Atherosclerotic lesions within carotid and cerebral vessels are likely to influence hemodynamics and manifest into vascular pathologies, including Alzheimer's Disease and ischemic stroke. Hemodynamics are influenced by changes in luminal diameter of vessels and wall shear stress derived from vortex formation which directly relates to the surface topography of the lumen. In this study, we performed a quantitative assessment of surface metrology of carotid and cerebral arteries in relation to calcification, vessel size and location among individuals. We speculate intracranial vessels will follow suit of extracranial vessels, with increased surface roughness in larger-diameter vessels. Samples of the internal carotid, common carotid, and multiple branches of the Circle of Willis were collected at 18 different sites from 10 human whole body donors. For each vessel, arterial calcification was quantified from image analyses of Alizarin red stained histological sections. The arterial surface metrology of the adjacent parts of the same segments was opened and gently cleaned, and then analyzed using a Sensofar S Neox 3D optical profiler, from which scale-sensitive fractal analyses (SSFA) were analyzed using SensoMap software. ANOVAs testing for the influence of calcification percentage, vessel identity, vessel size, individual differences, age, sex, and the role of cardiovascular disease in the donor's cause of death found no significant differences in SSFA variables for vessel identity, individuals, age, sex, and cause of death. The most significant differences are correlated with vessel calcification percentage, though surface roughness appears also greater in the larger vessels. These findings support ideas that calcification plays a role in alterations of vortex formation and wall shear stresses in intracranial vessels as they do in coronaries. With further research in this field, the pathophysiology of intracranial atherosclerosis and the role of atherosclerosis in neurodegenerative disorders might be understood at another, more granular level.

Given the multifactorial pathogenesis of Alzheimer's disease (AD) and the limited efficacy of single-target drug therapy, there is a growing scientific need for combination regimens to concurrently target various AD-associated cascades. Currently, plant-derived phytoconstituents, with their intrinsic multi-target properties, represent a promising component for combination therapy, offering translational potential with enhanced neuroprotection. In this avenue, the current study aimed to explore the combined neuroprotective effects of geraniol (a monoterpenoid alcohol) and Z-guggulsterone (a phytosterol) in streptozotocin (STZ)-induced AD model of adult zebrafish (4-6 months old). Following intracerebroventricular STZ injection, zebrafish were treated with geraniol and Z-guggulsterone per se and in combination for 28 consecutive days. On day 27, a novel tank diving test and a light/dark preference test were performed to evaluate locomotive and cognitive impairments. Afterwards, the fish were evaluated for numerous blood parameters, including blood glucose and serum cholesterol levels, followed by biochemical assessment of oxidative stress markers, mitochondrial complexes, neuroinflammatory cytokines, and neurotransmitter levels. Results demonstrated that co-therapy of geraniol and Z-guggulsterone significantly ameliorated cognitive deficits, reduced anxiety-like behaviours, impeded acetylcholinesterase activity, regulated neurotransmitter levels (glutamate and acetylcholine), mitigated oxidative stress markers, and prevented mitochondrial dysfunction, compared to monotherapies. Additionally, downregulation of TNF-α was also observed, affirming suppression of detrimental neuroinflammatory processes. Collectively, these findings support the neuroprotective potential of geraniol and Z-guggulsterone co-therapy in the zebrafish model of AD; however, future research is warranted to explore the potential clinical application of this combination therapy in AD.

