Citations

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Abstract INTRODUCTION Tau species lacking truncation of the N‐terminal region, including plasma N‐terminal tau fragment 1 (NT1), have been previously associated with cognitive decline, neurodegeneration, and tau pathology in late‐onset sporadic Alzheimer's disease (AD). METHODS Here, we examined cross‐sectional and longitudinal plasma NT1 as a possible predictor of cognitive, clinical, and core AD biomarker trajectories in autosomal dominant AD (ADAD). RESULTS NT1 levels in ADAD mutation carriers (MC; n = 132) increased across the disease continuum, compared to non‐carriers (NC; n = 75), becoming elevated about a decade prior to estimated symptom onset. Cross‐sectional and longitudinal NT1 levels in MC were associated with clinical, cognitive, and biomarker changes. NT1 increases continued in symptomatic phases of disease, a distinct trajectory from that seen with CSF p‐tau217 and other phospho‐tau species. DISCUSSION Together, our results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related clinical, cognitive, and biomarker outcomes. Highlights Leveraging a deeply phenotyped cohort of individuals carrying a pathogenic variant for autosomal dominant Alzheimer's disease (ADAD) and their non‐carrier family members, our results suggest that plasma N‐terminal tau fragment 1 (NT1) levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with cerebrospinal fluid (CSF) measures of tau pathology but less so with CSF or imaging measures of β‐amyloid pathology. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related tau pathology and neurodegeneration across a wide spectrum of disease.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract BACKGROUND Tau‐derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid‐beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long‐term anti‐Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them. METHODS A post‐hoc analysis of the DIAN‐TU‐001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab ( n = 50), gantenerumab ( n = 52), or placebo ( n = 40). High‐resolution mass spectrometry quantified CSF tau species over four years. RESULTS Phosphorylated tau (p‐tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab‐mediated Aβ plaque reduction. Nearly a decade later, MTBR‐tau243 and p‐tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression. DISCUSSION Initially changing soluble p‐tau species track Aβ plaque reduction, while ptau205 and MTBR‐243 reflect tau tangle pathology, informing different pathways of therapeutic strategies. Highlights p‐tau217 and p‐tau231 correlate with Aβ‐PET and respond to Aβ‐plaque lowering therapies. Aβ immunotherapy trials support a direct link between p‐tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT‐related biomarkers. Blood‐based p‐tau217 assays may provide a non‐invasive tool to monitor Aβ therapies. MTBR‐tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT‐targeting therapies.

Objectives Directly compare the brain glucose patterns seen with [F‐18] fluorodeoxyglucose (FDG) positron emission tomography (PET) between 2 genetically determined forms of Alzheimer's disease: Down syndrome (DS) and autosomal dominant Alzheimer's disease (ADAD). Methods Cross‐sectional analyses of FDG were performed in individuals with DS (n = 76) from the Alzheimer Biomarker Consortium‐Down Syndrome (ABC‐DS), ADAD (n = 297), and neurotypical familial controls (n = 188) from the Dominantly Inherited Alzheimer Network (DIAN). Within‐group linear regression models and generalized additive models were performed for select regional FDG uptake measures (isthmus cingulate and inferior parietal, precuneus, middle temporal gyrus, and precentral gyrus). Age, sex, apolipoprotein (APOE) ε4 carrier status, and cortical amyloid burden were included within these analyses. Results Even 20 years before expected onset of clinical symptoms, FDG uptake was lower for DS compared to neurotypical familial controls ( p < 0.01). ADAD baseline FDG was similar to neurotypical familial controls until 7 years before expected symptom onset. Both symptomatic individuals with DS and ADAD had lower FDG compared to neurotypical familial controls ( p < 0.01). A higher amyloid burden was associated with lower FDG for both genetic forms, with similar rates of decline in FDG uptake for DS and ADAD who were amyloid positive. Interpretation Brain glucose metabolism is substantially lower for people with DS, even in individuals who are cognitively stable. The patterns of FDG decline are distinct in these 2 genetically determined forms of AD. The diagnostic utility of FDG‐PET is specific to the genetic form of AD. ANN NEUROL 2025;98:1237–1248

Abstract INTRODUCTION Monoclonal anti‐amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS In the DIAN‐TU‐001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [ 11 C]‐Pittsburgh compound‐B (PiB) positron emission tomography (PET), [ 18 F]‐fluoro‐2‐deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS Gantenerumab significantly reduced PiB‐PET uptake overall and in most regions and showed no changes in FDG‐PET or MRI measures. Drug effects were associated with baseline PiB‐PET uptake, and the largest effects occurred in medial regions. DISCUSSION Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB‐PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. Highlights Gantenerumab unevenly decreased Aβ burden as measured by PiB‐PET across brain regions. The strongest decrease in PiB‐PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG‐PET metabolism or MRI volumetrics after 4 years.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

AbstractINTRODUCTIONThis study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.METHODThe SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.RESULTSSubtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS‐activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late‐stage tau biomarkers, microglia, and axonal degeneration.DISCUSSIONThe rise in UPS proteins alongside tau‐related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.Highlights This study investigates the ubiquitin‐proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late‐stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau‐pathology‐driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.