducanumab in a patient with patchy areas showing minimal residual amyloid levels. DESIGN, SETTING, AND PARTICIPANTS: This clinicopathologic case report from a single academic memory center includes a male carrier of the p.R47H TREM2 variant, which is associated with a higher risk of Alzheimer disease, who was in his 50s, had mild cognitive impairment, and received aducanumab while participating in a randomized clinical trial. Fourteen untreated controls, who were matched by age or presence of the TREM2 variant, also are included. EXPOSURES: The male carrier of the p.R47H TREM2 variant had received 30 doses of aducanumab (cumulative dose of 280 mg/kg) over 4.5 years. MAIN OUTCOMES AND MEASURES: Neuropathologic evaluation at autopsy, positron emission tomography to measure standardized uptake value ratio as a measure of amyloid and tau levels, and magnetic resonance imaging to determine longitudinal change in cortical thickness. RESULTS: Four years after receiving the final dose of aducanumab, the patient died. An autopsy showed variable levels of amyloid pathology, including brain regions with very low levels of amyloid juxtaposed with brain regions that had typically high levels of amyloid in the deep cortical layers and only low levels of amyloid in the superficial cortical layers. Compared with the brain regions of the untreated controls, the brain regions of the patient after treatment with aducanumab showed low levels of amyloid that were preferentially found in the gyral crests, were associated with less tau pathology at autopsy, and were associated with slower longitudinal atrophy on in vivo magnetic resonance imaging (β = -0.50 [95% CI, -0.62 to -0.37]; t = -7.96 and P < .001). In contrast, the patient's brain regions with high amyloid burden were preferentially found in the sulcal depths and had similar levels of tau pathology as seen at autopsy in the untreated controls. CONCLUSIONS AND RELEVANCE: In this case report, areas of extensive amyloid clearance after amyloid-targeting therapy were associated with less downstream neuropathologic change. In addition, amyloid clearance appears to preferentially occur in the gyral crests. Future studies should evaluate the differential mechanisms involved in amyloid clearance from superficial and deep cortical layers and in gyri and sulci because extensive amyloid clearance may be necessary to achieve downstream neuropathologic benefit after removal of amyloid.

BACKGROUND: Voxel-based specific regional analysis system for Alzheimer's disease () software using MRI scanner allows quantification of hippocampal and parahippocampal atrophy in the medial temporal structures by Z-score, and this score is widely used in clinical Alzheimer's disease () diagnosis. However, it is unclear whether the Z-score is useful to discriminate normal aging from cognitive impairment () or mild cognitive impairment (). The present study examined the associations between VSRAD Z-score and cognitive performance quantified by Memory Performance Index () and determined a Z-score cut-off value. METHOD: Three-tesla brain MRI was conducted in 100 outpatients without dementia, and all MRI data were analyzed using VSRAD. The target region of interest () mainly consisted of the para hippocampal gyrus. The degree of atrophy in the ROI was obtained from the averaged positive Z-score of the ROI. Cognitive performance was evaluated with the Japanese version of the MCI screen (). Patients were classified into normal () and below normal () cognitive groups by MPI. The relation between MPI and VSRAD Z-score were assessed with logistic regression analysis, and the cut-off value for Z-score was determined by receiver operating characteristic curve analysis. RESULTS: Sixty-two percent (62%) were identified as the BNL group by MPI. Univariate analyses found that the BNL group had a significantly higher age, shorter years of education, and higher Z-score in VSRAD compared to the NL group, but no statistically significant difference was observed between genders. Bivariate correlation found that MPI, which is adjusted for age, gender, and years of education, was significantly correlated with Z-score assessed by VSRAD (Pearson's  = -0.52,  < .001). A subsequent logistic regression of VSRAD Z-score on BNL classification was used to generate a receiver operating characteristic curve (AUC = 0.75). The Youden index was applied to identify a cut-off value of VSRAD Z-score of 1.14 (sensitivity = 62.9%; specificity = 84.2%) to classify MPI < 50.2 (BNL) with overall accuracy of 73.5%. CONCLUSIONS: VSRAD Z-score using VSRAD software was one independent factor significantly associated with cognitive performance measured by MPI. The determination of a cut-off value for Z-score (1.14) that can help discriminate normal patients from those with MCI.

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in exon one of the gene that encodes for the protein huntingtin (HTT). PolyQ expansion drives HTT aggregation into multimeric species that range from soluble oligomers to fibrillar, insoluble inclusion bodies. Cellular mechanisms facilitating HTT aggregation are incompletely understood, hindering efforts to develop strategies that prevent inclusion body formation or promote clearance of misfolded protein. To enable future unbiased screening approaches to identify genetic modifiers and pharmacological strategies to suppress HTT aggregation, we have developed HTT, a split-luciferase-based detector of HTT-HTT interaction in adult neurons. This system permits real-time monitoring of HTT multimerization in living, active flies. The non-lethal nature of the HTT system enables subsequent analysis of HTT aggregation, neurotoxicity, and other phenotypes in the same flies, thus serving as a platform for medium-throughput screening followed by mechanistic validation of potential modifier candidates.

