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Background and aims: Adolescent polysubstance use has been associated with adverse social and health outcomes. Our aim was to measure rates and transitions to polysubstance use during adolescence and identify factors associated with initiation and discontinuation of polysubstance use. Design: Prospective cohort study. Multistate Markov modelling was used to estimate rates and identify correlates of transitions between substance use states. Setting and participants: Adolescent-parent dyads (n = 1927; adolescents in grade 7, age ≈13 years) were recruited from Australian schools during 2010/11 (Wave 1). Adolescents were surveyed annually until 2016/17 (n = 1503; age ≈19 years; Wave 7) and parents were surveyed annually until 2014/15 (Wave 5). Measurements: Alcohol, tobacco, cannabis and 3,4-methylenedioxymethamphetamine (MDMA) use outcomes were collected at Waves 3–7. Potential confounders were collected at Waves 1–6 and consisted of sex, anxiety and depression symptoms and externalizing problems, parental monitoring, family conflict and cohesion, parental substance use and peer substance use. Covariates were age and family socioeconomic status. Findings: Few adolescents engaged in polysubstance use at earlier waves (Wave 3: 5%; Wave 4: 8%), but proportions increased sharply across adolescence (Waves 5–7: 17%, 24%, 36%). Rates of transitioning to polysubstance use increased with age, with few (<9%) adolescents transitioning out. More externalizing problems (odds ratio [OR] = 1.10; 99.6% confidence interval [CI] = 1.07–1.14), parental heavy episodic drinking (OR = 1.22; 99.6% CI = 1.07–1.40), parental illicit substance use (OR = 3.56; 99.6% CI = 1.43–8.86), peer alcohol use (OR = 5.68; 99.6% CI = 1.59–20.50) and peer smoking (OR = 4.18; 99.6% CI = 1.95–8.81) were associated with transitioning to polysubstance use. Conclusions: Polysubstance use in Australia appears to be rare during early adolescence but more common in later adolescence with low rates of transitioning o

AIM: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). METHODS: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. RESULTS: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. CONCLUSIONS: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.

Background and Aims: Alcohol consumption is a leading risk factor for premature mortality globally, but there are limited studies of broader cohorts of people presenting with alcohol-related problems outside of alcohol treatment services. We used linked health administrative data to estimate all-cause and cause-specific mortality among individuals who had an alcohol-related hospital inpatient or emergency department presentation. Design: Observational study using data from the Data linkage Alcohol Cohort Study (DACS), a state-wide retrospective cohort of individuals with an alcohol-related hospital inpatient or emergency department presentation. Setting: Hospital inpatient or emergency department presentation in New South Wales, Australia, between 2005 and 2014. Participants: Participants comprised 188 770 individuals aged 12 and above, 66% males, median age 39 years at index presentation. Measurements: All-cause mortality was estimated up to 2015 and cause-specific mortality (by those attributable to alcohol and by specific cause of death groups) up to 2013 due to data availability. Age-specific and age–sex-specific crude mortality rates (CMRs) were estimated, and standardized mortality ratios (SMRs) were calculated using sex and age-specific deaths rates from the NSW population. Findings: There were 188 770 individuals in the cohort (1 079 249 person-years of observation); 27 855 deaths were recorded (14.8% of the cohort), with a CMR of 25.8 [95% confidence interval (CI) = 25.5, 26.1] per 1000 person-years and SMR of 6.2 (95% CI = 5.4, 7.2). Mortality in the cohort was consistently higher than the general population in all adult age groups and in both sexes. The greatest excess mortality was from mental and behavioural disorders due to alcohol use (SMR = 46.7, 95% CI = 41.4, 52.7), liver cirrhosis (SMR = 39.0, 95% CI = 35.5, 42.9), viral hepatitis (SMR = 29.4, 95% CI = 24.6, 35.2), pancreatic diseases (SMR = 23.8, 95% CI = 17.9, 31.5) and liver cancer (SMR = 18.3

