Although plasma pTau181 has been shown to accurately discriminate patients with Alzheimer’s disease from healthy older adults, there are few studies of plasma biomarkers among middle-aged populations. Given the potential utility of plasma AD biomarkers such as pTau181 in screening for disease risk, examining pTau181 in a middle-aged cohort without AD is important for future implementation. The objectives of this study were to characterise plasma pTau181 in a middle-aged birth cohort aged 45 years and to investigate associations with early indicators of dementia risk. Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972–1973. Plasma pTau181, self-reported cognitive concerns, MRI-based brain structure, and DunedinPACE (an epigenetic biomarker of biological ageing) were measured at age 45; cognition was measured in childhood and age 45. Plasma pTau181 concentrations at age 45 (n = 854, 49

Elevated blood pressure (BP) in midlife is a well-established risk factor for impaired brain health and cognitive ability in old age. We hypothesized that exposure to elevated BP within the first five decades of life may contribute to this risk through impacts on brain health and/or cognitive ability evident by midlife. Participants (n = 893) were selected from the Dunedin Multidisciplinary Health and Development Study (The Dunedin Study). Exposures were systolic (SBP) and diastolic (DBP) blood pressures measured at ages 7, 11, 18, 26, 32, 38 and 45. Cumulative early-life exposure to blood pressure was also quantified as the area under the curve (AUC). Brain health was assessed at age 45 via imaging measures comprising BrainAGE (difference between chronological age and age predicted from machine-learning models of brain-imaging data), white matter hyperintensity (WMH) burden, and retinal arteriolar calibres (RAC)-a proxy for cerebral small vessel remodelling. Cognitive ability (assessed using IQ) was also measured at age 45, with replication of cognitive findings tested in a larger contemporary cohort, the 1970 British Cohort Study. We found limited evidence for any association between BP in the first four decades of life and brain health or cognitive ability at age 45. Most associations instead emerged for BP from early-midlife onwards. Midlife BP was associated with older BrainAGE (Beta for DBP at age 45 = 0.11 [0.04, 0.19]; P = 0.003) and higher WMH burden (Beta = 0.09 [0.02, 0.17]; P = 0.019). Effect estimates for SBP were similar. For cognitive ability, DBP at ages 38 and 45 showed modest associations with age 45 IQ, which became null after accounting for childhood IQ. These findings were broadly replicated in the 1970 British Cohort Study for age 47 IQ. Only RAC in The Dunedin Study were found to associate with BP from childhood (Beta for age 7 DBP = -0.09 [-0.16, -0.03]; P = 0.006), and the magnitude of these estimates increased during midlife (Beta at age 45 = -0.37 [-0.45, -0.30]; P < 0.001). We found little evidence for any association between BP prior to age 40 and BrainAGE, WMH volume, or cognitive ability in midlife. However, cumulative exposure to elevated BP from childhood was associated with reduced RAC, suggesting a potential link between BP and adverse cerebral small vessel remodelling from childhood.

Environmental exposures influence the risk of psychiatric disorders, yet the biological mechanisms by which such experiences become embedded in brain structure remain poorly understood. The human cerebral cortex is crucial for cognition and emotional regulation, and variation in cortical thickness (CT) and surface area (SA) is linked to various behavioural and psychiatric traits. Here, we present a large-scale epigenome-wide association study that combines peripheral blood DNA methylation (DNAm) with MRI-derived cortical measures in over 7,400 individuals across 20 cohorts within the ENIGMA consortium. We identify mostly non-overlapping DNAm signatures associated with CT and SA, consistent with their distinct developmental and regulatory architectures. CT-associated CpGs are replicated across independent cohorts and are enriched for environmentally responsive regulatory elements and pathways associated with stress, metabolism, and immune signalling. In contrast, SA-associated CpGs cluster within chromatin-regulatory regions involved in early cortical development. Phenome-wide and Mendelian randomisation analyses reveal pleiotropic associations between DNAm, cortical structure, and psychiatric and cognitive traits. These findings suggest that peripheral DNAm captures environmentally sensitive biological processes that link exposure, cortical organisation, and behavioural vulnerability.