BACKGROUND: Polypharmacy is common in people with dementia but may be insufficiently tailored to personal preferences and goals, particularly in the presence of a life-limiting condition. OBJECTIVES: To evaluate the effectiveness of pharmacists working with general practitioners (GPs) to optimise medicine regimens and health outcomes of people with dementia by applying the Medication Appropriateness Tool for Comorbid Health Conditions During Dementia (MATCH-D) as part of a structured Team Approach to Polypharmacy Evaluation and Reduction (AusTAPER). DESIGN: Randomised controlled trial. METHODS: This study was conducted in Perth, Western Australia, with 12month follow‑up. The intervention was a collaborative medicine review that included a medicines history, interview by a research pharmacist, and a case conference with the participant's GP. Outcomes included medicines regimen, emergency department presentation, hospitalisations, and health outcomes at 12 months. RESULTS: Overall, 19 GPs and 31 participants were recruited (five directly; 26 through GP practices). The pharmacist spent an additional mean of 5.5 hours with intervention participants. At baseline, the median number of regular medicines was 8.5 (IQR 3) in the control group and 10 (IQR 7) in the intervention group, and at 12 months, 11 (IQR 4) and 9.5 (IQR 5), respectively. Emergency department presentations were observed for 9/16 (56%) control and 10/15 (66%) intervention participants, with a median of 1 (IQR 1.5) versus 1 (IQR 4) presentations ( = 1.18,  = 0.25). Eight participants in each group had at least one day of unplanned hospital admission with a similar length of stay (0.5 (IQR 5) versus 1 (IQR 9) days;  = 0.44,  = 0.67). Quality of life, physical function, cognition, frailty, and falls were similar between groups. CONCLUSION: Over 12 months, participants in both groups had similar medicine use, outcomes and quality of life. It was feasible to recruit people with dementia, and their doctors, to a medicine review intervention. TRIAL REGISTRATION: This study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ANZCTR; ACTRN12619000453189) on 19 March 2019.

Focused ultrasound (FUS) combined with intravenous microbubbles (MB) enables precise and reversible modulation of the blood-brain barrier (BBB) to enhance the delivery of therapeutics from the blood to targeted brain areas. Beyond this application, we discovered over a decade ago that FUS-BBB modulation, without the addition of exogenous therapeutics, activates endogenous regenerative events, "most notably" hippocampal neurogenesis. Here, we investigate the effects of FUS on oligodendrogenesis, a key process for myelination and white matter integrity. In adult mice, we targeted FUS-BBB modulation unilaterally to the hippocampus. The proliferation of oligodendrocyte precursor cells (OPCs) was quantified at 1, 4, 7, and 10 days post-treatment and myelinating oligodendrocytes were assessed at 30 days. At 1 and 4 days post-sonication, the proliferation of hippocampal OPCs increased by 6.8-fold and 2.3-fold, respectively; this resulted in a 5.3-fold increase in myelinating oligodendrocytes one month later. Next, we tested the robustness of FUS-induced oligodendrogenesis using an independent experimental design and targeting the striatum in a separate cohort of mice. The proliferation of striatal OPCs increased by 3.9-fold at 7 days post-FUS. This led to a 5.2-fold increase in oligodendrogenesis 30 days post-treatment, as observed in the hippocampus. Finally, we found that treatments at the same FUS parameters but without MB and without altering the BBB, did not lead to the proliferation of OPCs or oligodendrogenesis. Therefore, with these FUS parameters, MB-induced BBB modulation emerged as a key factor that promoted oligodendrogenesis. Given the long-validated application of FUS-BBB modulation for drug delivery, the additional stimulation of oligodendrogenesis broadens the therapeutic potential of this modality for white matter repair.

BACKGROUND: [F]flortaucipir tau-PET detects neurofibrillary tangle (NFT) pathology in Alzheimer's disease (AD), one of the core pathological hallmarks of the disease. In clinical settings, tau-PET is usually interpreted qualitatively, and therefore quantitative estimates of how scan results alter the probability that AD explains a patient's symptoms are lacking. Here, we evaluate the probability of clinicopathological AD given a positive or negative tau-PET scan and examine how patient age and amyloid-PET status modulate this probability. METHODS: We computed positive and negative predictive values (PPV/NPV) of tau-PET for clinicopathological AD, defined as mild cognitive impairment or dementia with AD as the primary etiology. To account for potential pathological and clinicopathological mismatches, PPV and NPV were modeled using literature-derived sensitivity and specificity estimates of [F]flortaucipir PET for postmortem Braak V/VI NFT pathology, together with literature-derived age-dependent tau-PET positivity rates in cognitively unimpaired individuals. We also considered hypothetical clinician-estimated pre-PET AD probabilities. PPV and NPV were calculated for tau-PET and for sequential amyloid- and tau-PET scenarios. RESULTS: Tau-PET PPV for clinicopathological AD was generally high, particularly in individuals with higher clinician-estimated pre-PET AD probabilities, and showed minor age-related declines (e.g., 84% at ages 50-55 vs. 75% at ages 85-90, at 50% pre-PET probability). Tau-PET NPV was consistently higher than PPV and showed negligible age-related decline (e.g., 92% at ages 50-55 vs. 90% at ages 85-90, at 50% pre-PET probability). A positive tau-PET following positive amyloid-PET substantially increased PPV, particularly in older individuals (e.g., PPV increased from 56% to 83% at ages 75-80 and 30% pre-PET probability), whereas the corresponding gain in NPV after tau-PET following amyloid-PET was smaller. CONCLUSIONS: Tau-PET demonstrates high PPV and NPV for clinicopathological AD. A positive tau-PET following positive amyloid-PET further increases the probability of clinicopathological AD, particularly in older adults. This underscores tau-PET's clinical utility and highlights the effect of age and pre-PET certainty on post-PET AD probabilities.

