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How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56–66 (n = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for <1% of the variance in cognitive outcomes. The impact of these other factors likely reflects reverse causation—namely, downstream effects of early adult GCA. Supporting that idea, age 20 GCA, but not education, was associated with late midlife cortical surface area (n = 367). In our view, the most parsimonious explanation of our results, a meta-analysis of the impact of education, and epidemiologic studies of the Flynn effect is that intellectual capacity gains due to education plateau in late adolescence/early adulthood. Longitudinal studies with multiple cognitive assessments before completion of education would be needed to confirm this speculation. If cognitive gains reach an asymptote by early adulthood, then strengthening cognitive reserve and reducing later-life cognitive decline and dementia risk may really begin with improving educational quality and access in childhood and adolescence.

There is a growing realization that early life influences have lasting impact on brain function and structure. Recent research has demonstrated that genetic relationships in adults can be used to parcellate the cortex into regions of maximal shared genetic influence, and a major hypothesis is that genetically programmed neurodevelopmental events cause a lasting impact on the organization of the cerebral cortex observable decades later. Here we tested how developmental and lifespan changes in cortical thickness fit the underlying genetic organizational principles of cortical thickness in a longitudinal sample of 974 participants between 4.1 and 88.5 y of age with a total of 1,633 scans, including 773 scans from children below 12 y. Genetic clustering of cortical thickness was based on an independent dataset of 406 adult twins. Developmental and adult age-related changes in cortical thickness followed closely the genetic organization of the cerebral cortex, with change rates varying as a function of genetic similarity between regions. Cortical regions with overlapping genetic architecture showed correlated developmental and adult age change trajectories and vice versa for regions with low genetic overlap. Thus, effects of genes on regional variations in cortical thickness in middle age can be traced to regional differences in neurodevelopmental change rates and extrapolated to further adult aging-related cortical thinning. This finding suggests that genetic factors contribute to cortical changes through life and calls for a lifespan perspective in research aimed at identifying the genetic and environmental determinants of cortical development and aging.

While genome wide association studies (GWASs) of Alzheimer’s Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer’s disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia ( n  = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer’s Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE ( p  = 2.48 × 10 − 101 ), in ROBO1 (rs11919682, p  = 1.63 × 10 − 8 ), and RNA RP11-340A13.2 (rs148433063, p  = 8.56 × 10 − 9 ). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p  = 2.95 × 10 − 9 ), CD2AP (rs7738720, p  = 1.14 × 10 −9 ), and ABCA7 (rs73505251, p  = 3.26 × 10 −10 ), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine ( CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4 , and TREM2 ) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non- APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

Women show greater pathological Tau biomarkers than men along the Alzheimer’s disease (AD) continuum, particularly among apolipoprotein ε-E4 (APOE4) carriers; however, the reason for this sex difference in unknown. Sex differences often indicate an underlying role of sex hormones. We examined whether testosterone levels might influence this sex difference and the modifying role of APOE4 status. Analyses included 172 participants (25 cognitively normal, 97 mild cognitive impairment, 50 AD participants) from the Alzheimer’s Disease Neuroimaging Initiative (34% female, 54% APOE4 carriers, aged 55–90). We examined the separate and interactive effects of plasma testosterone levels and APOE4 on cerebrospinal fluid phosphorylated-tau181 (p-Tau) levels in the overall sample and the sex difference in p-Tau levels before and after adjusting for testosterone. A significant APOE4-by-testosterone interaction revealed that lower testosterone levels related to higher p-Tau levels among APOE4 carriers regardless of sex. As expected, women had higher p-Tau levels than men among APOE4 carriers only, yet this difference was eliminated upon adjustment for testosterone. Results suggest that testosterone is protective against p-Tau particularly among APOE4 carriers. The lower testosterone levels that typically characterize women may predispose them to pathological Tau, particularly among female APOE4 carriers.