Aims: The aim of this study is to examine age, period and birth cohort trends in the prevalence of any alcohol-related risky behaviour and to compare these trends between men and women. Design and setting: We used an age–period–cohort analysis of repeated cross-sectional survey data from the Australian National Drug Strategy Household Survey from 2001 to 2016. Participants: Participants were 121 281 people aged 14–80 years who reported consuming alcohol in the past 12 months. Measurements: Any risky behaviour undertaken while under the influence of alcohol in the past 12 months (e.g. operating a motor vehicle) was measured: male or female. Findings: Controlling for age and cohort, cubic spline models showed that any alcohol-related risky behaviour declined with time among participants who consumed alcohol [2016 versus 2007 rate ratio (RR) = 0.80, 95% confidence interval (CI) = 0.76–0.84]. Risky behaviour peaked in the 1954 birth cohort (1954 versus 1971 RR = 1.42, 95% CI = 1.30–1.55) and then steadily declined with more recent birth cohorts (2002 versus 1971 RR = 0.32, 95% CI = 0.27–0.39). Risky behaviour peaked at age 21 years, followed by steady decline and stabilization at approximately age 70 years. Males were overall twice as likely as females to report alcohol-related risky behaviour (RR = 2.10, 95% CI = 1.84–2.39), but this effect was smaller in cohorts born after 1980 [1980 prevalence rate ratios (PRR) = 2.09, 95% CI = 1.81–2.43; 2002 PRR = 1.31, 95% CI = 1.03–1.68]. Conclusions: Alcohol-related risky behaviour in Australia has declined generally since 2001, with rates for recent cohorts having the sharpest decline. Risky behaviour remains most prevalent in young adults, and the male–female gap in risky behaviour is closing for more recent birth cohorts. These trends are consistent with alcohol consumption trends observed in Australia and world-wide.

Employing monoclonal antibodies to target vaccine antigens to different immune cells within lymph nodes where adaptive immunity is initiated can provide a mechanism to fine-tune the magnitude or the quality of immune responses. However, studying the effects of different targeting antibodies head-to-head is challenging due to the lack of a feasible method that allows rapid screening of multiple antibodies for their impact on immunogenicity. Here self-assembling ferritin nanoparticles are prepared that co-display vaccine antigens and the Fc-binding domain of Staphylococcal protein A, allowing rapid attachment of soluble antibodies to the nanoparticle surface. Using this tunable system, ten antibodies targeting different immune cell subsets are screened, with targeting to Clec9a associated with higher serum antibody titers after immunization. Immune cell targeting using ferritin nanoparticles with anti-Clec9a antibodies drives concentrated deposition of antigens within germinal centers, boosting germinal center formation and robust antibody responses. However, the capacity to augment humoral immunity is antigen-dependent, with significant boosting observed for prototypic ovalbumin immunogens but reduced effectiveness with the SARS-CoV-2 RBD. This work provides a rapid platform for screening targeting antibodies, which will accelerate mechanistic insights into optimal delivery strategies for nanoparticle-based vaccines to maximize protective immunity.

The current enthusiasm for the circular economy (CE) offers a unique opportunity to advance the impact of research on sustainability transitions. Diverse interpretations of CE by scholars, however, produce partly opposing assessments of its potential benefits, which can hinder progress. Here, we synthesize policy-relevant lessons and research directions for a sustainable CE and identify three narratives—optimist, reformist, and skeptical—that underpin the ambiguity in CE assessments. Based on 54 key CE scholars’ insights, we identify three research needs: the articulation and discussion of ontologically distinct CE narratives; bridging of technical, managerial, socio-economic, environmental, and political CE perspectives; and critical assessment of opportunities and limits of CE science–policy interactions. Our findings offer practical guidance for scholars to engage reflexively with the rapid expansion of CE knowledge, identify and pursue high-impact research directions, and communicate more effectively with practitioners and policymakers.