Growing evidence indicates that traumatic brain injury constitutes a significant risk factor for the development of age-related tauopathies, yet the consequences of repeated mild spinal cord injuries (rmSCI) remain insufficiently explored. In this context, we developed a mouse model undergoing two successive mild cervical contusions during young adulthood, which do not produce immediate functional motor deficits, thereby mimicking real-life conditions of occupational- or sports-related trauma. rmSCI were induced in PS19 (hTau) mice developing late-onset tauopathy in the brain and in the spinal cord. The consequences of rmSCI were assessed on motor outcomes and tauopathy signature in injured PS19 mice during ageing. rmSCI exacerbated age-dependent motor deficits and significantly increased tau hyperphosphorylation on the pSer422 and pSer202/Thr205 epitopes. Pathological changes, initially confined to the epicenter of the contusions, extended along a caudo-rostral axis reaching the thalamus. While rmSCI did not modify intraspinal tau aggregation, spinal cord-derived protein extracts displayed enhanced seeding activity in vitro. Although causality was not established with tau hyperphosphorylation status, early response towards mild spinal contusions included p38 MAPK activation, glial activation and upregulation of interferon-stimulated genes. Together, these data identify rmSCI as a previously underappreciated modifier of tau pathology and disease progression. Moreover, this study provides a novel experimental link between mild central nervous system injuries and exacerbation of tauopathy and suggests the involvement of type I interferon signalling or sustained glial activation. Ultimately, these findings underscore the importance of preventing even mild spinal injuries in individuals at risk of tauopathy.

BACKGROUND: Blood-based biomarkers are increasingly recognized as promising tools for the diagnosis and monitoring of neurodegenerative diseases, offering a minimally invasive alternative to cerebrospinal fluid (CSF) testing. We evaluated the analytical performance and clinical utility of the Olink Target 48 Neurodegeneration panel, a novel multiplex proteomic platform based on the proximity extension assay (PEA) technology, in a large, clinically diverse dementia cohort. METHODS: We retrospectively analyzed plasma samples from 238 patients with Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration, along with 65 healthy controls, quantifying 41 proteins in each sample. We assessed analytical performance using intra- and inter-assay coefficients of variation, evaluated diagnostic accuracy through receiver operating characteristic curve analysis, and investigated associations between biomarker levels, clinical severity measures, and pathology-specific CSF biomarkers for AD and Lewy body pathology (LBP) using general linear models. RESULTS: The platform quantified 32 proteins with variable analytical performance; nine were excluded due to poor detectability. Strong correlations were observed between PEA-based measurements and established immunoassays for plasma pTau217, NEFL, and GFAP (all p < 0.001). Plasma pTau217 demonstrated superior diagnostic accuracy for AD, achieving an area under the curve (AUC) exceeding 0.91 against all comparison groups. Novel ratios combining NEFL with markers of immune function or synaptic integrity (NEFL/ITGB2, NEFL/ITGAM, NEFL/SCG2) achieved AUCs exceeding 0.93 for discriminating patients from controls, significantly outperforming NEFL alone (all p < 0.001). Thirteen proteins, spanning markers of neuroaxonal damage, myelin-associated processes, and immune function (i.e., Abeta40, Abeta42, BMP7, CLSTN3, ENO2, KLK8, MMP10, NEFL, NPTXR, OMG, RTN4R, SCG2, SDC4, all p < 0.01) showed significant independent associations with disease stage as measured by the Clinical Dementia Rating scale. Four proteins (i.e., pTau217, GFAP, SYT1, and SDC4) were significantly associated with AD pathology, while three (ENO2, ITGAM, and ITGB2) showed significant associations with LBP (all p < 0.05). CONCLUSIONS: This multiplex platform provides multiplex biomarker measurements with potential utility for AD diagnosis and disease staging across neurodegenerative disorders. These findings support further validation studies for its implementation in clinical and research settings.

