Synaptic dysfunction in Alzheimer's disease (AD) may drive synapse loss and cognitive impairment. Whether AD-related synaptic pathophysiology occurs globally, or in specific synapses, is unclear. We investigate in vivo AD-related synaptic dysfunction during early-stage amyloidosis in AppNL-G-F mice. We find reduced presynaptic GABAergic proteins at c-Fos-positive excitatory neurons and increased calcium-mediated activity at excitatory and inhibitory neuronal assemblies. In vivo synaptic structure/function imaging finds reduced density and calcium-mediated activity of GABAergic axonal boutons. Rather than occurring globally, reduced synaptic activity is focused at GABAergic boutons strongly coupled to population activity in the amyloid microenvironment. The selective weakening of population-coupled synaptic activity also occurs in excitatory dendritic spines. Spatial transcriptomics finds parvalbumin-positive inhibitory neurons show differential gene expression associated with downregulated GABAergic synaptic transmission at early stages. We propose that early-stage AD-related synaptic pathophysiology is focused at population-coupled synapses, with molecular measures implicating abnormal synaptic processing as an early-stage feature in parvalbumin-positive interneurons.

Tau aggregation plays a critical role in the development and progression of Alzheimer's disease (AD). Tau aggregates of different sizes and shapes are formed, which ultimately lead to the deposition of fibrillar tangles. We used single-molecule techniques to characterize tau aggregates in the middle temporal gyrus and somatosensory cortex in post-mortem brain homogenates at different Braak stages from patients with AD. Total and phosphorylated tau aggregates increased dramatically in late Braak stages. The aggregates showed greater multi-site phosphorylation with increased Braak stage, but there was only a moderate change in the aggregate size distribution. Paired single nuclei transcriptomic analyses provided evidence for greater pro-inflammatory microglial and complement pathway activation with increasing phosphorylated tau aggregate concentration and length. Based on this correlation, we hypothesize a cascade of disease progression in which microglial inflammation induces tau aggregation in neighboring neurons that, in turn, further enhances inflammation and the spread of tau pathology to increase the concentration of small tau aggregates.

Cerebral hypoperfusion and blood-brain barrier (BBB) leakiness are pathological features of Alzheimer's disease (AD). To understand their relationship to the distribution and progression of Alzheimer's disease neuropathologic change (ADNC), we analysed associations between biochemical markers and mediators of cerebral hypoperfusion and BBB leakiness, and amyloid-β (Aβ) and hyperphosphorylated tau, in multiple brain regions at different Braak tangle stages (BS). We studied the frontal, temporal, parietal, entorhinal, calcarine and cingulate cortex, putamen and trigonal white matter from eight controls with low pathology (BS0-II), 17 brains with early-stage/intermediate AD pathology (BSIII-IV) and 11 late-stage AD cases (BSV-VI), from the South West Dementia Brain Bank and the London Neurodegenerative Diseases Brain Bank. We excluded cases with widespread moderate-severe arteriolosclerosis, macroscopic infarcts or foci of haemorrhage, Lewy body pathology or other neurodegenerative pathology. ELISAs were used to measure the myelin-associated glycoprotein:proteolipid protein-1 ratio (MAG:PLP1), an index of ante-mortem cerebral perfusion, and fibrinogen levels, to assess BBB leakiness. Also by ELISA, we measured vascular endothelial growth factor-A (VEGF-A), upregulated in cerebral ischaemia; endothelin-1 (EDN1), a mediator of vasoconstriction; CD31, an endothelial marker; platelet-derived growth factor-β (PDGFRβ), a pericyte marker; and Aβ1-40, Aβ1-42 and ptau-231 concentrations. In the temporal cortex from a subset of cases, 55 angiogenesis-related proteins were assayed using a multiplex profiler assay. MAG:PLP1 was lower in BSIII-IV than BS0-II in all brain regions. VEGF-A, EDN1 and CD31 concentrations were highest in BSIII-IV in most regions and correlated inversely with MAG:PLP1. EDN1 level correlated strongly with Aβ1-42 concentration in low-pathology controls. Angiogenesis-related protein assays showed elevated levels of endoglin (CD105), a marker of neoangiogenesis, in BSIII-IV, coinciding with altered expression of several angiogenic mediators. The PDGFRβ:CD31 ratio, a marker of pericyte content adjusted for vessel density, was lower in BSIII-IV than BS0-II and correlated positively with MAG:PLP1 and inversely with Aβ1-42. BBB leakiness, evidenced by elevated fibrinogen in brain tissue homogenates, was highest in BSV-VI in most brain regions and correlated with VEGF-A, CD31 and ptau-231 concentrations. The present data provide evidence of widespread cerebral hypoperfusion associated with pathogenic angiogenesis and vascular remodelling in AD. The study highlights a complex and dynamic temporal relationship, beginning in early-stage AD, between mediators of cerebrovascular dysfunction and the regional spread of Aβ and tau pathology. The study also identifies several therapeutic targets, including EDN1 and VEGF-A signalling, with the potential to limit cerebrovascular damage in early AD.