The brain is vulnerable to DNA damage and cardiometabolic risk. Yet, whether genetic variation in DNA repair interacts with cardiometabolic factors to explain cognitive variability remains unclear. Participants (n = 376,533) of white-British ancestry from the UK biobank with cognitive, neuroimaging, and whole-exome sequencing data were included. Six cognitive outcomes were assessed: fluid intelligence (FIQ), symbol-digit matching task (SDMT), visual matching (MATCH), trail making (TRAIL1 and TRAIL2), and prospective memory (PMEM). Seven brain regions of interest were assessed: total brain (TBV), grey matter (GMV), left and right white matter (LWM/RWM), left and right hippocampi (LHC/RHC), and white matter hyperintensities (WMH) volumes. A total of 3487 genetic variants across 39 DNA repair genes were tested. SNP and gene/gene-set level associations were tested using regression models adjusted for age, sex, APOE ε4, ancestry, and outcome-specific covariates. Genetic interactions with a multidimensional cardiometabolic risk index (CMRI), encompassing established risk factors, were assessed. We detected 107 genetic variants (mostly extremely rare) across 36 DNA repair genes associated at Bonferroni-significance (p ≤ 1.4 × 10) with neurocognitive and brain outcomes. Most associations were observed for WMH (43 variants across 27 genes) and SDMT (26 variants across 17 genes). Most associations (60.8% of variants) were identified only in interaction models with CMRI. Associations across 35 of the 36 previously identified genes were also observed (p < 0.05) for dementia. Interactions between rare genetic variants involved in DNA repair mechanisms and cardiometabolic risk may explain some of the observed cognitive variability.

Deficits in spatial and navigation abilities are among the earliest signs of dementia. Yet, traditional neuropsychological tests primarily target memory and attention. The Spatial Performance Assessment for Cognitive Evaluation (SPACE) is a novel gamified digital assessment for iPads that uses various spatial tasks to detect early deficits in spatial navigation abilities indicative of cognitive impairment. In this study, 348 participants aged 21-76 completed the Montreal Cognitive Assessment (MoCA), SPACE, and a sociodemographic and health questionnaire. We investigated whether SPACE could predict scores on the MoCA beyond known risk factors for cognitive impairment. Using a factor analysis, we then assessed whether SPACE could complement the MoCA by capturing latent variables independent of MoCA scores that represent additional spatial aspects of cognitive functioning. Results from a hierarchical regression revealed that the pointing and perspective-taking tasks in SPACE significantly predicted MoCA scores beyond age and gender. Surprisingly, none of the risk factors predicted MoCA scores. The factor analysis revealed that the MoCA and perspective-taking contributed to a separate factor from the other navigation tasks in SPACE. We also provide normative data on age and gender for each task in SPACE, which can serve as benchmarks for future studies to identify individuals at risk.

There is much interest in the role of sweeteners such as table sugar (sucrose) and high-fructose corn syrup in obesity and metabolic disease. Both sweeteners consist of glucose and fructose, two six-carbon isomeric sugars. Whereas glucose ingestion may promote obesity through its effects to stimulate insulin secretion, fructose has unique metabolic effects that promote triglyceride synthesis and fat accumulation. These effects arise from fructose's well-known role as a signal of metabolic plenty. Under modern conditions of overnutrition, chronic excess fructose drives features of metabolic syndrome. Emerging evidence further links fructose to cancer and dementia. Here we review the biochemical, molecular and physiological distinctions between fructose and glucose, as well as the endogenous fructose pathway that makes fructose from glucose. Through this Review, we highlight the role of fructose not only as a caloric source, but also as a regulator of metabolic health and disease.

Alzheimer's disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores from a disease progression model. Voxel-wise analyses revealed widespread loss of deactivation and activation with disease progression. Trajectories for the loss of deactivation were nonlinear, associated with amyloid- and tau-positivity and visually preceded trajectories of cognitive decline. The relationship between deactivation and cognitive decline was partly independent of neurodegeneration. Our results provide evidence that synaptic dysfunction and neurodegeneration are independent drivers of cognitive decline, providing a rationale for targeting synaptic dysfunction along the AD cascade.

