INTRODUCTION
Although large‐scale genome‐wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline.
METHODS
We ...conducted a cross‐ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts.
RESULTS
We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non‐Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene‐level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD‐related traits, neuropsychiatric traits, and autoimmune traits.
DISCUSSION
We discovered several novel loci, genes, and genetic correlations associated with late‐life memory performance and decline.
Highlights
Late‐life memory has high heritability that is similar across ancestries.
We discovered four novel variants associated with late‐life memory.
We identified four novel genes associated with late‐life memory.
Late‐life memory shares genetic architecture with psychiatric/autoimmune traits.
BACKGROUND
Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory ...performance remain unclear.
METHODS
We conducted the largest sex‐aware genetic study on late‐life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex‐stratified and sex‐interaction genome‐wide association studies in 24,216 non‐Hispanic White and 3367 non‐Hispanic Black participants.
RESULTS
We identified three sex‐specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ‐SCHIP), including an X‐chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex‐specific pathway and found sex‐specific genetic correlations between memory and cardiovascular, immune, and education traits.
DISCUSSION
This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex‐specific genes, pathways, and genetic correlations that related to late‐life memory.
Highlights
Demonstrated the heritable component of late‐life memory is similar across sexes.
Identified two genetic loci with a sex‐interaction with baseline memory.
Identified an X‐chromosome locus associated with memory decline in females.
Highlighted sex‐specific candidate genes and pathways associated with memory.
Revealed sex‐specific shared genetic architecture between memory and complex traits.
Background
Two‐thirds of Alzheimer’s disease (AD) patients are women and there are well‐established sex differences in the association between APOE and cognitive impairment in AD. However, it is not ...clear whether sex‐specific cognitive consequences of APOE emerge across all cognitive domains or in a domain‐specific manner.
Method
Data were obtained from 38,386 participants in four longitudinal studies of aging and AD. The average age of participants at baseline was 75±8 years (10% AD, 42% male, 12% African American AA, 12% APOE‐ε2 carriers, and 36% APOE‐ε4 carriers). Based on detailed neuropsychological exams, harmonized composite scores for memory, executive function, and language were generated using latent variable modeling. Linear regression assessed APOE*sex interactions on each baseline cognitive domain score. Mixed‐effects regression models assessed sex interactions with APOE on cognitive trajectories, including fixed and random effects for both the intercept and the slope (years from baseline). All models adjusted for age at baseline, sex, and race/ethnicity. Exploratory analyses of the potential effect of race/ethnicity were also performed using an APOE*sex*race interaction term in the model.
Result
As expected, APOE‐ε4 was associated with worse cognitive performance, and APOE‐ε2 was associated with better performance in all domains, both at baseline and longitudinally (p<0.001). At baseline, we observed a significant sex*APOE‐ε4 interaction on memory (β=‐0.06, p<0.001) and significant sex*APOE‐ε2 interaction on memory (β=0.05, p=0.03). In both cases, the association between APOE and memory was significantly stronger in females compared to males. Notably, despite the large sample size, no interactions were observed in the two other cognitive domains or in the longitudinal analysis. Additionally, we observed a significant interaction between sex*APOE‐ε2*race on baseline memory (β=‐0.19, p=0.02), whereby the APOE‐ε2*sex interaction was significant in non‐Hispanic whites (β=0.06, p<0.01) but not in AA (β=‐0.11, p=0.10).
Conclusion
We provide new evidence that the sex difference in APOE in cognition is most pronounced in relation to memory performance and is particularly driven by differences in baseline performance rather than trajectories of performance over time. Future work will examine intersections with clinical diagnosis to better differentiate sex differences in APOE associations in the context of normal aging and neurodegenerative disease.
Background
We completed a large genetic analysis of resilience to cognitive decline in Alzheimer’s Disease (AD) and discovered novel variants, genes, and complex traits associated with better‐than or ...worse‐than‐expected cognitive performance given an individual’s age, sex, and APOE genotype.