Neuroinflammation contributes to the progression of many neurological diseases. Here, we explore whether ultrasound can reduce microglia-mediated inflammation in vitro and in vivo. We tested a broad range of ultrasound parameters in a BV2 microglial cell line, treated with lipopolysaccharide (LPS) to induce an inflammatory response. We found that specific combinations of centre frequency, acoustic pressure and treatment duration can significantly lower the levels of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. These effects lasted up to 72 h and were associated with the downregulation of the nuclear factor κB (NF-κB), suggesting a mechanistic link between ultrasound and inflammation. Further investigation in vivo, in LPS-treated mice, revealed a reduction in TNF-α expression in the hippocampus following ultrasound. Overall, our findings showcase the potential of ultrasound as a non-invasive therapeutic strategy to reduce neuroinflammation and restore brain homeostasis.

TREM2 plays multiple functional roles in microglia and variants are associated with increased risks of Alzheimer’s disease (AD). Genetic polymorphisms reducing expression of the functionally related protein CD33 are protective. Here we have contrasted cellular pathology in human post-mortem brain with and without AD to test mechanisms associated with the differential genetic risks conferred by R47H and R62H TREM2 variants (TREM2var) with and without heterozygosity for the protective rs3865444 CD33 polymorphism. Epistasis between CD33 and TREM2 was demonstrated by relative normalisation of differences in β-amyloid load in TREM2var carriers of the protective CD33 allele. These functional differences were mirrored by differential microglial transcriptomic responses to β-amyloid. Controlling for CD33 genotype, microglial transcriptional responses to increasing β-amyloid were lower for TREM2var, particularly for R47H compared to CV, and there was a reduction in expression of neuroplasticity pathways in TREM2var. R62H microglial signatures were distinguished from those of R47H by upregulation of genes associated with phagocytosis and from CV by differences in inflammatory gene expression including those involved in NF-kappaB signalling. Differential gene expression with increasing β-amyloid also suggested upregulation of β-amyloid production and binding pathways in excitatory neurons in TREM2var heterozygotes. There was lower enrichment for pathways positively adaptive to pathology and expressed in inhibitory neurons from CV samples for both TREM2var. Exploratory bulk tissue proteomics support these observations with evidence for adaptive plasticity in response to β-amyloid pathology in CV tissue not found for the TREM2var, which showed evidence of increased β-amyloid formation and neuroplasticity changes. Together, these results highlight differences in molecular pathology between CV and TREM2var and between the TREM2var risk variants. They highlight mechanisms of AD risk mediated by secondary effects on astroglial and neuronal functions. Demonstration of strong epistasis between TREM2 and CD33 with AD supports the therapeutic potential of modulators of CD33 inhibition or expression.

