Dan Rujescu

Alzheimer’s disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050¹. AD is highly heritable, with twin-based heritability estimates of 60–80%². Although 1,200 causal loci are predicted to exist for AD³, approximately 80 loci have been associated with AD in two recent studies^4,5. Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be found⁶. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.

BACKGROUND Digital therapeutics (DTx) are increasingly used to address gaps in access to evidence-based treatments for depression, yet rigorous trials isolating content-specific effects remain limited. OBJECTIVE This study evaluated a prescribable, web-based DTx (edupression.com®) integrating cognitive-behavioral and psychoeducational content, measurement-based care elements, and structured mood monitoring in adults with mild-to-moderate depression. METHODS We conducted a single-center, rater-blinded, parallel-group randomized controlled trial delivered entirely remotely from a coordinating center in Vienna, Austria, with participants residing in Austria and Germany recruited online and through clinical referral. Adults aged 18-65 years with mild-to-moderate unipolar depression were allocated 1:1 to the intervention group (IG) or an active sham control (ASC), both in addition to unrestricted usual care. Both arms were stand-alone, unguided self-help applications. The ASC matched the intervention in interface and engagement intensity but excluded therapeutic content and feedback. The primary endpoint was change in self-administered PHQ-9 from baseline to week 12, analyzed in an intention-to-treat framework using baseline-adjusted linear regression with multiple imputation (MICE); reference-based multiple imputation (RBMI) was prespecified as a conservative sensitivity analysis. Safety was assessed in all participants. RESULTS Of 907 individuals who expressed interest, 250 were randomized (IG=125; ASC=125). Observed week-12 PHQ-9 data were available for 40/125 (32%) IG and 56/125 (44.8%) ASC participants. Non-adherence did not differ significantly between arms (44.0% IG vs 39.2% ASC). In the primary intention-to-treat analysis, the intervention showed a greater reduction in PHQ-9 than the ASC (adjusted mean difference −4.0 points, 95% CI −5.8 to −2.1; Cohen d=0.84; P=.004). The RBMI sensitivity analysis yielded a smaller but statistically significant difference (adjusted mean difference −1.1 points, 95% CI −1.7 to −0.5; Cohen d=0.20; P=.001), and the complete-case estimate was −4.8 points (Cohen d=0.99). Response was more frequent in the IG than the ASC (52.8% vs 15.4%; number needed to treat 2.7), as was remission (24.3% vs 7.0%). Depression literacy improved more in the IG (between-group difference 1.4 points, P<.001) and remained significant under the conservative RBMI analysis. No serious adverse events, suicide attempts, or deaths were reported. Clinically relevant deterioration was less frequent in the IG (4.0% vs 11.2%). Emergent suicidal ideation on the daily mood chart did not differ between arms (6.9% vs 10.9%; risk difference −4.0%, 95% CI −15.7% to 7.2%). CONCLUSIONS In this outpatient sample, the DTx was associated with greater short-term reductions in depressive symptoms and improvements in depression literacy than a structurally matched active sham. The design enabled a conservative, content-specific efficacy test with no evidence of intervention-related harm. Limitations include the selective outpatient sample, the high proportion of unobserved primary-endpoint data, and a 12-week observation period. These findings support the use of structured, unguided DTx as an accessible adjunct within routine outpatient care. CLINICALTRIAL ClinicalTrials.gov NCT04839822; German Clinical Trials Register DRKS00032121.

Regional differences in human brain glucose metabolism reflect local energy demands, but their cellular and mitochondrial determinants remain unclear. We combined [ ¹⁸ F]FDG positron emission tomography in healthy human participants with estimates of cellular composition and mitochondrial density to unravel (sub)cellular correlates of heterogeneity in brain glucose metabolism. By correcting for RNA content and differential gene expression due to postmortem sampling, we addressed methodological shortcomings in multimodal neuroimaging integration. We introduce transcriptionally derived cytoarchitectonic maps of the human cortex that are consistent with histological findings, providing a biologically grounded framework for relating in vivo neuroimaging signals. Accordingly, mitochondrial distribution showed strong association with the intrinsic energy requirements at resting state. In contrast, relations between metabolism and neuronal composition were driven by sensory input and mitochondria-sparse thin-axon neurons, suggesting that stimulation-induced energy demand is met rather by neuronal processes that are independent of mitochondrial abundance to maintain efficient information processing.