INTRODUCTION: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are progressive neurodegenerative conditions with limited therapeutic options. Neuromodulation techniques such as transcranial direct current stimulation (tDCS) and photobiomodulation (PBM) have shown promise in improving cognitive function, but their combined effects remain underexplored. METHODS: In a pilot randomized, double-blind, placebo-controlled trial, 33 participants were assigned to either active or sham stimulation groups. The intervention consisted of 50 sessions over 10 weeks, with tDCS (2 mA, F3-F4 montage) and intranasal near-infrared stimulation (iNIRS) (850 nm, 40 Hz, 50% duty cycle) administered simultaneously. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and ADAS-Cog at baseline, post-treatment, and at the 12-week follow-up. RESULTS: Significant improvements were observed in the active group across both scales. MMSE scores increased from 21.89 ± 2.35 to 27.22 ± 1.96 (p = 0.0001), with sustained effects at follow-up. ADAS-Cog scores decreased from 34.78 ± 4.99 to 18.22 ± 4.4 (p < 0.0001). Post hoc analyses revealed significant changes in attention, recall, praxis, and executive domains. No serious adverse events were reported. CONCLUSION: Combined tDCS and iNIRS therapy significantly enhances cognitive performance in patients with MCI and mild AD. This synergistic, non-invasive approach may offer a promising therapeutic strategy to delay cognitive decline and reduce care-related burdens. TRIAL REGISTRATION: ClinicalTrials.gov NCT07290686; Registration date 14 December 2023.

Prion diseases are transmissible, fatal, neurodegenerative disorders driven by the conformational misfolding of the cellular prion protein (PrP) into an infectious, aggregation-prone conformer (PrP). While the accumulation of PrP represents the central pathogenic event, targeting it directly and specifically has proven difficult due to its structural heterogeneity and similarity to PrP. Consequently, previous immunization efforts have largely focused on PrP, though with limited success. Here, we employed a model-based approach to design a vaccine that specifically mimics immunogenic features hypothesized to be present on the surface of PrP. By mimicking predicted surface residues and using an innocuous, cross-beta fibril scaffold derived from the fungal protein HET-s (218-289), we were able to generate unique, conformation-dependent epitopes not found on PrP. We evaluated our vaccine by immunizing a genetic prion disease mouse model of Gerstmann-Sträussler-Scheinker disease, a genetic prion disorder. Vaccination was able to significantly delay the onset of disease in immunized mice (412 ± 88 days) compared to unimmunized (177 ± 17 days) and scaffold-immunized (161 ± 27 days) animals, and supplementation with adjuvants including Freund's adjuvant (448 ± 39 days), QS-21 (479 ± 58 days), and Alum (506 ± 52 days) was able to further enhance the vaccine efficacy. To investigate the mechanism of neuroprotection, we derived a monoclonal antibody from a vaccinated mouse and mapped its discontinuous, conformation-specific epitope, comprising an aspartate-histidine pair that may be occluded in PrP, and confirmed the antibody's ability to differentiate between infectious and uninfected prion samples. Our study demonstrates the feasibility of a model-based approach for prion vaccine design and targeting of the infectious prion protein, providing groundwork for future development of not only potential prion therapeutic interventions, but also targeting related neurodegenerative disorders characterized by protein misfolding.

UNLABELLED: This target-trial emulation study sought to assess the association between romosozumab and incident dementia. We analyzed longitudinal claims data from 69,543 Japanese individuals with osteoporosis (using teriparatide as an active comparator), finding that romosozumab initiation among individuals with osteoporosis may correlate with a lower dementia risk than teriparatide initiation. PURPOSE: The neurocognitive benefits of osteoporosis treatments remain underexplored despite growing interest in the bone-brain connection. We aimed to analyze the association between romosozumab and incident dementia, using teriparatide as the active comparator. METHODS: We emulated a target trial using longitudinal commercial claims data from Japan. We identified individuals aged ≥ 50 years with osteoporosis who newly initiated either romosozumab or teriparatide between 2019 and 2023. The primary outcome was incident dementia, and the secondary outcome was Alzheimer's disease. We estimated the absolute risk reduction (ARR) and relative risk (RR) using a weighted Kaplan-Meier estimator, conducting both intention-to-treat and per-protocol analyses. RESULTS: A total of 69,543 individuals were included in the study (90% female; mean age, 81 years). In the 2-year intention-to-treat analyses, the ARR was 0.7% (95% confidence interval, - 0.1 to 1.3%), with a RR of 0.91 (95% confidence interval, 0.84 to 1.01). For Alzheimer's disease specifically, the ARR was 0.6% (95% confidence interval, 0.0 to 1.1%), with an RR of 0.88 (95% confidence interval, 0.79 to 1.00). In the 1-year per-protocol analyses, the ARR was 1.0% (95% confidence interval, 0.7 to 1.4%), with a RR of 0.76 (95% confidence interval, 0.69 to 0.82). For Alzheimer's disease specifically, the ARR was 0.6% (95% confidence interval, 0.3 to 0.9%), with an RR of 0.77 (95% confidence interval, 0.65 to 0.86). CONCLUSIONS: In this target trial emulation study, romosozumab initiation among individuals with osteoporosis may be associated with a lower risk of dementia, particularly Alzheimer's disease, than teriparatide initiation.