Abstract Variants in ABCA7 are among the most consistently replicated genetic risk factors for late-onset Alzheimer’s disease (AD), yet the cellular mechanisms remain poorly defined. Here, we characterise the impact of the common ABCA7 rs3752231 risk variant on amyloid-β (Aβ) pathology and glial responses in human post-mortem brain, combining quantitative neuropathology of 4G8-immunostained mid-temporal gyrus from 99 donors (Braak 0-VI) with glial-enriched single-nucleus RNA sequencing from 54 of them. ABCA7 rs3752231 carriers exhibited an increased Aβ burden and larger plaques with late AD explained by a selective expansion of diffuse plaques and relative reduction in compact plaques, consistent with impaired microglial-mediated plaque maturation. Transcriptional responses to increasing Aβ burden were largely genotype-specific: non-carriers showed canonical disease-associated microglial activation, including upregulation of complement, phagocytic, and inflammatory pathways, alongside astrocyte responses consistent with preserved synaptic support, while carriers exhibited a distinguishable activation state. Exploratory ligand-receptor analysis identified carrier-specific intercellular signals suggesting non-cell autonomous suppression of microglial phagocytosis. Together, these findings position ABCA7 rs3752231 as a regulator of glial responses to AD pathology, linking a common coding variant to impaired microglial plaque containment and maladaptive astrocyte responses and nominate microglial TREM2 activation and CD33 inhibition and astrocytic EAAT2 induction as candidate therapeutic strategies.

We investigated ketamine's neuroplastic effects in healthy human subjects using integrated Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) measures before and 1-8 days after a single psychedelic dose of ketamine (1 mg/kg, intravenous). Eleven male participants underwent two PET/MRI scans with [11C]-UCBJ (synaptic density/plasticity), 1H-MRS (glutamate and GABA) and resting-state fMRI (intrinsic brain activity, functional connectivity), before and after ketamine. While group-level analyses showed no significant increases in PET synaptic markers, ketamine administration resulted in significantly elevated glutamate levels within the anterior cingulate cortex (ACC). Functional connectivity analyses revealed reduced coupling between the ACC and the dorsolateral prefrontal cortex (dlPFC) and increased coupling between the ACC and the amygdala in the days following ketamine administration. Our multimodal analysis revealed that participants showing an increase in [11C]-UCBJ volume distribution (VT), a putative index of synaptic plasticity, showed a correlated reduction in intrinsic activity within regions belonging to the default mode network (DMN). By linking molecular, cellular and network-level changes, our results point to the DMN as a central hub where ketamine may reshape brain hierarchies in the long term, providing new directions for understanding its therapeutic mechanisms and developing targeted treatments.

INTRODUCTION:The prognostic value of emerging dementia-related blood-based biomarkers for post-stroke cognitive impairment is poorly understood. We addressed this critical gap in this systematic review. METHODS:Four databases were searched in March 2025 for studies of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid beta (Aβ), tau, and placental growth factor (PlGF) in relation to post-stroke cognitive outcomes. Risk of bias, narrative synthesis, and meta-analysis were performed. RESULTS:Eighteen studies were included, eleven assessing NfL. Meta-analysis of four studies (n = 2020) showed higher acute NfL was associated with worse cognition at 1-6 months (Z = -0.518, 95% confidence interval [CI] -0.684 to -0.351). Baseline GFAP was associated with worse cognition longitudinally, whereas results for amyloid and tau species were inconsistent between studies. Risk of bias was high. DISCUSSION:NfL and GFAP show the most consistent associations with post-stroke cognition, particularly acutely. Evidence for amyloid and tau was inconsistent between studies, and PlGF remains unexplored.

