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  • 1
    In: JAMA Neurology, American Medical Association (AMA), Vol. 79, No. 10 ( 2022-10-01), p. 975-
    Abstract: National Institute on Aging–Alzheimer’s Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD). Objective To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD. Design, Setting, and Participants This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years. Exposures Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T−, A−T+, A−T−). Presence (+) or absence (−) of neurodegeneration (N) was assessed using temporal cortical thickness. Main Outcomes and Measures Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups. Results Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable. Conclusions and Relevance The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
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  • 2
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 314, No. 5801 ( 2006-11-10), p. 941-952
    Abstract: We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus , a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    RVK:
    RVK:
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2006
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 3
    In: NeuroImage, Elsevier BV, Vol. 58, No. 3 ( 2011-10), p. 732-740
    Type of Medium: Online Resource
    ISSN: 1053-8119
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
    detail.hit.zdb_id: 1471418-8
    SSG: 5,2
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  • 4
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 7 ( 2022-07-29), p. 2541-2554
    Abstract: Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer’s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer’s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer’s disease. It is well established that there are sex differences in response to Alzheimer’s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20–25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15–44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10−09, β (males) = −0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10−04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer’s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer’s disease may be personalized based on their biological sex and genetic context.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 5
    In: Neurobiology of Aging, Elsevier BV, Vol. 83 ( 2019-11), p. 95-104
    Type of Medium: Online Resource
    ISSN: 0197-4580
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 1498414-3
    SSG: 12
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  • 6
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S3 ( 2022-12)
    Abstract: 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 (N males =7,267, N females =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; P Interaction =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; P Interaction =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; P Interaction =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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 7
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 8
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S2 ( 2020-12)
    Abstract: Identifying genetic factors that provide resilience against the clinical consequences of Alzheimer’s disease (AD) pathology is likely to accelerate the development of novel therapeutics. Sex differences in AD prevalence, neuropathological presentation, and clinical progression suggest that exploring the sex‐specific genetic architecture of resilience to AD may be a critical first step towards the characterization and development of precision interventions. Method We completed sex‐stratified and sex‐interaction genome‐wide association studies (GWAS) of resilience across 5,109 non‐Hispanic white individuals from two autopsy cohorts (ACT and ROS/MAP) and two positron emission tomography (PET) cohorts (ADNI and A4). A continuous measure of resilience was quantified using latent variable modeling and represented better‐than‐expected cognition for the given level of amyloid in the brain. The final dataset included 2,130 males (77 ± 9 years) and 2,979 females (77 ± 10 years), the majority of whom were cognitively normal (73% of males; 76% of females). GWAS of resilience were performed in the combined autopsy dataset and combined PET dataset individually and then meta‐analyzed. Covariates included age and three principal components. Analyses were run in all individuals as well as in the subset of cognitively normal individuals. Result An intergenic variant on chromosome 10 (rs827389, MAF = 0.46) showed a female‐specific genome‐wide significant association with resilience in cognitively normal females (β = 0.08, p = 7.6 × 10 −9 ) but not in males (β = ‐5.3 × 10 ‐3 , p = 0.77; sex interaction p = 1.4 × 10 −4 ). This variant is a modest brain eQTL for the KIN gene that is implicated in DNA repair. We also observed a strong sex‐interaction effect among all individuals on chromosome 3 (rs113968105, MAF = 0.10, p = 7.5 × 10 −8 ), in which the minor allele was associated with higher resilience in males (β = 0.10, p = 4.2 × 10 −7 ) but lower resilience in females (β = ‐0.04, p = 0.03). This variant is an eQTL for three genes, including the acetylcholinesterase binding gene COLQ . Conclusion We identified two putative sex‐specific loci that provide protection against the downstream consequences of amyloid pathology. The associations implicate DNA damage repair genes among females, and acetylcholinesterase genes in males, suggesting the pathways providing neuroprotection may differ by sex.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2201940-6
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  • 9
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S3 ( 2022-12)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 10
    In: Frontiers in Aging Neuroscience, Frontiers Media SA, Vol. 13 ( 2022-1-13)
    Abstract: Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline. Materials and Methods: N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample ( n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging ( n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed & gt;0.10 SD annual decline on the PACC-5. Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p & lt; 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p & lt; 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden ( r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex ( r = −0.38, 95% CI [−0.54 – −0.19], p & lt; 0.001) and inferior-temporal lobe ( r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 ( p & lt; 0.001) and baseline PACC-5 scores ( p = 0.02). Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.
    Type of Medium: Online Resource
    ISSN: 1663-4365
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2558898-9
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