Browsing by Author "Alzheimer’s Disease Neuroimaging Initiative (ADNI)"

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    Circular-SWAT for deep learning based diagnostic classification of Alzheimer's disease: application to metabolome data
    (Elsevier, 2023) Jo, Taeho; Kim, Junpyo; Bice, Paula; Huynh, Kevin; Wang, Tingting; Arnold, Matthias; Meikle, Peter J.; Giles, Corey; Kaddurah-Daouk, Rima; Saykin, Andrew J.; Nho, Kwangsik; Alzheimer’s Disease Metabolomics Consortium (ADMC); Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
    Background: Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the classification accuracy in predicting AD using serum-based metabolomics data, specifically lipidomics. Methods: The c-SWAT methodology builds upon the existing Sliding Window Association Test (SWAT) and utilizes a three-step approach: feature correlation analysis, feature selection, and classification. Data from 997 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) served as the basis for model training and validation. Feature correlations were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), and Convolutional Neural Networks (CNN) were employed for feature selection. Random Forest was used for the final classification. Findings: The application of c-SWAT resulted in a classification accuracy of up to 80.8% and an AUC of 0.808 for distinguishing AD from cognitively normal older adults. This marks a 9.4% improvement in accuracy and a 0.169 increase in AUC compared to methods without c-SWAT. These results were statistically significant, with a p-value of 1.04 × 10ˆ-4. The approach also identified key lipids associated with AD, such as Cer(d16:1/22:0) and PI(37:6). Interpretation: Our results indicate that c-SWAT is effective in improving classification accuracy and in identifying potential lipid biomarkers for AD. These identified lipids offer new avenues for understanding AD and warrant further investigation.
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    Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume
    (Springer, 2022) Milicic, Lidija; Vacher, Michael; Porter, Tenielle; Doré, Vincent; Burnham, Samantha C.; Bourgeat, Pierrick; Shishegar, Rosita; Doecke, James; Armstrong, Nicola J.; Tankard, Rick; Maruff, Paul; Masters, Colin L.; Rowe, Christopher C.; Villemagne, Victor L.; Laws, Simon M.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Australian Imaging Biomarkers and Lifestyle (AIBL) Study; Medical and Molecular Genetics, School of Medicine
    The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer's Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer's disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.
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    CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET
    (Springer Nature, 2024-09-20) Nho, Kwangsik; Risacher, Shannon L.; Apostolova, Liana G.; Bice, Paula J.; Brosch, Jared R.; Deardorff, Rachael; Faber, Kelley; Farlow, Martin R.; Foroud, Tatiana; Gao, Sujuan; Rosewood, Thea; Kim, Jun Pyo; Nudelman, Kelly; Yu, Meichen; Aisen, Paul; Sperling, Reisa; Hooli, Basavaraj; Shcherbinin, Sergey; Svaldi, Diana; Jack, Clifford R., Jr.; Jagust, William J.; Landau, Susan; Vasanthakumar, Aparna; Waring, Jeffrey F.; Doré, Vincent; Laws, Simon M.; Masters, Colin L.; Porter, Tenielle; Rowe, Christopher C.; Villemagne, Victor L.; Dumitrescu, Logan; Hohman, Timothy J.; Libby, Julia B.; Mormino, Elizabeth; Buckley, Rachel F.; Johnson, Keith; Yang, Hyun-Sik; Petersen, Ronald C.; Ramanan, Vijay K.; Ertekin-Taner, Nilüfer; Vemuri, Prashanthi; Cohen, Ann D.; Fan, Kang-Hsien; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Ali, Muhammad; Benzinger, Tammie; Cruchaga, Carlos; Hobbs, Diana; De Jager, Philip L.; Fujita, Masashi; Jadhav, Vaishnavi; Lamb, Bruce T.; Tsai, Andy P.; Castanho, Isabel; Mill, Jonathan; Weiner, Michael W.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI); Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
    Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.
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    Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways
    (Nature Research, 2019-10-10) Horgusluoglu-Moloch, Emrin; Risacher, Shannon L.; Crane, Paul K.; Hibar, Derrek; Thompson, Paul M.; Saykin, Andrew J.; Nho, Kwangsik; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Medical and Molecular Genetics, School of Medicine
    Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer's Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.