Autopsy-derived brain tissue analysis is crucial for understanding neurobiology, but post-mortem handling can introduce artifacts. We studied adult human brain transcriptomic signatures from tissue immediately extracted from brains (< 0 hours) and compared to autopsy brain tissue with short (~6 hours) and long (~36 hours) post-mortem intervals (PMIs). Significant deviations in gene signatures were observed in both short and long PMIs compared to immediately extracted tissue, which we defined as Brain Artifact Genes (BAGs). By subjecting brain samples to processing variables that are unavoidable in autopsy programs (post-mortem time and temperature), we characterized a set of artifact-responsive genes and mapped this signature onto matched single-nucleus RNA-seq data, revealing that it was predominantly glutamatergic neurons that exhibited the earliest induction of artifact genes followed by oligodendrocytes later. Using deep learning, we distilled this broader processing-response program into a predictive signature, called Time and Temperature Response genes Underlying Transcriptional Heterogeneity (TTRUTH) and provide an Open Science tool for assigning TTRUTH scores to brain RNA-seq data. Together, this work will help better standardize datasets, enable additional sample stratification, and enhance data interpretation.

Spatio-temporal (3D+t) generative modelling of cardiac shape and motion is crucial for understanding heart structure and function at population scale. Existing generative models for cardiac shape synthesis either adopt volumetric shape representations that lack anatomical correspondence across different time points and subjects, or rely on VAE-based frameworks that suffer from a trade-off between reconstruction fidelity and generative diversity. In this work, we propose Cardiac Mesh Flow, a novel generative flow model for 3D+t cardiac four-chamber mesh generation with anatomical correspondence, temporal coherence, and periodic consistency. Leveraging the flow matching technique, Cardiac Mesh Flow performs efficient one-step generation of multi-scale free-form deformation fields, which warp a template mesh to generate cardiac four-chamber meshes across a cardiac cycle. Furthermore, Cardiac Mesh Flow enables controllable generation conditioned on cardiac chamber volumes, allowing precise control of the synthetic heart. Experimental results demonstrate that Cardiac Mesh Flow achieves high fidelity and diversity on both unconditional and conditional generation, compared to state-of-the-art 3D+t cardiac mesh generation methods.

The human heart is a sophisticated system composed of four cardiac chambers with distinct shapes, which function in a coordinated manner. Existing shape models of the heart mainly focus on the ventricular chambers and they are derived from relatively small datasets. Here, we present a spatio-temporal (3D+t) statistical shape model of all four cardiac chambers, learnt from a large population of nearly 100,000 participants from the UK Biobank. A deep learning-based pipeline is developed to reconstruct 3D+t four-chamber meshes from the cardiac magnetic resonance images of the UK Biobank imaging population. Based on the reconstructed meshes, a 3D+t statistical shape model is learnt to characterise the shape variations and motion patterns of the four cardiac chambers. We reveal the associations of the four-chamber shape model with demographics, anthropometrics, cardiovascular risk factors, and cardiac diseases. Compared to conventional image-derived phenotypes, we validate that the four-chamber shape-derived phenotypes significantly enhance the performance in downstream tasks, including cardiovascular disease classification and heart age prediction. Furthermore, we demonstrate the effectiveness of shape-derived phenotypes in novel applications such as heart shape retrieval and heart re-identification from longitudinal data. To facilitate future research, we will release the learning-based mesh reconstruction pipeline, the four-chamber cardiac shape model, and return all derived four-chamber meshes to the UK Biobank.

Identifying robust associations between cardiac imaging phenotypes and clinical diseases is fundamental to population-scale cardiovascular research and reliable risk stratification. However, current phenome-wide association studies rely on pre-defined, single-variable phenotypes or expert-crafted features, which limits their ability to capture clinically meaningful non-linear effects and cross-phenotype interactions. To address this, we propose CPAgents, an iterative phenotype-Composition framework for cardiovascular Phenome-wide association study (PheWAS) that automatically constructs and validates interpretable composite phenotypes (e.g., polynomial, ratio, and interaction forms) from base imaging features. Specifically, our system coordinates three agents: (i) an Analyst that identifies statistical pathologies and nominates candidate transformations; (ii) a Proposer that generates constrained, medically and statistically motivated expressions under numerical safety rules; and (iii) a Verifier that evaluates candidates using multi-stage criteria and produces transparent evidence trails for accepted phenotypes. Evaluated on a population-scale cardiac imaging cohort, the discovered composite phenotypes markedly improve disease discrimination: across 72 classifier-disease-metric combinations, our variants achieve the top rank in 56 cases versus 18 for baselines, with gains observed across all nine clinical disease categories. Our framework yields compact, clinically interpretable phenotype formulas with transparent evidence trails, enabling scalable discovery of stronger phenotype-disease associations beyond expert-driven feature selection.