Animal data show that cortical development is initially patterned by genetic gradients largely along three orthogonal axes. We previously reported differences in genetic influences on cortical surface area along an anterior-posterior axis using neuroimaging data of adult human twins. Here, we demonstrate differences in genetic influences on cortical thickness along a dorsal-ventral axis in the same cohort. The phenomenon of orthogonal gradations in cortical organization evident in different structural and functional properties may originate from genetic gradients. Another emerging theme of cortical patterning is that patterns of genetic influences recapitulate the spatial topography of the cortex within hemispheres. The genetic patterning of both cortical thickness and surface area corresponds to cortical functional specializations. Intriguingly, in contrast to broad similarities in genetic patterning, two sets of analyses distinguish cortical thickness and surface area genetically. First, genetic contributions to cortical thickness and surface area are largely distinct; there is very little genetic correlation (i.e., shared genetic influences) between them. Second, organizing principles among genetically defined regions differ between thickness and surface area. Examining the structure of the genetic similarity matrix among clusters revealed that, whereas surface area clusters showed great genetic proximity with clusters from the same lobe, thickness clusters appear to have close genetic relatedness with clusters that have similar maturational timing. The discrepancies are in line with evidence that the two traits follow different mechanisms in neurodevelopment. Our findings highlight the complexity of genetic influences on cortical morphology and provide a glimpse into emerging principles of genetic organization of the cortex.

Surface area of the cerebral cortex is a highly heritable trait, yet little is known about genetic influences on regional cortical differentiation in humans. Using a data-driven, fuzzy clustering technique with magnetic resonance imaging data from 406 twins, we parceled cortical surface area into genetic subdivisions, creating a human brain atlas based solely on genetically informative data. Boundaries of the genetic divisions corresponded largely to meaningful structural and functional regions; however, the divisions represented previously undescribed phenotypes different from conventional (non-genetically based) parcellation systems. The genetic organization of cortical area was hierarchical, modular, and predominantly bilaterally symmetric across hemispheres. We also found that the results were consistent with human-specific regions being subdivisions of previously described, genetically based lobar regionalization patterns.

Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems. The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse ('baseline') and the longitudinal Vietnam Era Twin Study of Aging ('follow-up'). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)]. Total depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07-1.57), erectile dysfunction (OR 1.32, 95% CI 1.10-1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04-1.53), and sleep apnea (OR 1.40, 95% CI 1.13-1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09-1.60). A history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.

Given the various roles of testosterone in men’s health, we conducted a multi-ancestral genetic analysis of total testosterone, free testosterone, SHBG, and hypogonadism in men within the Million Veteran Program (MVP). Here we identified 157 significant testosterone genetic variants, of which 8 have significant ancestry-specific associations. These variants implicate several genes, including SERPINF2 , PRPF8 , BAIAP2L1 , SHBG , PRMT6 , and PPIF , related to liver function. Genetic regulators of testosterone have cell type-specific effects in the testes, liver, and adrenal gland and are associated with disease risk. We conducted a meta-analysis amongst ancestry groups to identify 188 variants significantly associated with testosterone, of which 22 are novel associations. We constructed genetic scores for total testosterone, SHBG levels, and hypogonadism and find that men with higher testosterone genetic scores have lower odds of diabetes, hyperlipidemia, gout, and cardiac disorders. These findings provide insight into androgen regulation and identify novel variants for disease risk stratification. Here, the authors perform a genome-wide association study to identify 157 significant testosterone genetic variants in male veterans, of which 8 are ancestry-specific. Men with higher testosterone genetic scores have lower odds of diabetes, hyperlipidemia, gout, and cardiac disorders.