Pathogenic somatic MTOR variants in the cerebral cortex are a frequent cause of focal cortical dysplasia (FCD). We describe a child with drug and surgery-resistant focal epilepsy due to FCD type II who developed progressive enlargement and T2 signal hyperintensity in the ipsilateral caudate and lentiform nuclei. Histopathology of caudate nucleus biopsies showed dysmorphic neurons, similar to those in resected cortex. Genetic analysis of frontal and temporal cortex and caudate nucleus identified a pathogenic somatic MTOR variant [NM_004958.4:c.4375G > C (p.Ala1459Pro)] that was not present in blood-derived gDNA. The mean variant allele frequency ranged from 0.4% to 3.2% in cerebral cortex and up to 5.4% in the caudate nucleus. The basal ganglia abnormalities suggest more widespread, potentially hemispheric dysplasia in this patient, consistent with the pathogenic variant occurring in early cerebral development. This finding provides a potential explanation for persistent seizures in some patients with seemingly complete resection of FCD or disconnection of a dysplastic hemisphere.

INTRODUCTION: As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

Introduction: Alcohol is a leading risk factor for death and disease in young people. We compare age-specific characteristics of young people who experience their first (‘index’) alcohol-related hospitalisation or emergency department (ED) presentation, and whether age at index predicts 12-month rates of readmission. Methods: We used a retrospective linked-data cohort of 10,300 people aged 12–20 years with an index alcohol-related hospital and/or ED record in New South Wales, Australia from 2005 to 2013. Age group (early adolescent [12–14 years], late adolescent [15–17 years], young adult [18–20 years]) and diagnosis fields were used in logistic regression analyses and to calculate incidence rates with adjustment for year of index event, sex, socioeconomic disadvantage and residence remoteness. Results: People who experienced their index event in early adolescence (adjusted relative risk ratio [ARRR] 0.45 [95% confidence interval 0.39, 0.52]) or late adolescence (ARRR 0.82 [0.74, 0.90]) were less likely to be male compared to young adults. Early adolescents (ARRR 0.60 [0.51, 0.70]) and late adolescents (ARRR 0.84 [0.76, 0.93]) were less likely to have a hospitalisation index event. Early adolescents (adjusted incidence rate ratio 1.40 [1.15, 1.71]) and late adolescents (adjusted incidence rate ratio 1.16 [1.01, 1.34]) were more likely than young adults to have a subsequent 12-month non-poisoning injury ED presentation. Discussion and Conclusions: We identified preventable hospital events in young people who have previously experienced an alcohol-related ED presentation or hospitalisation, with age-specific characteristics and outcomes that can be used to inform future health policy and service planning.

OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.

In 2020, the Australian and New Zealand flux research and monitoring network, OzFlux, celebrated its 20th anniversary by reflecting on the lessons learned through two decades of ecosystem studies on global change biology. OzFlux is a network not only for ecosystem researchers, but also for those 'next users' of the knowledge, information and data that such networks provide. Here, we focus on eight lessons across topics of climate change and variability, disturbance and resilience, drought and heat stress and synergies with remote sensing and modelling. In distilling the key lessons learned, we also identify where further research is needed to fill knowledge gaps and improve the utility and relevance of the outputs from OzFlux. Extreme climate variability across Australia and New Zealand (droughts and flooding rains) provides a natural laboratory for a global understanding of ecosystems in this time of accelerating climate change. As evidence of worsening global fire risk emerges, the natural ability of these ecosystems to recover from disturbances, such as fire and cyclones, provides lessons on adaptation and resilience to disturbance. Drought and heatwaves are common occurrences across large parts of the region and can tip an ecosystem's carbon budget from a net CO2 sink to a net CO2 source. Despite such responses to stress, ecosystems at OzFlux sites show their resilience to climate variability by rapidly pivoting back to a strong carbon sink upon the return of favourable conditions. Located in under-represented areas, OzFlux data have the potential for reducing uncertainties in global remote sensing products, and these data provide several opportunities to develop new theories and improve our ecosystem models. The accumulated impacts of these lessons over the last 20 years highlights the value of long-term flux observations for natural and managed systems. A future vision for OzFlux includes ongoing and newly developed synergies with ecophysiologists, ecologists