This study tested whether parents' social mobility is associated with parent-child interactions. Data came from 719 Dunedin Parenting Study members (mean age: 32.7; 52.3% female, 90.2% New Zealand European ethnicity) who have been followed from birth to midlife and participated in parenting assessments with their 3-year-old children (50% female). Upwardly mobile parents provided more sensitive parenting and cognitively stimulating environments than parents from stable-low socioeconomic backgrounds, but less sensitive parenting and cognitively stimulating environments than parents from stable-high socioeconomic backgrounds. These results were not fully explained by pre-existing differences between parents in experienced parenting and childhood characteristics. Our findings underscore the importance of supporting families with fewer socioeconomic resources through a life-course and intergenerational approach to caregiving environments.

Oxidative stress and mitochondrial dysfunction are proposed to play prominent roles in the biology of aging. Human studies are limited and confounded by metabolic disturbances associated with age-related diseases. In this study, we have measured biomarkers of oxidative and mitochondrial stress in blood samples from up to 864 participants in the longitudinal Dunedin Multidisciplinary Health and Development Study at age 45. We then determined the correlation between these cross-sectional biomarkers and the longitudinal Pace of Aging, a composite score that represents whole-organism functional decline in each participant from 26 to 45 years old, and facial age at 45 years old. Protein carbonyls and allantoin were selected as biomarkers for oxidative stress, and GDF-15 as a marker of mitochondrial stress. Midlife levels of these biomarkers were low but varied across the population. GDF-15 showed the strongest associations with the Pace of Aging (β = 0.26, p < .0001) and facial age (β = 0.12, p = .001) in sex- and smoking-adjusted models. The Pace of Aging was also significantly associated with allantoin (β = 0.14, p < .0001) and protein carbonyls (β = 0.09, p = .005), and allantoin was associated with facial age (β = 0.08, p = .02). These associations remained when the limited number of participants with age-related disease were removed from the analyses. Our results provide evidence of increased oxidative stress and mitochondrial stress in faster-aging humans at midlife, well before the onset of age-related disease.

BACKGROUND:Although plasma pTau181 has been shown to accurately identify patients with AD in case-control studies, its utility as a preclinical biomarker in middle-aged community-based cohorts is unclear. Our objective was to investigate whether plasma pTau181 was associated with indicators of AD risk in a middle-aged cohort (aged 45 years). METHOD:Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972-1973. Most recently, 94% of the living Study members were assessed at age 45 (2017-2019). Plasma pTau181 was measured using the Simoa SR-X analyser (Quanterix). MRI scans were conducted at the same timepoint. Cognitive ability was assessed at ages 7, 9, 11, and at age 45. Pace of ageing, a composite measure of 19 biomarkers of ageing, was determined from data collected at ages 32, 38, and 45. RESULT:We observed a wide range of pTau181 levels in our same-aged sample (n = 856), from below the lower limit of detection to 147pg/ml (M=13.6pg/ml, SD=9.1). Excluding n<5 participants with chronic kidney disease, males had significantly higher pTau181 levels than females. No statistically significant associations were observed with cognitive measures, MRI-derived brain measurements, or composite ageing variables. CONCLUSION:The range of pTau181 levels observed suggests that blood biomarkers of AD may increase early in middle age, decades prior to any potential disease onset and possibly before any measurable cognitive decline or neurostructural abnormalities. Future assessment waves in the same cohort will elucidate whether plasma pTau181 in midlife is predictive of AD onset later in life.

We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHDSYMP). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHDOVERALL). ADHDSYMP returned no genome-wide significant variants. We show that the combined ADHDOVERALL GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (rg < -0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHDOVERALL outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.