BACKGROUND: We conceptualize the Real-World Reassessment Threshold (RWRT) as representing the smallest change that exceeds expected measurement variability while accounting for clinically expected cognitive decline over the assessment interval, whereas the minimum clinically important difference (MCID) indicates the smallest change likely to be clinically meaningful. To date, no study has empirically defined the RWRT or MCID for Mini-Mental State Examination (MMSE) scores in Lewy body dementia (LBD) or frontotemporal dementia (FTD), limiting the interpretation of longitudinal changes and clinical trial designs. We therefore aimed to estimate 12-month, diagnosis-specific MMSE thresholds for RWRT and MCID among individuals with LBD and FTD, and to evaluate the generalizability of these thresholds in an independent validation cohort. METHODS: This registry-based cohort study included individuals diagnosed with LBD or FTD from the Swedish Registry for Cognitive/Dementia Disorders (SveDem, 2007-2022) with a 91-400-day MMSE follow-up, and an independent validation cohort from the U.S. National Alzheimer's Coordinating Center (NACC). The RWRT was estimated using distribution-based methods based on intraclass correlation coefficients (ICCs). MCID was estimated using both anchor-based and distribution-based (0.5 standard deviation) approaches. RESULTS: We included 1,158 individuals from SveDem (873 LBD, 285 FTD) and 1,060 individuals from NACC (469 LBD, 591 FTD). Over the 91-400-day follow-up interval, MMSE scores demonstrated moderate to high reliability (ICC 0.70-0.90), corresponding to RWRT estimates ranged from 5 to 7 MMSE points. Anchor-based MCIDs differed by diagnosis, with a mean threshold of 0.7 points in LBD and 3.8 points in FTD in SveDem; similar diagnosis- and baseline severity-dependent patterns were observed in NACC. In contrast, distribution-based MCIDs were consistent across diagnoses, clustering around 2-3 MMSE points. CONCLUSIONS: MMSE changes of less than five points over one year may reflect expected test variability combined with expected individual decline. However, average changes of 2-3 points may still be meaningful when combined with a clinical anchor of change, depending on diagnosis and disease stage. These results emphasize the importance of using both RWRT and MCID when evaluating MMSE change and selecting clinical trial endpoints.

BACKGROUND: Mitochondrial dysfunction and neuroinflammation are critically implicated in the pathogenesis of Alzheimer's disease (AD). However, a systematic exploration of key mitochondrion-related genes (MRGs) in AD, and their specific roles in reshaping the immune microenvironment and serving as diagnostic biomarkers, remains insufficient. METHODS: To address this, we conducted an integrative bioinformatics analysis. Differentially expressed MRGs were identified from public AD transcriptomic datasets. Their biological functions were elucidated through enrichment analyses. The correlations between core MRGs and ssGSEA-derived immune-cell signature enrichment scores were quantified using transcriptome-based computational analysis. Finally, machine learning models were constructed and validated to assess the diagnostic potential of identified MRG signatures. RESULTS: A robust set of dysregulated MRGs was identified in AD brains, showing predominant enrichment in pathways of oxidative phosphorylation and energy metabolism. Notably, the expression of key MRGs correlated significantly with altered infiltration abundances of specific immune cell types, including neutrophil-, eosinophil-, NK CD56bright cell-, and T follicular helper cell-related signatures. A diagnostic model constructed from a refined MRG signature exhibited promising predictive accuracy, with area under the curve (AUC) values reaching approximately 0.82 in the training cohort and around 0.74 in independent validation cohorts. CONCLUSION: Our study defines a novel landscape of MRGs in AD, deciphers their tight crosstalk with the immune microenvironment, and establishes a promising MRG-based signature for AD diagnosis. These findings provide fresh insights into the potential molecular interplay between mitochondrial dysfunction and neuroinflammation in AD and nominate candidate mitochondrion-related biomarkers and regulatory mechanisms that warrant further experimental and clinical validation.

Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n = 21) and healthy controls (n = 16), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P = 0.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.