BACKGROUND AND AIMS: Tolerance to the effects of alcohol is an important element in the diagnosis of alcohol use disorders (AUD); however, there is ongoing debate about its utility in the diagnosis AUD in adolescents and young adults. This study aimed to refine the assessment of tolerance in young adults by testing different definitions of tolerance and their associations with longitudinal AUD outcomes. DESIGN: Prospective cohort study. SETTINGS: Australia. PARTICIPANTS: A contemporary cohort of emerging adults across Australia (n = 565, mean age = 18.9, range = 18-21 at baseline). MEASUREMENTS: Clinician-administered Structured Clinical Interview for DSM-IV Research Version (SCID-IV-RV) assessed for AUD criteria across five interviews, at 6-month intervals over 2.5 years. Tolerance definitions were operationalized using survey-type response (yes/no), clinician judgement (SCID-IV-RV), different initial drinking quantity and percentage increase thresholds and average heavy consumption metrics. AUD persistence was operationalized by the number of times AUD was present across the 2.5-year study period (n = 491), and new-onset AUD was operationalized as any new incidence of AUD during the follow-up period (n = 461). FINDINGS: The (i) SCID-IV-RV clinician judgement [odds ratio (OR) = 2.50, P = 0.005], (ii) an initial drinking quantity threshold of four to five drinks and 50% minimum increase (OR = 2.48, P = 0.007) and (iii) 50% increase only (OR = 2.40, P = 0.005) were the tolerance definitions more strongly associated with any new onset of AUD throughout the four follow-up time-points than other definitions. However, these definitions were not associated with persistent AUD (Ps > 0.05). Average heavy consumption definitions of tolerance were most strongly associated with persistent AUD (OR = 6.66, P = 0.001; OR = 4.65, P = 0.004) but not associated with new-onset AUD (Ps > 0.05). CONCLUSIONS: Initial drink and percentage change thresholds appear to improve the efficacy

OBJECTIVES: Following infection with SARS-CoV-2, virus-specific antibodies are generated, which can both neutralise virions and clear infection via Fc effector functions. The importance of IgG antibodies for protection and control of SARS-CoV-2 has been extensively reported. By comparison, other antibody isotypes including IgA have been poorly characterised. METHODS: Here, we characterised plasma IgA from 41 early convalescent COVID-19 subjects for neutralisation and Fc effector functions. RESULTS: Convalescent plasma IgA from > 60% of the cohort had the capacity to inhibit the interaction between wild-type RBD and ACE2. Furthermore, a third of the cohort induced stronger IgA-mediated ACE2 inhibition than matched IgG when tested at equivalent concentrations. Plasma IgA and IgG from this cohort broadly recognised similar RBD epitopes and had similar capacities to inhibit ACE2 from binding to 22 of the 23 prevalent RBD mutations assessed. However, plasma IgA was largely incapable of mediating antibody-dependent phagocytosis in comparison with plasma IgG. CONCLUSION: Overall, convalescent plasma IgA contributed to the neutralising antibody response of wild-type SARS-CoV-2 RBD and various RBD mutations. However, this response displayed large heterogeneity and was less potent than IgG.

OBJECTIVES: Pregnancy is defined as a 'red flag' in headache assessment. We aimed to describe the prevalence and causes of serious secondary headache in pregnant ED patients. METHODS: Unplanned secondary analysis of HEAD Study/HEAD Colombia data. RESULTS: 3.2% (117/3643) of ED headache patients aged 18-50 years were pregnant, of whom six (5.1%) had a serious secondary cause identified. The proportion of patients with serious headache causes was not significantly different between pregnant female, non-pregnant female and male patient subgroups (P = 0.89). CONCLUSION: Inclusion of pregnancy as a 'red flag' in ED headache assessment is not supported by these data.