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    Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease
    (Wiley, 2022-09-20) Kim, Bo-Hyun; Vasanthakumar, Aparna; Li, Qingqin S.; Nudelman, Kelly N.H.; Risacher, Shannon L.; Davis, Justin W.; Idler, Kenneth; Lee, Jong-Min; Seo, Sang Won; Waring, Jeffrey F.; Saykin, Andrew J.; Nho, Kwangsik; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
    Introduction: The acceleration of biological aging is a risk factor for Alzheimer's disease (AD). Here, we performed weighted gene co-expression network analysis (WGCNA) to identify modules and dysregulated genes involved in biological aging in AD. Methods: We performed WGCNA to identify modules associated with biological clocks and hub genes of the module with the highest module significance. In addition, we performed differential expression analysis and association analysis with AD biomarkers. Results: WGCNA identified five modules associated with biological clocks, with the module designated as "purple" showing the strongest association. Functional enrichment analysis revealed that the purple module was related to cell migration and death. Ten genes were identified as hub genes in purple modules, of which CX3CR1 was downregulated in AD and low levels of CX3CR1 expression were associated with AD biomarkers. Conclusion: Network analysis identified genes associated with biological clocks, which suggests the genetic architecture underlying biological aging in AD. Highlights: Examine links between Alzheimer's disease (AD) peripheral transcriptome and biological aging changes. Weighted gene co-expression network analysis (WGCNA) found five modules related to biological aging. Among the hub genes of the module, CX3CR1 was downregulated in AD. The CX3CR1 expression level was associated with cognitive performance and brain atrophy.
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    Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk
    (PLOS, 2022-05-26) Ali, Muhammad; Sung, Yun Ju; Wang, Fengxian; Fernández, Maria V.; Morris, John C.; Fagan, Anne M.; Blennow, Kaj; Zetterberg, Henrik; Heslegrave, Amanda; Johansson, Per M.; Svensson, Johan; Nellgård, Bengt; Lleó, Alberto; Alcolea, Daniel; Clarimon, Jordi; Rami, Lorena; Molinuevo, José Luis; Suárez-Calvet, Marc; Morenas-Rodríguez, Estrella; Kleinberger, Gernot; Haass, Christian; Ewers, Michael; Levin, Johannes; Farlow, Martin R.; Perrin, Richard J.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Dominantly Inherited Alzheimer Network (DIAN); Cruchaga, Carlos; Neurology, School of Medicine
    Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
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    Multi-task deep autoencoder to predict Alzheimer's disease progression using temporal DNA methylation data in peripheral blood
    (Elsevier, 2022-10-23) Chen, Li; Saykin, Andrew J.; Yao, Bing; Zhao, Fengdi; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
    Traditional approaches for diagnosing Alzheimer's disease (AD) such as brain imaging and cerebrospinal fluid are invasive and expensive. It is desirable to develop a useful diagnostic tool by exploiting biomarkers obtained from peripheral tissues due to their noninvasive and easily accessible characteristics. However, the capacity of using DNA methylation data in peripheral blood for predicting AD progression is rarely known. It is also challenging to develop an efficient prediction model considering the complex and high-dimensional DNA methylation data in a longitudinal study. Here, we develop two multi-task deep autoencoders, which are based on the convolutional autoencoder and long short-term memory autoencoder to learn the compressed feature representation by jointly minimizing the reconstruction error and maximizing the prediction accuracy. By benchmarking on longitudinal DNA methylation data collected from the peripheral blood in Alzheimer's Disease Neuroimaging Initiative, we demonstrate that the proposed multi-task deep autoencoders outperform state-of-the-art machine learning approaches for both predicting AD progression and reconstructing the temporal DNA methylation profiles. In addition, the proposed multi-task deep autoencoders can predict AD progression accurately using only the historical DNA methylation data and the performance is further improved by including all temporal DNA methylation data. Availability:: https://github.com/lichen-lab/MTAE.
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    Serum Bile Acids Improve Prediction of Alzheimer's Progression in a Sex-Dependent Manner
    (Wiley, 2024) Chen, Tianlu; Wang, Lu; Xie, Guoxiang; Kristal, Bruce S.; Zheng, Xiaojiao; Sun, Tao; Arnold, Matthias; Louie, Gregory; Li, Mengci; Wu, Lirong; Mahmoudiandehkordi, Siamak; Sniatynski, Matthew J.; Borkowski, Kamil; Guo, Qihao; Kuang, Junliang; Wang, Jieyi; Nho, Kwangsik; Ren, Zhenxing; Kueider-Paisley, Alexandra; Blach, Colette; Kaddurah-Daouk, Rima; Jia, Wei; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer Disease Metabolomics Consortium (ADMC); Radiology and Imaging Sciences, School of Medicine
    Sex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid-beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.
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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.
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    Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer’s disease
    (bioRxiv, 2024-06-12) Peterson, Amalia; Sathe, Aditi; Zaras, Dimitrios; Yang, Yisu; Durant, Alaina; Deters, Kacie D.; Shashikumar, Niranjana; Pechman, Kimberly R.; Kim, Michael E.; Gao, Chenyu; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Huo, Yuankai; Dumitrescu, Logan; Gifford, Katherine A.; Wilson, Jo Ellen; Cambronero, Francis; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Tosun, Duygu; Toga, Arthur W.; Thompson, Paul M.; Mormino, Elizabeth C.; Zhang, Panpan; Schilling, Kurt; Alzheimer’s Disease Neuroimaging Initiative (ADNI); BIOCARD Study Team; Alzheimer’s Disease Sequencing Project (ADSP); Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Johnson, Sterling C.; Schneider, Julie; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Archer, Derek B.; Radiology and Imaging Sciences, School of Medicine
    Introduction: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. Methods: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. Results: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. Discussion: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.