Background and ObjectivesBilateral vestibulopathy (BVP) is a chronic disorder resulting from bilateral loss of peripheral vestibular function. Although several etiologies have been identified, such...

Despite decades of extensive research, the complex architecture underlying human brain signaling remains incompletely understood. Previous work investigating the relationship between brain glucose metabolism and functional connectivity (FC) employed whole-brain analysis, without accounting for network interactions, dependencies or hierarchies. Here, we assess network-specific differences in the relationship between FC and metabolic demand, using [18F]FDG PET/MR data from three independent datasets. The metabolic cost of FC, i.e., the change in glucose demand associated with corresponding changes in FC, was modeled at rest, during cognitive task performance and in Alzheimer′s disease (AD). Our findings reveal network-specific differences in metabolic cost, with the default mode (DM), somatomotor (SM) and fronto-temporal networks accounting for highest, intermediate and lowest metabolic demands, respectively. Similarly, time-resolved variability of FC demonstrated highest costs for states with DM network involvement and lowest for SM network participation. This relationship was reversed in participants with AD, who exhibited decreased demands in the DM network and increased costs in the SM network. Cognitive performance consistently revealed cost reductions in the DM and SM networks, as well as increases in task relevant networks. Together, these results highlight the flexibility of functional network architecture associated with cognitive demands and neuropathology, and shed light on the complex interplay between glucose metabolism and network interactions.

Psychosocial stress engages coordinated physiological and neural responses that enable adaptation to environmental challenges. Maladaptive stress responses and reduced resilience are major risk factors for psychiatric and neurodegenerative disorders. As the brain’s metabolic response to stress remains largely unexplored, we used simultaneous [ ¹⁸ F]FDG PET/MRI during performance of the Montreal Imaging Stress Task to assess cerebral glucose metabolism, BOLD activation and functional connectivity. Multimodal data analysis identified the posterior cingulate cortex (PCC) as hub of stress processing beyond cognitive input, with increased glucose metabolism and attenuated BOLD deactivations. This was accompanied by reduced PCC connectivity within the default mode network and increased influence onto frontoparietal and dorsal attention networks. Endocrine stress responsivity was further reflected in lower resilience sub scores, failure to downregulate anterior cingulate cortex (ACC) metabolism during stress, and an inverse relationship between ACC glucose metabolism and anterior insula functional connectivity. These results indicate that acute psychosocial stress does not merely increase overall energy demand but reconfigures the relationship between regional metabolism and large-scale network organization, which further differs with individual endocrine stress responsivity. Our findings unify the roles of stress and the DMN in brain disorders, providing a multimodal framework for assessment in patient populations.

Eating disorders—including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case–control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

Background: Real-world data for intranasal esketamine in treatment-resistant depression (TRD) are needed to characterize effectiveness, suicidality, and tolerability in routine care. We evaluated induction phase outcomes in outpatients with TRD treated at the University Hospital Vienna. Methods: This retrospective single-center registry study included adults with TRD initiating supervised intranasal esketamine. The primary endpoint was the change in clinician-rated depressive symptom severity (MADRS) from the pre-treatment (PV) to the end of induction (EOI) visit. MADRS scores across baseline (BL), PV, and EOI were analyzed using a mixed model for repeated measures. Secondary outcomes included MADRS three-factor change, self-rated depression score trajectories (PHQ-9), response/remission rates, suicidal ideation, and tolerability. Results: Of 229 screened patients, 176 initiated esketamine and 156 completed induction. MADRS at BL was 31.5 (SD 6.4), PHQ-9 was 18.5 (SD 4.7). In the primary model, adjusted mean MADRS was 30.3 at PV and 17.7 at EOI, yielding a change of −12.5 points (95%CI −14.1 to −11.0; p < 0.001; Hedges’ g = 1.8). All MADRS factors improved, with the largest reduction in the affective–anhedonic domain. PHQ-9 decreased steadily across treatments. Remission was 27.2% and response 57.4% at EOI. Suicidal ideation decreased significantly; no suicide or serious self-harm occurred during induction. Adverse events (AEs) were recorded in 34.7%, with AE-related discontinuation in 3.4%. Conclusions: Esketamine induction was associated with marked improvement in depressive symptoms and suicidality, with acceptable tolerability under supervised administration. Longer-term registry follow-up and controlled comparative studies are needed to further define the benefit–risk profile beyond induction phase.