BACKGROUND: Dementia presents complex challenges for causal inference due to its multifactorial aetiology and slow, heterogeneous progression. Randomized controlled trials are often limited in their potential to fully address these challenges because of ethical and practical constraints. As the field evolves, observational studies incorporating advanced causal inference methods are increasingly used to estimate real-world effects in dementia research. However, the implementation of these methods varies widely and has not been systematically evaluated, with an emerging trend towards integration with techniques such as machine learning. This systematic review will critically examine how causal inference techniques are applied in dementia research, assess their methodological rigor, and identify trends, assumptions, and gaps that may inform future applications and methodological innovation in the field. METHODS: Following PRISMA guidelines, searches will be conducted in MEDLINE, EMBASE, Web of Science, PsycINFO, Scopus, and the Cochrane Library for studies published between 1960 and 2024. Eligible studies will include observational designs that use causal inference methods to investigate outcomes such as cognitive decline, disease progression, and quality of life. Data extraction will capture study characteristics, methodological details, and key findings, with risk of bias assessed using ROBINS-I. A narrative synthesis will summarize qualitative results, and meta-analyses will be performed when methodological homogeneity permits. DISCUSSION: This review will address a critical gap in the evaluation of the application of causal inference methods in real-world dementia research. By identifying methodological challenges, underlying assumptions, and emerging analytical techniques, it aims to strengthen research rigor and reproducibility and inform future methodological development, with potential implications for policy and practice in dementia care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42024619228).

Non-transferrin-bound iron (NTBI) transport constitutes a critical pathway for cellular iron uptake in the kingdom Animalia that remains mechanistically unresolved. Its physiological importance is underscored by atransferrinemia, a rare disorder in which individuals lacking plasma transferrin nonetheless retain the capacity to distribute dietary iron to essential organs, implying the presence of compensatory iron transport routes. Melanotransferrin (MFI2; also designated p97 or CD228) is an evolutionarily conserved iron-binding protein that exists in both a secreted form and a glycosylphosphatidylinositol (GPI)-anchored membrane-bound form, suggesting a fundamental role in iron homeostasis. In mammals, the secreted isoform mediates iron transport across the blood-brain barrier, whereas GPI-anchored MFI2 is expressed by microglia in proximity to β-amyloid plaques in Alzheimer's disease, implicating it in neuroinflammatory processes. Moreover, it is also recognized as a tumor-associated antigen in melanoma, indicating a potential role in tumor progression. In the present study, we delineate a previously uncharacterized NTBI internalization pathway mediated by GPI-MFI2. Using human melanoma cells, we demonstrate that GPI-MFI2, together with its bound iron, undergoes caveolae-dependent internalization followed by trafficking through a Rab5-mediated endosomal pathway. The internalized iron is subsequently trafficked to ferritin, underscoring its functional importance in maintaining intracellular iron stores. These findings establish the first molecularly defined pathway for transferrin-independent iron uptake in mammalian cells, providing a framework to interrogate MFI2's role in iron mobilization and dysregulation in neurodegeneration and cancer.

