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Identifying genes underlying memory function will help characterize cognitively resilient and high‐risk declining subpopulations contributing to precision medicine strategies. We estimated episodic memory trajectories in 35,245 ethnically diverse older adults representing eight independent cohorts. We conducted apolipoprotein E (APOE)‐stratified genome‐wide association study (GWAS) analyses and combined individual cohorts' results via meta‐analysis. Three independent transcriptomics datasets were used to further interpret GWAS signals. We identified DCDC2 gene significantly associated with episodic memory (Pmeta = 3.3 x 10‐8) among non‐carriers of APOE ε4 (N = 24,941). Brain transcriptomics revealed an association between episodic memory maintenance and (1) increased dorsolateral prefrontal cortex DCDC2 expression (P = 3.8 x 10‐4) and (2) lower burden of pathological Alzheimer's disease (AD) hallmarks (paired helical fragment tau P =.003, and amyloid beta load P =.008). Additional transcriptomics results comparing AD and cognitively healthy brain samples showed a downregulation of DCDC2 levels in superior temporal gyrus (P =.007) and inferior frontal gyrus (P =.013). Our work identified DCDC2 gene as a novel predictor of memory maintenance. [ABSTRACT FROM AUTHOR]

Background: Understanding genetic modulation of episodic memory will yield insight into the biological mechanisms underlying normal cognitive aging and dementia. Genetic studies based on longitudinal measures of episodic memory are scarce, predominantly focused on candidate genes, and have interrogated common genetic variation. We aimed to identify common and rare genetic variation that may be responsible for uncharacterized genetic risk underlying individual differences in longitudinal performance on memory. Method: A sample of 24,769 elderly individuals was ascertained from eight independent cohorts (ADGC_NACC, NIA‐LOAD, ROSMAP, WHICAP, LLFS, CHAP, ADNI and UK Biobank). Data on study participants included socio‐demographic variables, longitudinal scores on episodic memory (2 to 15 follow‐up visits), clinical diagnosis of cognitive impairment and genome‐wide imputed genotyped data using the haplotype reference consortium for accurate imputation of low‐frequency genetic variants. The Latent Class Mixed Model was used to derive episodic memory trajectories within each of the study cohorts. The slope of residualized episodic memory scores was used as outcome in an APOE stratified (non‐APOE stratified, APOE_ε4 and APOE_nonε4 sub‐samples) genome‐wide gene‐based analyses. Common (minimum allele frequency, MAF, between 5%‐10%), rare (1% < MAF ≤ 5%) and ultra‐rare variants (≤1% MAF) were analyzed. Association results from each study cohort within each sub‐sample were meta‐analyzed. Result: Consistent with previous studies, the majority of the study participants maintain their memory performance over time (ranging from 51% to 98%). The strongest association signal for the episodic memory trajectories (p = 4.8 × 10−8) was achieved at chromosomal region 6p22 among in the APOE_nonε4 sub‐sample. Meta‐analysis results in the non‐APOE stratified and APOE_ε4 sub‐samples also yielded several chromosomal regions associated with memory performance over time, although significance level was diminished (p∼ 10−6). Conclusion: To our knowledge, this is the largest gene‐based GWAS meta‐analysis of high quality imputed common, rare and ultra‐rare variants influence on episodic memory performance over time. Identifying genes associated with progression of episodic memory performance over time in older adulthood provides the possibility of identifying at‐risk population subgroups that can benefit from possible interventions to enhance cognitive function. [ABSTRACT FROM AUTHOR]