Most etiological research on mental disorders tries to find specific causes of specific disorders. However, the search for causal specificity has been elusive. In fact, new evidence reveals that the major etiological factors are transdiagnostic. One possible reason for why the search for specificity has been elusive is that most disorders are more similar than they are distinct, an idea that prompted research on "p"-the tendency of a person to develop a wide range of different mental disorders. Here we bring together data from unique sources to provide the intergenerational and developmental empirical evidence base for understanding "p." Men and women with a history of mental disorders tend to mate with partners who are also prone to have mental disorders, but not necessarily the same disorders. This creates a situation whereby their offspring, whether through genetic and/or environmental transmission, are at heightened risk of developing a variety of different mental disorders, but which specific disorder offspring ultimately develop is not easy to predict. Given that offspring inherit these multiple liabilities, it may not surprise that these liabilities manifest as different disorders at different points throughout their lives, but which disorder emerges at a particular time is difficult to foretell. The intergenerational and developmental evidence about the familiality and course of mental disorders helps to deconstruct "p" and invites psychopathology research and clinical science to reconsider their common approach to studying one mental disorder at a time. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Polygenic indexes (PGIs) - DNA-based predictors of individual phenotypes - have become essential tools across biomedical and social sciences. We introduce Version 2 of the Polygenic Index Repository, which expands phenotype coverage from 47 to 61, increases the number of participating datasets from 11 to 20, and adopts a more consistent and improved methodology for PGI construction. For 16 phenotypes, we leverage summary statistics from an updated GWAS meta-analysis with greater statistical power compared to the original release, thereby improving the PGI's predictive power. To improve power for family-based analyses, we provide imputed parental PGIs in all datasets with first-degree relatives and offer a framework for interpreting results from analyses that control for parental PGIs. We illustrate the utility of parental PGIs using two applications: (1) comparing PGI associations with and without parental PGI controls for all phenotypes in two Repository datasets with family data, and (2) for BMI and diastolic blood pressure, exploring the contribution of causal versus non-causal components of PGI associations to the imperfect portability of PGIs across subgroups within a genetic ancestry. Collectively, the updates enhance predictive performance, broaden the Repository's scope, and introduce novel resources that reduce confounding bias and improve interpretability.

INTRODUCTION:Cannabis is widely used and is becoming legal in many countries. Although some acute ocular effects of cannabis are well known (e.g., reduced intraocular pressure, vasodilation), little is known about the consequences of long-term cannabis use for ocular health. The aim of this study was to examine the association between persistent cannabis use across adulthood and measures of ocular health in midlife. METHODS:Participants were members of the Dunedin Study (N=1,037), a longitudinal cohort followed since birth. Cannabis use has been measured by self-report at every assessment from age 18 years to age 45 years. Ocular health data were collected as part of a larger assessment at age 45 years (2017-2019). Statistical analysis was performed in 2022. RESULTS:Cannabis use and ocular health data were obtained from 887 study members. Generalized estimating equation analysis showed that higher cannabis use was associated with poorer visual acuity, wider retinal arterioles and venules, and a thicker inferior hemifield of the ganglion cell-inner plexiform layer. However, when controlling for tobacco smoking and SES (known to be associated with these ocular health domains), the associations with visual acuity, arterioles, and venules were no longer significant. The association with ganglion cell-inner plexiform layer remained significant in this adjusted model. CONCLUSIONS:Persistent cannabis use appears to be neither harmful nor beneficial to the eye at age 45 years, although the thicker inferior ganglion cell-inner plexiform layer hemifield in users of cannabis suggests biologically plausible neuroprotection. Further assessments as this cohort ages will illuminate the relationship between persistent cannabis use and ocular neuroprotection.