The relationship between peripheral and central biomarkers in mild cognitive impairment (MCI), and the potential role of blood-brain barrier (BBB) dysfunction in this process, remain unclear. MCI, an intermediate state between normal aging and dementia, is characterized by early neuroinflammation and neuronal injury, yet how systemic markers reflect central pathology is poorly understood. In this study, we enrolled 74 participants, including 37 MCI patients and 37 cognitively normal controls. Based on the CSF/serum albumin ratio, subjects were classified into four groups-NC (cognitively normal with intact BBB), NMCI (MCI with intact BBB), BC (cognitively normal with BBB disruption), and BMCI (MCI with BBB disruption)-and further grouped as BBB-intact or BBB-disrupted. Serum and cerebrospinal fluid (CSF) levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light (Nf-L) were measured using enzyme-linked immunosorbent assay. Spearman correlation analysis was applied to examine peripheral-central associations. No significant correlations were observed in NC or NMCI groups. A moderate serum-CSF GFAP correlation was found in the BC group (r = 0.446, P = 0.033), which became markedly stronger in the BMCI group (r = 0.753, P < 0.001). In the BBB-disrupted group, significant correlations were detected for GFAP (r = 0.652, P < 0.001), IL-4 (r = 0.412, P = 0.003), IL-6 (r = 0.296, P = 0.035), and TNF-α (r = 0.352, P = 0.011), with GFAP showing the strongest association. In contrast, within the BBB-intact group, only serum-CSF IL-6 correlation reached significance (r = 0.469, P = 0.024). These findings suggest that BBB disruption markedly enhances peripheral-central biomarker associations, especially for GFAP, highlighting the regulatory role of BBB integrity in linking systemic inflammation, neuronal injury, and MCI pathophysiology.

Collectively, neurodegenerative diseases impose an escalating global health burden, representing one of the leading causes of death and disability worldwide. Despite their growing prevalence, diagnosis and treatment remain major challenges, partly due to the absence of specific and reliable biomarkers for early detection, disease monitoring, and prognosis. Epigenetic biomarkers are emerging as promising clinical tools, although their potential in the context of neurodegenerative diseases is not yet fully realised. In this review, we provide an overview of advances in the understanding of DNA modifications and chromatin architecture in neurodegeneration, highlighting translational relevance for biomarker discovery and therapeutic development. Finally, building on insights from other diseases where epigenetic biomarkers are already applied, we discuss the key steps required to enable implementation in neurodegenerative diseases.

Amyloid beta-40 (Aβ40) aggregation constitutes a central pathological mechanism in Alzheimer's disease and cerebral amyloid angiopathy, yet the structural evolution from early-stage assemblies to mature fibrils remains incompletely characterized. Here, we employ atomic force microscopy coupled with infrared spectroscopy (AFM-IR) to resolve morphological and structural heterogeneity of Aβ40 at the single-fibril level across aggregation stages. Early-stage fibrils exhibit two distinct morphological polymorphs characterized by predominantly disordered structures with coexisting antiparallel β-sheet motifs. Upon maturation, fibrils converge toward a single dominant polymorph and transition to parallel β-sheet conformations, yielding morphologically homogeneous yet structurally heterogeneous populations. Critically, seeding experiments with isotopically labeled Aβ40 demonstrate that the disordered polymorphs do not propagate efficiently, explaining their longstanding absence in structural studies of both in vitro and brain-derived aggregates. These findings establish the transient nature of early-stage antiparallel intermediates and provide mechanistic insights into fibril maturation pathways with implications for understanding amyloid polymorphism and therapeutic targeting strategies.