The golden ratio ([Formula: see text]) exhibits unique autosimilarity properties that appear throughout biological systems, including human physiology and neural organization. The Tree Drawing Test (TDT), a simple cognitive assessment tool that mainly implies visuospatial, praxic and executive functions, may capture φ-based organizational principles that become disrupted in neurodegenerative conditions. This study examined the relationship between golden ratio proportions and cognitive impairment in tree drawings through quantitative analysis of a large cohort of cognitively impaired patients. We evaluated 613 Alzheimer's disease (AD) patients, 328 mild cognitive impairment (MCI) patients, and 438 healthy controls who completed the TDT. Five novel golden ratio-based deviation indices were developed to quantify proportional relationships between trunk and crown dimensions; among these, the trunk-based index [Formula: see text]showed the most consistent group separation (Distance-to-Diameter Ratio [Formula: see text]; Fisher Ratio [Formula: see text]), with all three pairwise diagnostic comparisons reaching [Formula: see text] (Mann-Whitney U, Bonferroni-corrected) in the full sample and across sex and education strata. Within a multinomial logistic regression framework with stratified 5-fold cross-validation, [Formula: see text]retained independent discriminative value after adjustment for age, education, and the established Space Occupation (SO) index, reaching a macro-averaged AUC of 0.834 (AD vs. rest: 0.855, 95% CI [Formula: see text]; CNTRL vs. rest: 0.911, 95% CI [Formula: see text]; MCI vs. rest: 0.736); the Likelihood Ratio Test confirmed that [Formula: see text]contributes information not captured by SO, age, and education combined ([Formula: see text], [Formula: see text]), and convergent results under two independent matched-subgroup strategies indicated that age and education differences do not explain this signal. Pre-specified operational cut-offs derived from the cohort yielded clinically interpretable sensitivity/specificity trade-offs, with AUC [Formula: see text] [0.894, 0.927] for healthy-control identification using the full multivariate model. As a secondary descriptive observation, group means of [Formula: see text]approximated the Fibonacci values F(5), F(7), F(9); a permutation-based null model (B [Formula: see text], [Formula: see text]) and a Fibonacci-vs-Lucas specificity comparison (100% vs. 0% confidence-interval containment) indicated that this alignment is unlikely to arise by chance and is specific to φ-convergent sequences, although the algebraic link between [Formula: see text]and φ implies that this finding should be regarded as a starting point for future studies rather than as proof of a biological mechanism. Within these limitations, golden-ratio-based TDT measures provide a quantitative complement, not a replacement, to traditional TDT indices for cognitive impairment assessment and require confirmation in independent multi-centre samples before clinical adoption.

Early identification of Alzheimer's disease and related dementias (ADRD) remains limited by specialized tests and late-stage diagnosis. The Zero-burden Risk Assessment (ZeBRA) is an AI-driven score that predicts incident ADRD up to a decade before diagnosis using only routine electronic health record (EHR) data, without laboratory tests, imaging, or questionnaires. Trained on 487,989 cases and 12,483,718 controls from nationwide U.S. insurance claims and validated on held-out National samples and two independent cohorts, ZeBRA achieved AUC = 0.93 and 0.83 in the 50+ cohort for 1-year and 10-year horizons, respectively, with positive likelihood ratios exceeding 10 in the National 50+ held-out cohort at 95% specificity and stable discrimination over time. Performance was consistent across age, sex, race, and ethnicity subgroups. In a prospective feasibility pilot, higher ZeBRA scores showed concordance with lower Montreal Cognitive Assessment (MoCA) scores, indicating greater cognitive impairment (R = -0.78, 95% CI: -0.94 to -0.37). Compared with prior EHR-based models, ZeBRA provides superior accuracy, cross-site generalizability, and noise-corrected interpretability via our novel Λ-OR attribution metric. Scalability and low burden suggest application in population-level early detection and presymptomatic trial enrichment.

This prospective study evaluated the prognostic utility of Alzheimer's disease-related plasma biomarkers (phosphorylated tau [pTau217 and pTau231], the amyloid-β [Aβ] 42/40 ratio) and neurofilament light chain (NfL) in 123 Parkinson's disease (PD) patients and 40 controls. Over a mean 5.1-year follow-up, 35 of 109 initially non-demented PD patients (32.1%) progressed to dementia. Plasma pTau217 and NfL levels were elevated, whereas the Aβ42/40 ratio was reduced, in cognitively impaired PD groups versus controls. Baseline pTau217 accurately differentiated dementia converters from non-converters (AUC = 0.877; 95% CI: 0.798-0.956). Patients with pTau217 ≥ 0.268 pg/mL had a higher risk of dementia progression (HR: 5.49; 95% CI: 2.37-12.74). This risk was further elevated in patients in the highest quartile ( ≥ 0.36 pg/mL; HR: 11.35; 95% CI: 2.60-49.59) versus the lowest quartile ( < 0.20 pg/mL). Similarly, the pTau231 cut-off ( ≥ 2.575 pg/mL) predicted an increased risk of dementia (HR: 3.89; 95% CI: 1.67-9.03). Both pTau217 and pTau231 demonstrated high predictive performance in Cox models (C-index: 0.806 and 0.796, respectively). Plasma NfL exhibited longitudinal increases during follow-up. Baseline plasma pTau217 and pTau231 serve as surrogate markers for predicting dementia progression in PD. Further validation of these biomarker cut-off values is warranted.

The calcineurin (CaN)/nuclear factor of activated T cells (NFAT) signalling axis is a Ca²⁺-responsive pathway that translates intracellular Ca²⁺ signals into long-term transcriptional programmes. Chronic disruption of intracellular Ca²⁺ homoeostasis is a convergent feature of neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). In these conditions, sustained or repetitive Ca²⁺ elevations promote prolonged activation of the CaN/NFAT pathway, thereby linking Ca²⁺ dysregulation to persistent cellular responses. In this review, we summarise the molecular organisation and regulation of the Ca²⁺/CaN/NFAT pathway and discuss its physiological roles in neurons and glial cells, including synaptic plasticity, neurodevelopment, neurogenesis, and neuroinflammatory responses. We critically examine experimental evidence linking CaN/NFAT signalling to AD and PD, distinguishing direct mechanistic roles from associative and model-dependent findings. Across disease contexts, the CaN/NFAT axis appears to function as a molecular node at which diverse insults, including amyloid-β and tau aggregates, α-synuclein toxicity, mitochondrial dysfunction, and chronic inflammatory cues, converge under conditions of sustained Ca²⁺ dysregulation. We propose that the pathological relevance of CaN/NFAT lies less in pathway activation per se than in its capacity to convert chronic Ca²⁺-dependent stress signals into persistent transcriptional states affecting synaptic integrity, inflammatory tone, and cellular resilience. We conclude by discussing current therapeutic strategies targeting this pathway, their limitations, and the need for temporally and cell-type-specific modulation.

