Browsing by Author "Hedden, Trey"

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    Genetic variants and functional pathways associated with resilience to Alzheimer’s disease
    (Oxford, 2020-08-25) Dumitrescu, Logan; Mahoney, Emily R; Mukherjee, Shubhabrata; Lee, Michael L; Bush, William S; Engelman, Corinne D; Lu, Qiongshi; Fardo, David W; Trittschuh, Emily H; Mez, Jesse; Kaczorowski, Catherine; Hernandez Saucedo, Hector; Widaman, Keith F; Buckley, Rachel; Properzi, Michael; Mormino, Elizabeth; Yang, Hyun-Sik; Harrison, Tessa; Hedden, Trey; Nho, Kwangsik; Andrews, Shea J; Tommet, Doug; Hadad, Niran; Sanders, R Elizabeth; Ruderfer, Douglas M; Gifford, Katherine A; Moore, Annah M; Cambronero, Francis; Zhong, Xiaoyuan; Raghavan, Neha S.; Vardarajan, Badri; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Cruchaga, Carlos; Schellenberg, Gerard; Cox, Nancy J.; Haines, Jonathan L,; Keene, C. Dirk; Saykin, Andrew J.; Larson, Eric B.; Sperling, Reisa A.; Mayeux, Richard; Bennett, David A.; Schneider, Julie A.; Crane, Paul K.; Jefferson, Angela L.; Hohman, Timothy J.; Radiology and Imaging Sciences, School of Medicine
    Approximately 30% of older adults exhibit the neuropathological features of Alzheimer’s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer’s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10−20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10−4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer’s disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10−8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10−13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer’s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.
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    Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing
    (Oxford University Press, 2018-05-01) Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith A.; Hedden, Trey; Jaimes, Sehily; Benzinger, Tammie L S.; Jack, Clifford; Ances, Beau M.; Ringman, John M.; Marcus, Daniel S.; Ghetti, Bernardino; Farlow, Martin R.; Danek, Adrian; Levin, Johannes; Yakushev, Igor; Laske, Christoph; Koeppe, Robert A.; Galasko, Douglas R.; Xiong, Chengjie; Masters, Colin L.; Schofield, Peter R.; Kinnunen, Kirsi M.; Salloway, Stephen; Martins, Ralph N.; McDade, Eric; Cairns, Nigel J.; Buckles, Virginia D.; Morris, John C.; Bateman, Randall; Sperling, Reisa A.; Pathology and Laboratory Medicine, School of Medicine
    Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer's disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer's disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer's disease from the Dominantly Inherited Alzheimer's Network (DIAN), an Alzheimer's disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer's disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer's disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer's disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer's disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer's disease pathology (preclinical Alzheimer's disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer's disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer's disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimer's disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimer's disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimer's disease and ageing add to prior work arguing against Alzheimer's disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimer's disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimer's disease pathology within targeted neural networks.
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    Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease
    (Oxford University Press, 2022) Eissman, Jaclyn M.; Dumitrescu, Logan; Mahoney, Emily R.; Smith, Alexandra N.; Mukherjee, Shubhabrata; Lee, Michael L.; Scollard, Phoebe; Choi, Seo Eun; Bush, William S.; Engelman, Corinne D.; Lu, Qiongshi; Fardo, David W.; Trittschuh, Emily H.; Mez, Jesse; Kaczorowski, Catherine C.; Hernandez Saucedo, Hector; Widaman, Keith F.; Buckley, Rachel F.; Properzi, Michael J.; Mormino, Elizabeth C.; Yang, Hyun Sik; Harrison, Theresa M.; Hedden, Trey; Nho, Kwangsik; Andrews, Shea J.; Tommet, Douglas; Hadad, Niran; Sanders, R. Elizabeth; Ruderfer, Douglas M.; Gifford, Katherine A.; Zhong, Xiaoyuan; Raghavan, Neha S.; Vardarajan, Badri N.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); A4 Study Team; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li San; Cruchaga, Carlos; Schellenberg, Gerard D.; Cox, Nancy J.; Haines, Jonathan L.; Keene, C. Dirk; Saykin, Andrew J.; Larson, Eric B.; Sperling, Reisa A.; Mayeux, Richard; Cuccaro, Michael L.; Bennett, David A.; Schneider, Julie A.; Crane, Paul K.; Jefferson, Angela L.; Hohman, Timothy J.; Radiology and Imaging Sciences, School of Medicine
    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.