Method
Leveraging 15,933 non‐Hispanic white participants across four longitudinal cohort studies of aging and AD (Figure 1), our group determined the effects of genetic variants on resilience metrics using mixed‐effects regressions. Models adjusted for age, sex, APOE ε4 allele count, presence of the APOE ε2 allele and all covariate interactions with interval (years from baseline). The outcomes of interest were residual cognitive resilience, quantified from residuals in three cognitive domains (memory, executive function, and language), and combined resilience, summarized as the covariance of educational attainment with residual cognitive resilience. Post‐GWAS analyses included gene tests using MAGMA and estimates of genetic correlation with 65 complex traits using GNOVA.
Result
We observed genome‐wide significant associations at multiple established AD loci, including BIN1 and CR1 (Figure 2). We observed a novel association with combined resilience on chromosome 13 (top SNP: rs11838654, MAF = 0.06, P = 4.7×10−8; Figure 3) and a novel signal on chromosome 1 approaching significance (top SNP: rs2817183, MAF = 0.41, P = 5.1×10−8). Interestingly, rs11838654 is an eQTL for four genes in hippocampus (WBP4, COG6, MRPS31, and NHLRC3I; Braineac database). We also observed an association with residual cognitive resilience on chromosome 5 that approached genome‐wide significance (top SNP: rs4482935, MAF = 0.25, P = 5.5×10−8; Figure 2). Gene‐level tests identified associations of CD2AP (P.fdr = 0.027) and ZNF146 (P.fdr = 0.049) with residual cognitive resilience and combined resilience, respectively. Additionally, we identified negative genetic correlations of combined resilience with ischemic stroke and coronary artery disease (all P.fdr<2.5×10−2; Figure 4).
Conclusion
Compared to models of resilience that regress out the effects of AD neuropathology on cognition, the present models benefit from larger sample size at the cost of molecular precision. Although the genetic architecture of resilience from these less precise models more closely resembles that of clinical AD, we uncovered novel genetic drivers of resilience through this approach. Such findings will require future replication but suggest a trajectory‐based definition of resilience holds substantial promise for discovery.
Background
Alzheimer’s disease (AD) is more prevalent in women than men, and robust evidence shows sex differences in the biological response to the AD neuropathological cascade. However, there is a ...lack of large‐scale genetic studies on sex‐specific genetic predictors of AD‐related cognitive outcomes. Thus, we sought to elucidate the sex‐specific genetic etiology of memory, executive function, and language performance.
Method
This study included six cohorts of cognitive aging (Nmales=7,267, Nfemales=9,518). We applied psychometric approaches to build harmonized memory, executive function, and language composite scores. Next, for all domains, we calculated slopes from the cognitive scores (two or more timepoints) with linear mixed effects models. Then we performed sex‐stratified and sex‐interaction GWAS on these phenotypes, covarying for baseline age and the first three genetic principal components. We meta‐analyzed across cohorts with a fixed‐effects model. Sensitivity analyses for all models restricted the sample to cognitively unimpaired individuals.
Result
In addition to well‐established associations with cognition at the APOE locus, we identified three genetic loci that showed sex‐specific effects with cognition. A chromosome 16 locus (rs114106271), a splicing‐quantitative trait locus for RP11‐152O14.4 and LINC02180 in the testis (GTEx), associated with baseline memory performance in men (β=0.13, P=2.40×10‐8; PInteraction=8.96×10‐6; Figures 1‐2) but not in women (β=‐0.01, P=0.76). A chromosome 14 locus (rs34074573), an expression‐quantitative trait locus (GTEx) for HOMEZ (a homeobox gene), and for BCL2L2 (a previously reported AD risk gene), associated with longitudinal memory performance in men (β=‐0.01, P=4.15×10‐8; PInteraction=5.83×10‐7; Figures 3‐4) but not in women (β=0.001, P=0.09). Finally, a chromosome 6 locus (rs9382966) associated with longitudinal language performance in men with near genome‐wide significance (β=‐0.004, P=6.29×10‐8; PInteraction=2.01×10‐4) but not in women (β=‐0.0003, P=0.61).
Conclusion
Our results highlight some key sex differences in the genetic architecture of cognitive outcomes. Findings further suggest that some sex‐specific genetic predictors have domain‐specific associations, providing an exciting opportunity to better understand the molecular basis of memory, executive function, and language through genomic analysis. Although our findings need to be replicated, our GWAS analyses highlight the contribution of sex‐specific genetic predictors beyond the APOE locus in conferring risk for late‐life cognitive decline.