Subclinical psychotic symptoms (also known as psychotic experiences comprising positive features only, and schizotypy comprising positive, negative, and disorganized features) are important markers of schizophrenia liability. Different assessment methods detect different sources of meaningful variance and are vulnerable to different biases and sources of measurement error. Whereas interview-rated psychotic symptoms in childhood are known to predict adult schizophrenia diagnosis, the predictive value of parent-rated psychotic symptoms remains unknown. We tested whether clinician-rated psychotic symptoms and parent-rated positive, negative, and disorganized schizotypy in early adolescence are nonredundant predictors of schizophrenia diagnosis by age 38 years. In a representative birth cohort (n = 1037) from Dunedin, New Zealand, psychotic symptoms were assessed by clinical interview at age 11 years, schizotypy was assessed by parent or caregiver ratings at ages 13- and 15 years, and lifetime schizophrenia diagnosis was assessed throughout adulthood until age 38 years. We tested for redundancy using bootstrapped multivariable logistic regression. Clinician-rated psychotic symptoms at age 11 predicted adult schizophrenia diagnosis (OR = 2.68, 95% CI = 1.42, 5.06), as did parent-rated total schizotypy (OR = 1.83, 95% CI = 1.42, 2.36). In univariable models, clinician-rated psychotic experiences and parent-rated positive, negative, and disorganized schizotypy were significant predictors of schizophrenia diagnosis. In multivariable models where clinician- and parent-rated scores were entered, only parent-rated negative and disorganized schizotypy did not predict adult schizophrenia diagnosis. Parent-rated schizotypy and clinician-rated subclinical psychotic symptoms are valid, nonredundant indicators of lifetime risk for schizophrenia.

INTRODUCTION:Although plasma pTau181 has been shown to accurately discriminate patients with Alzheimer's disease from healthy older adults, its utility as a preclinical biomarker in middle-aged community-based cohorts is unclear. METHODS:Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972-1973. Plasma pTau181, MRI-based brain structure, and DunedinPACE (an epigenetic biomarker of biological ageing) were measured at age 45; cognition was measured in childhood and age 45. RESULTS:We observed a wide range of pTau181 concentrations in our same-aged sample (n=856; M=13.6pg/mL, SD=9.1pg/mL). Males had significantly higher pTau181 concentrations than females. No statistically significant associations were observed with cognitive decline, lower structural brain integrity, or accelerated biological ageing. DISCUSSION:In this midlife cohort, wide variation in pTau181 concentrations was present by age 45, but was not associated with patterns of AD-risk in cognition, brain structure, or biological ageing.

Oral and mental health are integral to overall health and well-being. Primary dentition caries is associated with poorer oral and general health and faster aging by midlife, but it remains unclear whether these associations also hold for mental health. OBJECTIVES:To investigate whether primary dentition caries, caries experienced in adolescence and adulthood, and caries trajectories across the life course are associated with mental disorders in the fifth decade of life in two New Zealand birth cohorts. METHODS:Data on childhood caries and adult mental disorders were obtained from the Dunedin Multidisciplinary Health and Development Study and the Christchurch Health and Development Study. Generalized Linear Models (GLMs) were used to estimate associations between caries at age 5 and mental disorders at age 45/40 for Dunedin and Christchurch studies, respectively. Additional analyses using Dunedin Study data investigated associations between permanent dentition caries trajectories from ages 9 to 45 and mental disorders at age 45. All analyses adjusted for sex, perinatal health, childhood SES, childhood IQ, and adult personality. RESULTS:Primary dentition caries experience was not associated with mental disorders in midlife in either cohort. Dunedin Study participants who were in a less favorable permanent dentition caries trajectory had higher rates of mental disorders at age 45 than those in the low-caries trajectory. CONCLUSIONS:People who experience poor oral health across the life course are also those who suffer from poorer mental health in mid-adulthood. A lifelong trajectory of poorer dental health indicates poorer mental health and well-being in adult life.

Deviations from normative brain ageing trajectories are linked to a wide range of adverse health outcomes. A number of brain age prediction models have been developed, based on various neuroimaging modalities, machine learning algorithms, training samples, and age ranges. However, it remains unknown whether these models converge on a shared genetic liability, and whether capturing this shared signal could provide a more sensitive marker of brain health than any single model alone. We first conducted a new brain age gap (BAG) GWAS in a sample of 60,735 individuals across 29 cohorts worldwide, and then applied genomic structural equation modelling to examine the shared genetic variance between five prior BAG GWASs and our new analysis, using a single latent BAG factor (30 cohorts overall). All six BAG GWASs loaded onto a single factor, explaining 63% of the total genetic variance. We identified 19 independent SNPs associated with the BAG factor, including four novel associations. Genetically, the BAG factor was positively correlated with multiple traits, with blood pressure, smoking, longevity, autism, and sleep showing putatively causal effects. A polygenic score (PGS) for the BAG factor showed associations with phenotypic BAGs already in childhood, with stronger links observed in adulthood. Phenome-wide association analyses indicated that BAG factor PGS captured associations with more health traits than individual BAG PGSs. Our findings underscore the importance of considering the shared variance across different BAG constructs to identify robust correlates of poor brain health.