Abstract Entorhinal cortex (EC) excitatory neurons are lost early in Alzheimer’s disease (AD), yet the specific subtype and characteristics contributing to this vulnerability are poorly understood. Combining imaging mass cytometry (206,913 cells; 62 donors) and single nucleus RNA sequencing (42,780 nuclei; 36 donors) of post-mortem EC, we found that calbindin-expressing layer 2-3 excitatory neurons accumulate high phospho-tau burden and are preferentially lost in AD. In non-diseased brains, these neurons exhibit elevated tau-modifying kinase expression (ERK1/2, FYN, ROCK), reduced phosphatase expression (PP2A/B, PP5) and low mitochondrial respiratory capacity which together are predicted to promote high vulnerability to tau pathology. Trajectory analysis resolved progression from homeostasis through DNA damage and proteostatic stress to developmental re-entry and death priming. In silico screening suggested histone deacetylase inhibitors and cyclooxygenase inhibitors as candidate resilience-promoting therapeutics. Our work thus reframes intrinsic features of neuronal identity promoting phospho-tau formation as modifiable determinants of the selective vulnerability of EC calbindin neurons.

UK Biobank is the world's most comprehensive longitudinal population-based data and biosample resource. Twenty years after UK Biobank was first established, the incidence of dementia among participants is rising and is set to increase rapidly over the next 5-10 years, creating a distinct opportunity for studies of dementia risk and onset. In addition to extensive clinical phenotyping of >500,000 volunteers from across the UK at recruitment and at follow-up time points, UK Biobank includes data from serial lifestyle questionnaires, cognitive testing, multimodal imaging, accelerometry, genomics and other omics that are linked to individual health, cancer and death records. In this Perspective, we discuss how the use of UK Biobank data has enabled the discovery of new interactions between systemic and brain health and illustrate how these data can be used to characterize and identify risk factors, support mechanistic hypotheses and identify new biomarkers that predict the onset and course of dementia and related disorders. We also consider future developments of UK Biobank, including the UK Biobank Brain Health Study, which will build on and leverage the increasing incidence of dementias to advance understanding of these conditions.

Previous studies have suggested that systemic viral infections may increase risks of dementia. Whether this holds true for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections is unknown. Determining this is important for anticipating the potential future incidence of dementia. To begin to do this, we measured plasma biomarkers linked to Alzheimer’s disease pathology in the UK Biobank before and after serology-confirmed SARS-CoV-2 infections. SARS-CoV-2 infection was associated with biomarkers associated with β-amyloid pathology: reduced plasma Aβ42:Aβ40 ratio and, in more vulnerable participants, lower plasma Aβ42 and higher plasma pTau-181. The plasma biomarker changes were greater in participants who had been hospitalized with COVID-19 or had reported hypertension previously. We showed that the changes in biomarkers were linked to brain structural imaging patterns associated with Alzheimer’s disease, lower cognitive test scores and poorer overall health evaluations. Our data from this post hoc case–control matched study thus provide observational biomarker evidence that SARS-CoV-2 infection can be associated with greater brain β-amyloid pathology in older adults. While these results do not establish causality, they suggest that SARS-CoV-2 (and possibly other systemic inflammatory diseases) may increase the risk of future Alzheimer’s disease. Blood biomarkers in a middle-aged population suggest that SARS-CoV-2 infection is associated with greater brain β-amyloid plaque accumulation.