More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring ...associations with AD-related endophenotypes.
We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software.
Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10
). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10
) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10
). GRN (rs5848, P = 4.21 × 10
) and PURG (rs117523305, P = 1.73 × 10
) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10
) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10
) and PTPRD (rs145989094, P = 8.34 × 10
) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10
) and PTPRD (rs145989094, P = 3.85 × 10
) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD.
Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.
Kenya is one of the main producers of tomato within Africa south of the Sahara, with an estimated market value of USD 237 million as of 2012, most of which was produced for the national market ...(Sibomana et al., 2016). Within Laikipia, the total value of tomato production was estimated as 148.5 million KSh in 2014 (Ministry of Agriculture). Due to their softness and perishability, tomatoes have significant potential for both quality and quantity losses postharvest.
PARI’s main goal is to contribute to sustainable agricultural growth and food security in Africa and India by supporting the scaling of proven innovations in the agri-food sector in collaboration ...with all relevant actors. PARI accompanies specified innovations with ex-ante impact research and identifies further innovation opportunities, including those expressed by end users of research in collaboration with the multi-stakeholder innovation platforms. Within PARI’s work, AGRODEP and IFPRI have the task of assisting in the development of a methodology and concept for strategic analysis and visioning by providing economic modelling tools to help understand where the best opportunities for innovation investments in value chains are. For this purpose, IFPRI has constructed agricultural typologies of micro-regions for 8 of the 12 African countries in PARI to identify micro-regional level opportunities, bottlenecks and investment gaps based on the concept of the production possibilities frontier applied to farm activities, drawing on highly detailed household-level survey and geospatial data on agroecological conditions, accessibility and poverty. The stochastic frontier approach allows the econometric exploration of the notion that, given the fixed local agroecological and economic conditions in a micro-region and the occurrence of random shocks that affect agricultural production (weather, prices, etc.), the investment, production decisions and technological innovations a farmer makes translate into higher or lower production and income. In such a context, inefficiency is defined as the loss incurred in by operating away from the frontier given the current prices and fixed factors faced by the household. By estimating where the frontier lies, and how far each producer is from it, the stochastic frontier approach helps to identify local potential and efficiency levels to construct the typology. With this estimation approach estimates are obtained that allow for the prediction and extrapolation of agricultural income potential and efficiency measures at the regional level, which can then be grouped and classified into types to construct the typology. The typology then allows the identification of types of regions with extremely different needs, bottlenecks and opportunities, which in turn will result in a different set of investment recommendations for development in each type of region, including decisions regarding investments in agricultural innovation.
PARI's main goal is to contribute to sustainable agricultural growth and food security in Africa and India by supporting the scaling of proven innovations in the agri-food sector in collaboration ...with all relevant actors. PARI accompanies specified innovations with ex-ante impact research and identifies further innovation opportunities, including those expressed by end users of research in collaboration with the multi-stakeholder innovation platforms. Within PARI's work, AGRODEP and IFPRI have the task of assisting in the development of a methodology and concept for strategic analysis and visioning by providing economic modelling tools to help understand where the best opportunities for innovation investments in value chains are. For this purpose, IFPRI has constructed agricultural typologies of micro-regions for 8 of the 12 African countries in PARI to identify micro-regional level opportunities, bottlenecks and investment gaps based on the concept of the production possibilities frontier applied to farm activities, drawing on highly detailed household-level survey and geospatial data on agroecological conditions, accessibility and poverty. The stochastic frontier approach allows the econometric exploration of the notion that, given the fixed local agroecological and economic conditions in a micro-region and the occurrence of random shocks that affect agricultural production (weather, prices, etc.), the investment, production decisions and technological innovations a farmer makes translate into higher or lower production and income. In such a context, inefficiency is defined as the loss incurred in by operating away from the frontier given the current prices and fixed factors faced by the household. By estimating where the frontier lies, and how far each producer is from it, the stochastic frontier approach helps to identify local potential and efficiency levels to construct the typology. With this estimation approach estimates are obtained that allow for the pred
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