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by brain atrophy and cognitive decline. While the amyloid cascade hypothesis remains the dominant framework, accumulating evidence indicates that mitochondrial dysfunction critically contributes to AD progression. Although improving mitochondrial function has been shown to rescue cognitive deficits in AD models, the underlying molecular mechanisms remain elusive. In this study, we identified a significant reduction in calpain small subunit 1 (CAPNS1) expression in both AD patient samples and male transgenic mouse models. Decreased CAPNS1 levels were strongly correlated with mitochondrial ultrastructural damage, reduced mitochondrial DNA (mtDNA) copy number, and progressive synaptic loss. Mechanistically, we found that CAPNS1 positively regulated mtDNA transcription and mitochondrial gene expression, and pharmacological data suggested the involvement of the Ca⁺-CaMKIIβ-MAPK-PGC-1α signaling axis, a master pathway governing mitochondrial biogenesis and respiratory capacity. This activation subsequently restored cellular ATP production and reduced mitochondrial reactive oxygen species accumulation. Importantly, neuronal-specific CAPNS1 upregulation in APP/PS1 transgenic mice markedly improved mitochondrial cristae integrity, reversed hippocampal long-term potentiation deficits, increased dendritic spine density, and partially alleviated spatial memory deficits in behavioral tests. We noted that loss-of-function experiments (e.g., CAPNS1 knockdown or knockout) were not performed in this study, and the proposed Ca⁺-CaMKIIβ-MAPK-PGC-1α axis should therefore be interpreted as a suggestive working model requiring further validation. Collectively, our findings indicate that CAPNS1 serves as a key regulator of mitochondrial function. By linking Ca⁺ signaling to mitochondrial gene expression and synaptic integrity, CAPNS1 represents a promising therapeutic target for ameliorating synaptic loss and cognitive decline in AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing global health challenge. Despite decades of research dominated by the amyloid cascade hypothesis, single-target therapies aimed at Aβ or tau have largely failed, underscoring the need for a broader framework. Emerging evidence implicates neuroimmune dysfunction as a central driver of AD pathology, with the "peripheral-central immune axis" emerging as a critical node. The APOE4 allele, the strongest genetic risk factor for sporadic AD, plays a pivotal role in both central nervous system (CNS) lipid metabolism and peripheral immune homeostasis. This review synthesizes the association between APOE4 and peripheral immune dysregulation and its impact on neurodegeneration. We discuss APOE expression in CNS and peripheral immune cells, highlighting APOE4-associated alterations in monocyte/macrophage polarization, T cell subsets via IL-7/IL-7R downregulation, and gut microbiota composition. We delineate mechanisms by which APOE4 is associated with blood-brain barrier compromise, may promote conditions for immune cell trafficking, and contributes to neuroinflammation. Integrating preclinical and clinical evidence, we propose an "APOE4-associated peripheral-central immune infiltration cascade" as a unifying framework for understanding systemic AD pathogenesis. Finally, we review emerging therapeutic strategies targeting peripheral immunity and APOE, discussing multi-target approaches guided by APOE genotype and immune biomarkers, shifting from a CNS-centric toward a systemic immunomodulatory paradigm for precision medicine.