BACKGROUND:Cardiovascular magnetic resonance (CMR) and electrocardiographic (ECG) abnormalities after coronavirus disease 2019 (COVID-19) are widely reported. However, the absence of pre-infection assessments limits causal inference from these studies. This study aims to compare interval change in CMR and ECG measures in participants with incident COVID-19 and matched uninfected controls in UK Biobank. METHODS:UK Biobank participants with documented COVID-19 who had CMR and ECG performed before the pandemic were invited for repeat assessment, along with uninfected participants matched on age, sex, ethnicity, location, and date of baseline imaging. Automated pipelines were used to extract ECG phenotypes and CMR measures of cardiac structure and function, aortic distensibility, aortic flow, and myocardial native T1. Logistic regression was used to examine associations of baseline metrics with incident COVID-19. Standardized residual approach was used to compare the degree of interval change in CMR and ECG metrics between cases and controls. RESULTS:We analyzed 2092 participants (1079 cases and 1013 controls) with average age of 60 ± 7 years. 47.1% were male. There was 3.2 ± 1.5 years between pre- and post-infection assessments. 3.6% of cases were hospitalized. Lower baseline left ventricular ejection fraction and worse longitudinal, circumferential, and radial strain were associated with higher risk of incident COVID-19. There were no significant differences in interval change of any CMR or ECG metric between cases and controls. CONCLUSION:While pre-existing cardiovascular abnormalities are linked to higher risk of COVID-19, exposure to infection does not alter interval change of highly sensitive CMR and ECG indicators of cardiovascular health.

Synapse loss is the greatest correlate of cognitive impairment in Alzheimer's Disease (AD) and offers a therapeutic avenue alongside disease-modifying therapies. However, the events preceding synapse loss in the human condition have not been well characterised. In this study, we describe a pseudotemporal profile of alterations in the synaptic proteome prior to excitatory synapse loss in human post-mortem brain AD tissue using synapse proteomics and synaptome mapping techniques. In a region with early-stage disease pathology, the most predominant changes were pre-synaptic and featured changes in metabolism and exocytosis. In a mid-stage disease state, alongside initial synapse loss, there was a dominance of inhibitory synaptic changes. In a region with late-stage disease pathology and profound synapse loss, post-synaptic changes were most prevalent with a range of canonical synaptic transmission pathways reduced and differential excitatory synapse subtype pathology. Synapse loss was associated with changes in astrocytic proteins which were enriched for those at peri-synaptic astrocytic processes, including an upregulation of complement activation and endocytosis; a signature that differed from the astrocyte cytosolic proteome. Taken together, this provides evidence of a cascade of events leading to synapse loss with multiple points for therapeutic intervention to alleviate cognitive decline in AD. Data are available via ProteomeXchange with identifier PXD056052. ### Competing Interest Statement PMM has received consultancy fees from Roche, Celgene, and Neurodiem. He has received honoraria or speakers' fees from Novartis and Biogen and has received research or educational funds from Biogen and Novartis. JSJ has received speakers' fees from Eli Lilly and research funds from Biogen.

Defining how amyloid-β and pTau together lead to neurodegeneration is fundamental to understanding Alzheimer's disease (AD). We used imaging mass cytometry to identify neocortical neuronal subtypes lost with AD in post-mortem brain middle temporal gyri from non-diseased and AD donors. Here we showed that L5,6 RORB+FOXP2+ and L3,5,6 GAD1+FOXP2+ neurons, which accumulate amyloid-β intracellularly from early Braak stages, are selectively vulnerable to degeneration in AD, while L3 RORB+GPC5+ neurons, which accumulate pTau but not amyloid-β, are not lost even at late Braak stages. We discovered spatial associations between activated microglia and these vulnerable neurons and found that vulnerable RORB+FOXP2+ neuronal transcriptomes are enriched selectively for pathways involved in inflammation and glycosylation and, with progression to AD, also protein degradation. Our results suggest that the accumulation of intraneuronal amyloid-β, which is associated with glial inflammatory pathology, may contribute to the initiation of degeneration of these vulnerable neurons.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.