Background: Understanding genetic modulation of memory will yield insight into the biological mechanisms underlying memory decline and dementia. The cognitive genetics field has largely focused on populations of European descent. Including genetically diverse populations, such as the Mexican population, the largest USA minority group, will increase our understanding of the genetic architecture of memory function. Method: The analysis sample consisted of 17,650 participants from the Mexican Health and Aging Study for whom socio‐demographic and longitudinal scores on episodic memory were available. Adjusted trajectories of memory performance were estimated using Latent Class Mixed Models. Genome‐wide gene‐based analyses were carried out in the sub‐sample of participants (n = 2,433) with imputed genotyped data (Haplotype Reference Consortium reference). The slope of episodic memory scores was used as the outcome in gene‐based analyses adjusted for sex, age, education, kinship matrix and principal components. Secondary analyses were restricted to participants with Native‐American ancestry (n = 1,842). Result: The majority of the participants (77%) clustered as Stables, those who maintained their memory performance over time. Compared to those classified within the Stable memory trajectory, the prevalence of dementia was higher among Decliners. Zinc metabolism appear to be essential for neurogenesis, and neural migration and dietary zinc deficiency has been associated with memory impairment. The Zinc Finger CCHC Domain‐Containing Protein 2 (ZCCHC2) gene yielded the strongest association (p = 4.1 × 10−5). A less strong association with ZCCHC2 was also observed (p = 0.003) in the Native‐American ancestry sub‐sample. However, among the Native‐American participants, a different gene yielded the strongest association (p = 1.3 × 10−4), the Intraflagellar Transport 74 (IFT74) gene. The gene is a member of the IFT complex implicated in the vesicular trafficking to axons and dendrites. Sequence variants in IFT74 have been linked to a form of amyotrophic lateral sclerosis accompanied by progressive cognitive impairment. Conclusion: Genetic variation influence longitudinal changes in episodic memory in a sample of Mexican population. Our results suggest that the indigenous Native American ancestry of Mexican population harbors novel and unique genetic variation underlying memory decline. Future work will include a larger sample (approximately 10,000 participants) and trans‐ethnic meta‐analysis with additional Caribbean‐Hispanics, African‐Americans and non‐Hispanic Whites cohorts. [ABSTRACT FROM AUTHOR]

Background: Genetic studies of Alzheimer's disease (AD) have focused on the clinical or pathological diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease. Our goal was to identify the underlying genetic bases for brain amyloidosis during the preclinical phase of AD. Method: We performed genome‐wide association studies of positron emission tomography (PET) amyloid levels and meta‐analyzed the results. Genetic and imaging data were acquired from ten cohorts of primarily non‐demented individuals. The largest cohort, the A4 study (n = 3,154) was a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. The other, smaller longitudinal cohort studies, similar in design, provided additional amyloid PET data with existing genetic data (n = 1,160 analyzed and n = 550 currently being analyzed). Result: We identified a locus for amyloidosis within RBFOX1 in addition to APOE along with several loci nearing significance. Conclusion: Multiple genetic loci may be associated with brain amyloidosis. Further research into these specific loci and genes will help in our understanding of the molecular bases of amyloid buildup in the brain. [ABSTRACT FROM AUTHOR]

Background: Sleep is implicated in cognitive functioning in young adults, while healthy older adults do not always demonstrate clear associations between sleep and cognitive functioning. Age‐related changes in sleep include a reduction in total sleep time and a greater incidence of sleep disorders, and are also an integral part of neurodegenerations. In the present study, we aimed to: a) identify common genetic variants that may influence self‐reported sleep duration, and b) examine the association between the identified genetic variants and performance in different cognitive domains. Method: A sample of 197 cognitively healthy participants, aged 20‐80 years, were selected from two study cohorts: The Reference Abilities Neural Network and the Cognitive Reserve. Each participant underwent an evaluation of sleep function and assessment of neuropsychological performance on four different domains (memory, speed of processing, fluid reasoning, language), and global cognition. Available imputed genome‐wide genotyped data was used to derive a Polygenic Risk Score (PRS) based on 69 genetic variants previously reported as associated with sleep duration. Multivariate linear models were used to test the associations between the PRS and sleep duration and cognitive performance. Age, sex, and education were used as covariates. Result: Higher PRS was linked to longer sleep duration and then, lower risk of poor performance in global cognition, fluid reasoning, speed of processing, and language, but was not associated with memory. Conclusion: We replicated the association between PRS and longer sleep duration. We additionally found a significant association between the PRS and cognitive function. Our results suggest that common genetic variants influence the link between sleep duration and cognitive health. Sleep duration may represent a potential causal pathway for cognition, and, thus, improving sleep habits might be as useful as a potential therapeutic target to improve cognitive performance. Funding: National Institute of Health (NIH)/ National Institute of Aging (NIA) [Grant numbers: R01 AG026158 and RF1 AG038465], and the Bodossakis foundation. [ABSTRACT FROM AUTHOR]