BACKGROUND: Malnutrition is common in patients with dementia and contributes to adverse clinical outcomes. Pancreatic exocrine dysfunction may theoretically contribute to nutritional impairment through defective digestion and absorption. This study investigated the association between fecal elastase-1 (FE-1), a marker of pancreatic exocrine function, and nutritional status in older adults with dementia. METHODS: In this case-control study, 55 patients with dementia and 55 cognitively healthy controls were evaluated. Nutritional status was assessed using the Mini Nutritional Assessment (MNA), cognitive performance using the Mini-Mental State Examination (MMSE), and pancreatic exocrine function using fecal elastase-1 (FE-1) measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Dementia was associated with significantly poorer nutritional status and lower MMSE scores compared with cognitively healthy controls (both p<0.001). However, FE-1 levels and FE-1 category distributions did not differ significantly between groups (p=0.361 and p=0.151, respectively). Correlation analyses demonstrated generally weak and non-significant associations between FE-1 levels, MMSE scores, and MNA parameters. In multivariable logistic regression analysis, dementia diagnosis was associated with an approximately threefold higher odds of malnutrition (OR=3.249, 95% CI: 1.358-7.773, p=0.008), whereas FE-1 levels were not associated with malnutrition status (p=0.888). CONCLUSIONS: Dementia was associated with an increased risk of malnutrition; however, FE-1 levels were not associated with nutritional status, cognitive performance, or malnutrition risk. These findings do not support a clear relationship between FE-1 levels and malnutrition in dementia, although a contribution of pancreatic exocrine function in specific clinical contexts cannot be excluded. Given the exploratory nature of the study, larger prospective studies are needed to confirm these findings.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by elevated concentrations of amyloid β1-42 (Aβ1-42) in the brain, where it exerts neurotoxic effects. A recent study demonstrated that medium flow at approximately 10 μm/s reduces Aβ1-42 neurotoxicity in explant brain cultures containing neurons and beating ependymal cilia; however, the underlying mechanisms remain unclear. Neurons migrating from the explant and located within 300 μm of the beating cilia were exposed to cilia-generated medium flow, allowing analysis of Aβ1-42 toxicity under fluid flow conditions. Aβ1-42-containing putative EV-related extracellular particles (putative EV-related Eps), with diameters of 100-400nm were detected in the culture medium and exhibited neurotoxic effects. Pharmacological inhibition of EV release and endocytosis reduced intracellular accumulation of Aβ1-42 and attenuated neuronal toxicity. Under medium flow, fewer putative EV-related EPs bound to neurons, and their binding duration was significantly shortened. Rhodamine-conjugated concanavalin A staining revealed enhanced cell-surface glycan labeling in damaged neurons on the non-ciliated side compared with neurons on the ciliated side. These results suggest that shear stress reduces neuronal accumulation of Aβ1-42-containing putative EV-related EPs, likely through modulation of cell-surface glycosylation composition.

The understanding of neurodegenerative diseases is evolving toward a systemic view, highlighting the connection between liver dysfunction and brain impairment, where metabolism and inflammation play central roles. Licochalcone A (LCA), has demonstrated antidiabetic and anti-inflammatory effects. This study aimed to evaluate its neuroprotective effects under metabolic syndrome conditions. For this purpose, male C57BL/6J mice were fed either with control (CT) or high-fat diet (HFD) from weaning. At eight months, animals received intraperitoneal LCA (15 mg/kg/day) or saline three times per week for four weeks. The resulting groups were CT Saline, HFD Saline, and HFD LCA. Cognitive and metabolic alterations were assessed through behavioral tests and glucose/insulin tolerance assays. Peripheral and/or central markers of metabolism, amyloid burden, inflammation, and synapsis were analyzed using histological staining, immunohistochemistry, Golgi staining, Western blot, ELISA, and RT-PCR. The results demonstrated that LCA administration improved metabolic outcomes by reducing body and liver weight, enhancing glucose tolerance, and improving liver histology. These effects were associated with modulation of insulin signaling pathways, including PTP1B inhibition and AKT activation in the liver and the hippocampus. LCA also reduced HFD-induced Aβ accumulation, which was accompanied by increased LRP1 expression, and attenuated the expression of inflammatory related markers, such as TLR4 and glial activation. Moreover, these improvements were associated with increased levels of synaptic proteins (BDNF, PSD95, DBN1), and synaptic plasticity markers (P-CREB and P-LIMK1), along with preservation of dendritic spine density and improved memory performance. In conclusion, these findings support LCA as a promising candidate for treating HFD-induced neurodegenerative conditions, acting through modulation of metabolic and inflammatory pathways across the liver-brain axis.

A major challenge in RNA therapeutics for central nervous system disorders is the lack of delivery systems capable of crossing the blood-brain barrier (BBB) while achieving cell-type-specific targeting. Herein, we develop an engineered exosomal siRNA delivery platform for systemic, neuron-targeted RNA transport to the brain. The platform leverages exosomes derived from an immortalized mouse hippocampal neuronal cell line as a biomimetic and functionally privileged material source, enhancing neuronal uptake and intracellular delivery efficiency. Through surface functionalization with a rabies virus glycoprotein-derived peptide, the system enables receptor-mediated BBB transcytosis and programmable siRNA loading. In human cortical organoids, the platform achieves efficient cytosolic delivery and robust gene silencing in neurons, demonstrating high delivery precision and bioavailability. As a proof of concept, targeting receptor-interacting protein kinase 3 (RIPK3) modulates necroptosis, a key pathway in inflammatory neurodegeneration. In transgenic mouse models, systemic administration suppresses RIPK3/MLKL signaling, reduces neuronal loss, and alleviates neuroinflammation and tau-associated pathology. Transcriptomic analyses further indicate stabilization of neuronal homeostasis across vulnerable brain regions. Collectively, the study establishes a modular and programmable exosomal RNA delivery platform and highlights age-defined, cell-derived biomaterials as a generalizable strategy for overcoming delivery barriers in neurological diseases.