Precise acoustic micromanipulation is emerging as an important tool in biomedical research, where acoustic forces have the advantage of being contact-free, label-free, and biocompatible. Conventional acoustofluidic approaches, however, produce device-scale effects that limit the ability to locally target acoustic energies at the microscale. In this study, we demonstrate an approach to generate designed and highly local acoustic fields using 3D resonant mass-spring microstructures, achieving local acoustic field gradients on the order of microns, orders of magnitude smaller than the fluid wavelength. In doing so, rapid and spatially defined controllable micromanipulation, including particle capture, transport, and patterning using arbitrarily arranged micro-resonator arrays is demonstrated. This sub-wavelength, 3D acoustofluidic approach results in highly localized and defined micromanipulation, with potential applications across sample preparation, cell analysis, and diagnostics.

Background and aims: Experience of alcohol-induced memory blackouts in adolescence may be an important risk factor for later harms. This longitudinal study (i) modelled trajectories of alcohol-related blackouts throughout adolescence, (ii) explored early-adolescent predictors of blackout trajectories and (iii) examined the association between blackout trajectories and alcohol use disorder (AUD) symptoms. Design: Longitudinal study in which data from six annual surveys of a longitudinal cohort of Australian adolescents were used to model latent class growth trajectories of blackouts, adjusting for alcohol consumption frequency and typical quantity. Regression models were used to determine whether parent, child and peer factors at baseline (mean age = 12.9) predicted profiles of blackout trajectory membership and whether blackout trajectories predicted meeting criteria for AUD in early adulthood (mean age = 19.8). Setting and participants: Australian adolescents (n = 1821; mean age = 13.9–18.8 years). Measurements: Alcohol-related blackouts, alcohol consumption frequency, typical consumption quantity and DSM-5 AUD in early adulthood were all self-reported. Findings: We identified a three-class solution: delayed alcohol initiation, rare blackouts (n = 701; 38.5%); early initiation, rare blackouts (n = 869; 47.7%); and early initiation, increasing blackouts (n = 251; 13.8%). Female sex was associated with increased risk of early initiation, increasing blackouts relative to delayed initiation, rare blackouts [relative risk ratio (RRR) = 3.90; 99.5% confidence interval (CI) = 1.96, 7.76] and relative to early initiation, rare blackouts (RRR = 2.89; 99.5% CI = 1.42, 5.87). Early initiation, rare blackouts [odds ratio (OR) = 1.96; 99.5% CI = 1.17, 3.29] and early initiation, increasing blackouts (OR = 4.93; 99.5% CI = 2.32, 10.48) were each associated with increased odds of meeting criteria for AUD in early adulthood relative to delayed initiation, rare blackouts. Early ini

Aims: To estimate change in young people's alcohol consumption during COVID-19 restrictions in Australia in early-mid 2020, and test whether those changes were consistent by gender and level of consumption prior to the pandemic. Design: Prospective longitudinal cohort. Setting: Secondary schools in New South Wales, Tasmania and Western Australia. Participants: Subsample of a cohort (n = 443) recruited in the first year of secondary school in 2010–11. Analysis data included three waves collected in September 2017–July 2018, September 2018–May 2019 and August 2019–January 2020), and in May–June 2020. Measurements: The primary predictors were time, gender and level of consumption prior to the pandemic. Outcome variables, analysed by mixed-effects models, included frequency and typical quantity of alcohol consumption, binge drinking, peak consumption, alcohol-related harm and drinking contexts. Findings: Overall consumption (frequency × quantity) during the restrictions declined by 17% [incidence rate ratio (IRR) = 0.83; 95% confidence interval (CI) = 0.73, 0.95] compared to February 2020, and there was a 35% decline in the rate of alcohol-related harms in the same period (IRR = 0.66; 95% CI = 0.54, 0.79). Changes in alcohol consumption were largely consistent by gender. Conclusions: From a survey of secondary school students in Australia, there is evidence for a reduction in overall consumption and related harms during the COVID-19 restrictions.