Although plasma pTau181 has been shown to accurately identify patients with AD in case-control studies, its utility as a preclinical biomarker in middle-aged community-based cohorts is unclear. Our objective was to investigate whether plasma pTau181 was associated with indicators of AD risk in a middle-aged cohort (aged 45 years). Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972-1973. Most recently, 94% of the living Study members were assessed at age 45 (2017-2019). Plasma pTau181 was measured using the Simoa SR-X analyser (Quanterix). MRI scans were conducted at the same timepoint. Cognitive ability was assessed at ages 7, 9, 11, and at age 45. Pace of ageing, a composite measure of 19 biomarkers of ageing, was determined from data collected at ages 32, 38, and 45. We observed a wide range of pTau181 levels in our same-aged sample ( n  = 856), from below the lower limit of detection to 147pg/ml (M=13.6pg/ml, SD=9.1). Excluding n<5 participants with chronic kidney disease, males had significantly higher pTau181 levels than females. No statistically significant associations were observed with cognitive measures, MRI-derived brain measurements, or composite ageing variables. The range of pTau181 levels observed suggests that blood biomarkers of AD may increase early in middle age, decades prior to any potential disease onset and possibly before any measurable cognitive decline or neurostructural abnormalities. Future assessment waves in the same cohort will elucidate whether plasma pTau181 in midlife is predictive of AD onset later in life.

OBJECTIVES:The Dunedin Multidisciplinary Health and Development Study provides a unique opportunity to document the progression of ear health and hearing ability within the same cohort of individuals from birth. This investigation draws on hearing data from 5 to 13 years and again at 45 years of age, to explore the associations between childhood hearing variables and hearing and listening ability at age 45. DESIGN:Multiple linear regression analyses were used to assess associations between childhood hearing (otological status and mid-frequency pure-tone average) and (a) age 45 peripheral hearing ability (mid-frequency pure-tone average and high-frequency pure-tone average), and (b) age 45 listening ability (listening in spatialized noise and subjective questionnaire on listening experiences). Sex, childhood socioeconomic status, and adult IQ were included in the model as covariates. RESULTS:Peripheral hearing and listening abilities at age 45 were consistently associated with childhood hearing acuity at mid-frequencies. Otological status was a moderate predicting factor for high-frequency hearing and utilization of spatial listening cues in adulthood. CONCLUSIONS:We aim to use these findings to develop a foundational model of hearing trajectories. This will form the basis for identifying precursors, to be investigated in a subsequent series of analyses, that may protect against or exacerbate hearing-associated cognitive decline in the Dunedin Study cohort as they progress from mid-life to older age.

Adversity that exhibits continuity across the life course has long-term detrimental effects on physical and mental health. Using 920 participants from the Dunedin Study, we tested the following hypotheses: (a) Children (ages 3–15) who experienced adversity would also tend to experience adversity in adulthood (ages 32–45), and (2) interim personality traits in young adulthood (ages 18–26) would help account for this longitudinal association. Children who experienced more adversity tended to also experience more stressful life events as adults, β = 0.11, 95% confidence interval [CI] = [0.04, 0.18], p = .002. Negative emotionality—particularly its subfacet alienation, characterized by mistrust of others—helped explain this childhood-to-midlife association (indirect effect: β = 0.06, 95% CI = [0.04, 0.09], p < .001). Results were robust to adjustment for sex, socioeconomic origins, childhood IQ, preschool temperament, and other young-adult personality traits. Prevention of early life adversity and treatment of young-adult negative emotionality may reduce vulnerability to later life stress and thereby promote the health of aging adults.