Psychiatric disorders frequently co-occur with insulin resistance (IR)-related conditions, including obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS). While genetic correlations have been reported, the genetics underlying this multimorbidity remains underexplored. Here, we investigate the joint genetic architecture of psychiatric-IR multimorbidity and explore links with the brain, tissue-specific gene expression, potential underlying biological mechanisms, and repurposable drugs. Genomic structural equation modeling (SEM) was applied to genome-wide association studies (GWAS) from five psychiatric disorders (attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), schizophrenia) and three IR-related conditions (MetS, obesity, T2DM) (N = 9725-933,970) previously showing pairwise genetic correlations. Factor analyses identified a latent genetic factor (Psych-IR factor) capturing shared genetics across psychiatric disorders (excluding schizophrenia) and IR-related conditions. Positive loadings were observed for ADHD, MDD, and IR-related conditions and negative loadings for AN and OCD. This factor showed genetic correlations with temporal, occipital, and total brain surface areas. A multivariate GWAS of the Psych-IR factor identified 150 associated loci and 366 genes (128 novel). Gene-set associations included insulin binding and Notch-signaling pathways, while gene-property analyses implicated the cerebellum, brain cortex, and pituitary gland, notably during prenatal development. Transcriptome-wide SEM (T-SEM) assessed tissue-specific gene expression associations and identified 499 genes (191 novel), including immune-related genes within the major histocompatibility complex (MHC) region. Drug repurposing analysis suggested six therapeutic candidates, including memantine and rosiglitazone. Enrichment of prioritized genes highlighted the chr16p11.2 region, BDNF-signaling, and lipid metabolism pathways. These findings advance understanding of the genetic and biological mechanisms underpinning psychiatric-IR multimorbidity, informing future research on precision medicine initiatives.

Alzheimer's disease (AD) is most likely to be caused by the accumulation of Aβ and dysfunction of the cholinergic pathology. Oxidative damage, alterations of brain glucose metabolism, and cognitive impairment are all demonstrated in the STZ models. In order to overcome such effects, a new set of phenolic-carbamate conjugates (5a-5h) was synthesized, and their structures were elucidated using FTIR, UV, and NMR spectroscopy. The in silico studies confirmed excellent binding capabilities against AChE and Aβ targets. In vitro antioxidant assays depicted a significant free radical scavenging ability, with compound 5c exhibiting the enhanced effect. Cell line study with SH-SY5Y and PC12 cells showed greater % cell viability. AChE activity demonstrated compound 5c has significant effectiveness (IC = 1.98 uM). Neurobehavioral activity showed an improvement in learning and memory during behavioural assessments. In vivo antioxidant study showed greater scavenging activity (SOD, CAT, GSH), reduced of oxidative stress (MDA, NO), and the improvement in total antioxidant activity. Overall, the compound 5c has demonstrated significant results comprising decreased cholinesterase and Aβ inhibition deciphering enhanced cholinergic restoration. Hippocampal integrity was preserved, as it was confirmed by histopathological examination. It concludes that bromo-vanillyl carbamate derivative 5c (30 mg/kg) has potent antioxidant, anti-amyloid, and neuroprotective characteristics, rendering it a promising multitarget lead that warrants further investigation for the treatment of AD.

BACKGROUND: Although blood-based biomarkers are now available for diagnosing Alzheimer's disease (AD), the best biomarker for AD-specific neurodegeneration and cognitive decline remains unclear. This study aimed to determine the relative importance of four plasma biomarkers-phosphorylated tau (p-tau) 217, p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)-in AD-specific neurodegeneration and cognition. METHODS: We analyzed cross-sectional data from two independent, ethnically distinct cohorts spanning the clinical spectrum from cognitively unimpaired to dementia: 150 participants from the SAMD cohort (100% Asian) and 284 participants from the ADNI cohort (94.0% White). Plasma biomarker levels were quantified using Single-Molecule Array (Simoa) assays. We employed dominance analysis to determine the hierarchical contributions of these biomarkers to AD signature regions of interest (ROI) thickness (entorhinal, inferior temporal, middle temporal, and fusiform regions), total cognition, and memory, stratified by amyloid-PET status. Three sensitivity analyses were further conducted to validate the findings across these cohorts, mitigating potential biases arising from differences in demographic characteristics and clinical severity. All analyses were adjusted for age, sex, education, and APOE ε4 status. RESULTS: The dominance hierarchy differed markedly according to the amyloid status. Plasma GFAP and p-tau217 emerged as the dominant predictors for AD signature ROI thickness and cognitive impairment in amyloid-positive participants. Specifically, GFAP demonstrated superior dominance in explaining cortical atrophy within the SAMD cohort, whereas p-tau217 was the dominant predictor in the ADNI cohort. P-tau217 generally outperformed the others in explaining total cognition and memory in the amyloid (+) group. In contrast, among amyloid (-) participants, plasma NfL showed greater explanatory power than GFAP for both neurodegeneration and cognitive decline across both cohorts. CONCLUSION: The efficacy of plasma biomarkers in reflecting AD-related neurodegeneration varies significantly depending on the presence of amyloid pathology. While GFAP and p-tau217 are robust indicators of AD-associated changes linked to plaque pathology, NfL better reflects non-specific neurodegeneration involving axonal damage. Consequently, a stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.