Background: Different forms of alcohol-related harm (e.g., hangovers, fighting) may confer differential risk of clinically relevant alcohol problems. We examine: (i) patterns of transition in experiencing alcohol-related harms across adolescence; (ii) whether factors in early adolescence predict transition patterns; and (iii) whether transition patterns predict later alcohol use disorder (AUD) symptoms. Methods: We used a longitudinal Australian cohort (n = 1828) to model latent class transition patterns of alcohol-related harms across three timepoints (Mage = 13.9, 16.8, 18.8 years). Regression models assessed whether child, peer, and parent factors in early adolescence (Mage = 12.9) predicted harms transition patterns and whether these patterns predicted AUD symptoms in early adulthood (Mage = 19.8). Results: Five transition patterns characterized most of the cohort (n ≈ 1609, 88.0%): (i) minimal harms (n ≈ 381, 20.8%); (ii) late physiological harms (n ≈ 702, 38.4%); (iii) early physiological harms (n ≈ 226, 12.4%); (iv) late all harms (n ≈ 131, 7.2%); and (v) gradual all harms (n ≈ 169, 9.2%). With late physiological harms as the reference, females had increased risk of experiencing early physiological harms (relative risk [RR]: 2.15; 99.5% CI: 1.19, 3.90). Late all harms (RR: 1.71; CI: 1.19, 2.47) and gradual all harms (RR: 1.84; CI: 1.37, 2.47) were each associated with increased odds of meeting criteria for AUD, even when patterns of alcohol consumption are considered. Conclusions: Adolescents display heterogeneous transition patterns across physiological and psychosocial alcohol-related harms. Females are at greater risk of experiencing early physiological harms. Experience of both physiological and psychosocial harms in late adolescence is an important and potentially modifiable precursor to clinically relevant alcohol problems in early adulthood.

Background Approximately 30% of older adults are cognitively normal at death despite presence of Alzheimer’s disease (AD) neuropathology at autopsy. Studying these “resilient” individuals may lead to the discovery of novel therapeutic targets. In addition, growing evidence suggests sex differences in downstream neurodegenerative consequences of AD neuropathology, with recent studies highlighting notable sex-specific genetic drivers of AD pathogenesis. We sought to extend this work by elucidating sex-specific genetic factors underlying resilience to AD. Method We used our published genetic resilience pipeline to assess sex-specific genetic predictors (Dumitrescu et al., 2020). Briefly, we used modern psychometric approaches to harmonize cognitive measures across four cohorts of cognitive aging (N=5054), in-vivo amyloid PET across two studies, and leveraged autopsy measures of amyloidosis (CERAD staging) across two studies. A continuous measure of resilience was quantified using a latent variable framework whereby higher scores reflected better-than-predicted cognitive performance given amyloidosis level and lower scores reflected worse-than-predicted performance. We then performed sex-stratified GWASs and sex-interaction GWASs, covarying for age and the first three principal components and meta-analyzed across cohorts. Finally, we performed sex-stratified genetic correlation analyses (GNOVA) between our meta-analysis results and summary statistics from 63 complex traits. Result Among individuals with normal cognition, we identified a female-specific locus on chromosome 10 (rs827389, [p(females)=7.4E-09, p(males)=0.64, p(interaction)=8.3E-05, MAF=0.46]). This variant is a modest eQTL for KIN (p=0.003), a gene encoding a DNA/RNA binding protein (http://www.braineac.org). In our genetic correlation analyses, we observed male-specific correlations between resilience and two heart rate-related traits, whereby higher resilience was associated with lower genetic risk for po