A woman in her 50s with genetically confirmed Huntington's disease presented with right-sided arm sensory symptoms that evolved over days and persisted for at least 1 month. Neurological examination revealed mild right arm hypoesthesia and mild generalised choreiform movements. Brain MRI demonstrated multiple supratentorial and infratentorial lesions suggestive of demyelination, along with a short-segment, contrast-enhancing cervical spinal cord lesion. Cerebrospinal fluid analysis revealed type 2 IgG-restricted and type 4 IgM-restricted oligoclonal bands. Comprehensive testing for infectious, paraneoplastic, metabolic and other autoimmune aetiologies yielded negative results. A diagnosis of relapsing-remitting multiple sclerosis was established, based on the 2024 McDonald criteria and after exclusion of alternative diagnoses. Dimethyl fumarate was initiated, with neither adverse effects nor new clinical relapses or MRI lesions. This case highlights the need to remain alert to subjective neurological symptoms in patients with Huntington's disease, ensuring that new manifestations are not automatically attributed to a single disease process.

Schizophrenia (SCZ) and frontotemporal dementia (FTD) are characterized by widespread neuroanatomical, neurophysiological and cognitive abnormalities and a progressive course leading to disability. Despite being two distinct clinical entities, SCZ and FTD present overlapping clinical features and neurobiological underpinnings, as highlighted by growing evidence. Both disorders are characterized by cognitive impairment, behavioral alterations, and substantial phenotypic heterogeneity. Parallel pathophysiological alterations include dopaminergic and glutamatergic dysfunction, particularly involving NMDA receptors, excitatory/inhibitory imbalance in the prefrontal cortex, and neuroimmune alterations. Additionally, dysregulation of the kynurenine pathway, driven by chronic inflammation, further contributes to cognitive decline in both conditions. Although SCZ is not conventionally classified as neurodegenerative, subtle neurodegenerative mechanisms may contribute to cognitive decline, complicating differential diagnosis with FTD. This narrative review explores biological systems and molecular pathways affected across both conditions, highlighting the potential for identifying transdiagnostic biomarkers and therapeutic targets. Recognizing the partial overlap in pathophysiology and symptomatology between SCZ and FTD may enhance diagnostic accuracy in atypical or early-stage presentations and support the development of mechanism-based transdiagnostic interventions targeting cognitive and behavioral domains. An integrated perspective on psychiatric and neurodegenerative disorders may inform both clinical practice and translational research.

Preclinical studies indicate that selective targeting of DR may improve behavioral and cognitive outcomes in animal models relevant to cognitive disorders, like ADHD and Alzheimer's disease, and substance use disorders (SUDs). In this study, we extend upon prior development of analogs of A-412997, a DR-selective partial agonist, by exploring ligand interactions within the secondary binding pocket. We modified the alkyl chain on the phenylacetamide's benzyl ring by extending and cyclizing the alkyl chain. A series of compounds were synthesized and tested using competition radioligand binding assays on DR, DR, and DR, using [H]N-methylspiperone as the competing radioligand. Herein, we report that while increasing the chain length beyond two carbons reduced DR affinity and selectivity, cyclizing the alkyl chain enhanced DR affinity and maintained selectivity over DR and DR by 120-fold or more. Molecular modeling results suggest that the cyclized rings engage in more favorable interactions within the DR binding pocket.

Senile plaques consist of Amyloid-β (Aβ) are the pathological hallmark of Alzheimer's disease (AD), which is the most common type of neurodegenerative disorder. Aβ is a small peptide that consists of 38 to 43 amino acids. It causes harmful effects through abnormal aggregation, like the formation of oligomers and protofibrils. These aggregates can disrupt normal synaptic function and trigger a series of neuroinflammatory and neurodegenerative changes. The aggregation dynamics of Aβ are modulated by multiple factors, such as conformational transitions, the exposure of hydrophobic segments, liquid-liquid phase separation, and post-translational modifications. These factors can promote the formation of diverse aggregates with distinct conformations. This review summarizes the structural characteristics of various Aβ aggregates, along with related regulatory elements, their effects on cellular processes, and therapeutic strategies targeting Aβ and its aggregates. This overview contributes to a better understanding of the complex mechanisms underlying Aβ aggregation and its pathological consequences, as well as the basis for future therapies targeted to Aβ and aggregates.