Background Past research suggests that low testosterone levels relate to poorer cognitive function and higher Alzheimer’s disease (AD) risk; however, these findings are inconsistent and are mostly derived from male samples, despite similar age-related testosterone decline in females. Both animal and human studies demonstrate that testosterone’s effects on brain health may be moderated by apolipoprotein E ε4 allele ( APOE -ε4) carrier status, which may explain some previous inconsistencies. We examined how testosterone relates to cognitive function in older women versus men across healthy aging and the AD continuum and the moderating role of APOE -ε4 genotype. Methods Five hundred and sixty one participants aged 55–90 (155 cognitively normal (CN), 294 mild cognitive impairment (MCI), 112 AD dementia) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), who had baseline cognitive and plasma testosterone data, as measured by the Rules Based Medicine Human DiscoveryMAP Panel were included. There were 213 females and 348 males (self-reported sex assigned at birth), and 52% of the overall sample were APOE -ε4 carriers. We tested the relationship of plasma testosterone levels and its interaction with APOE -ε4 status on clinical diagnostic group (CN vs. MCI vs. AD), global, and domain-specific cognitive performance using ANOVAs and linear regression models in sex-stratified samples. Cognitive domains included verbal memory, executive function, processing speed, and language. Results We did not observe a significant difference in testosterone levels between clinical diagnostic groups in either sex, regrardless of APOE -ε4 status. Across clinical diagnostic group, we found a significant testosterone by APOE -ε4 interaction in females, such that lower testosterone levels related to worse global cognition, processing speed, and verbal memory in APOE -ε4 carriers only. We did not find that testosterone, nor its interaction with APOE -ε4, related to cognitive outcomes in males. Conclusions Findings suggest that low testosterone levels in older female APOE -ε4 carriers across the aging-MCI-AD continuum may have deleterious, domain-specific effects on cognitive performance. Although future studies including additional sex hormones and longitudinal cognitive trajectories are needed, our results highlight the importance of including both sexes and considering APOE -ε4 carrier status when examining testosterone’s role in cognitive health. Highlights We investigated the relationship between testosterone levels and cognitive function in women and men across the Alzheimer’s dementia continuum and the modifying role of the APOE -ε4 allele. A significant testosterone by APOE -ε4 interaction indicated that lower plasma testosterone levels related to worse global and domain-specific cognition, for verbal memory and processing speed, in female APOE -ε4 carriers only. Plasma testosterone levels did not relate to global or domain-specific cognition in males, regardless of APOE -ε4 status. While most studies examine the testosterone and brain health connection in men, our findings suggest that it is equally important, if not more, to examine this connection in women and to account for APOE -ε4 status. Upon replication, our findings suggest the potential for low testosterone levels as a modifiable risk factor in which intervention approaches can be optimized for each sex. Plain English summary Sex differences often suggest a role of sex hormones, and in Alzheimer’s Disease (AD) research, women show higher disease prevalence, accelerated cognitive decline, and an enhanced effect of the strongest genetic risk factor for AD, the apolipoprotein E ε4 allele ( APOE -ε4). Testosterone, largely regarded as a “male” sex hormone, has demonstrated protective effects against AD in rodent studies including both sexes. However, human research often only includes males, limiting our understanding of testosterone's effect on AD risk and cognitive function. In this study, we investigated whether testosterone levels in the blood relate to cognitive performance measuring overall (global) cognition, verbal memory (remembering word lists or stories), executive function (complex thinking/multitasking), processing speed (how quickly one completes thinking tasks), and language (naming objects) in both sexes. We also tested whether this relationship is influenced by the APOE -ε4 genetic risk factor. We found that in females carrying APOE -ε4, lower testosterone levels related to worse performance on global cognition, processing speed, and verbal memory tests; however, testosterone levels did not relate to cognitive performance on any test in males nor in females without the APOE -ε4 genetic risk factor. Our findings suggest that the lower testosterone levels may be a contributing factor to worse AD outcomes in women, particularly for those at higher genetic risk for AD. Our results also demonstrate the importance of including female participants and considering the APOE -ε4 genetic risk factor when studying testosterone and brain health.

Background Blood-based neurofilament light chain (NfL) is a promising biomarker of neurodegeneration across multiple neurodegenerative diseases. However, blood-based NfL is highly associated with renal function in older adults, which leads to the concern that blood-based NfL levels may be influenced by renal function, rather than neurodegeneration alone. Despite growing interest in using blood-based NfL as a biomarker of neurodegeneration in research and clinical practices, whether renal function should always be accounted for in these settings remains unclear. Moreover, the mechanisms underlying this association between blood-based measures of NfL and renal function remain elusive. In this study, we first evaluated the effect of renal function on the associations of plasma NfL with other measures of neurodegeneration. We then examined the extent of genetic and environmental contributions to the association between plasma NfL and renal function. Methods In a sample of 393 adults (mean age=75.22 years, range=54–90), we examined the associations of plasma NfL with cerebrospinal fluid (CSF) NfL and brain volumetric measures before and after adjusting for levels of serum creatinine (an index of renal function). In an independent sample of 969 men (mean age=67.57 years, range=61–73) that include monozygotic and dizygotic twin pairs, we replicated the same analyses and leveraged biometrical twin modeling to examine the genetic and environmental influences on the plasma NfL and creatinine association. Results Plasma NfL’s associations with cerebrospinal fluid NfL and brain volumetric measures did not meaningfully change after adjusting for creatinine levels. Both plasma NfL and creatinine were significantly heritable ( h 2 =0.54 and 0.60, respectively). Their phenotypic correlation ( r =0.38) was moderately explained by shared genetic influences (genetic correlation=0.46) and unique environmental influences (unique environmental correlation=0.27). Conclusions Adjusting for renal function is unnecessary when assessing associations between plasma NfL and other measures of neurodegeneration but is necessary if plasma NfL is compared to a cutoff for classifying neurodegeneration-positive versus neurodegeneration-negative individuals. Blood-based measures of NfL and renal function are heritable and share common genetic influences.