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Item 2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception(Elsevier, 2016-06-01) Weiner, Michael W.; Veitch, Dallas P.; Aisen, Paul S.; Beckett, Laurel A.; Cairns, Nigel J.; Cedarbaum, Jesse; Green, Robert C.; Harvey, Danielle; Jack, Clifford R.; Jagust, William; Luthman, Johan; Morris, John C.; Petersen, Ronald C.; Saykin, Andrew J.; Shaw, Leslie; Shen, Li; Schwarz, Adam; Toga, Arthur W.; Trojanowski, John Q.; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineThe Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.Item A cross‐sectional study of α‐synuclein seed amplification assay in Alzheimer's disease neuroimaging initiative: Prevalence and associations with Alzheimer's disease biomarkers and cognitive function(Wiley, 2024) Tosun, Duygu; Hausle, Zachary; Iwaki, Hirotaka; Thropp, Pamela; Lamoureux, Jennifer; Lee, Edward B.; MacLeod, Karen; McEvoy, Sean; Nalls, Michael; Perrin, Richard J.; Saykin, Andrew J.; Shaw, Leslie M.; Singleton, Andrew B.; Lebovitz, Russ; Weiner, Michael W.; Blauwendraat, Cornelis; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineIntroduction: Alzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed. Methods: A validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories. Results: SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive. Discussion: SAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression. Highlights: SAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.Item Accelerated functional brain aging in pre-clinical familial Alzheimer’s disease(Springer Nature, 2021-09-09) Gonneaud, Julie; Baria, Alex T.; Binette, Alexa Pichet; Gordon, Brian A.; Chhatwal, Jasmeer P.; Cruchaga, Carlos; Jucker, Mathias; Levin, Johannes; Salloway, Stephen; Farlow, Martin; Gauthier, Serge; Benzinger, Tammie L.S.; Morris, John C.; Bateman, Randall J.; Breitner, John C.S.; Poirier, Judes; Vachon-Presseau, Etienne; Villeneuve, Sylvia; Neurology, School of MedicineResting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology.Item Accelerating diversity in Alzheimer's disease research by partnering with a community advisory board(Wiley, 2023-05-28) Pena-Garcia, Alex; Richards, Ralph; Richards, Mollie; Campbell, Christopher; Mosley, Hank; Asper, Joseph; Eliacin, Johanne; Polsinelli, Angelina; Apostolova, Liana; Hendrie, Hugh; Tackett, Andrew; Elliott, Caprice; Van Heiden, Sarah; Gao, Sujuan; Saykin, Andrew; Wang, Sophia; Medicine, School of MedicineIntroduction: Community advisory boards (CABs) and researcher partnerships present a promising opportunity to accelerate enrollment of underrepresented groups (URGs). We outline the framework for how the CAB and researchers at the Indiana Alzheimer's Disease Research Center (IADRC) partnered to accelerate URG participation in AD neuroimaging research. Methods: CAB and the IADRC researchers partnered to increase the CAB's impact on URG study enrollment through community and research interactions. Community interactions included the CAB collaboratively building a network of URG focused community organizations and collaborating with those URG-focused organizations to host IADRC outreach and recruitment events. Research interactions included direct impact (CAB members referring themselves or close contacts as participants) and strategic impact, mainly by the CAB working with researchers to develop and refine URG focused outreach and recruitment strategies for IADRC and affiliated studies to increase URG representation. We created a database infrastructure to measure how these interactions impacted URG study enrollment. Results: Out of the 354 URG research referrals made to the IADRC between October 2019 and December 2022, 267 referrals were directly referred by the CAB (N = 36) or from community events in which CAB members organized and/or volunteered at (N = 231). Out of these 267 referrals, 34 were enrolled in IADRC and 2 were enrolled in Indiana University Longitudinal Early Onset AD Study (IU LEADS). Of note, both studies require the prospective participants to be willing to do MRI and PET scans. As of December 2022, 30 out of the 34 enrolled participants have received a consensus diagnosis; the majority were cognitively normal (64.7%), with the remainder having mild cognitive impairment (17.6%) or early-stage AD (2.9%). Discussion: The IADRC CAB-researcher partnership had a measurable impact on the enrollment of African American/Black adults in AD neuroimaging studies. Future studies will need to test whether this conceptual model works for other sites and for other URGs.Item AD Informer Set: Chemical tools to facilitate Alzheimer's disease drug discovery(Wiley, 2022-04-20) Potjewyd, Frances M.; Annor-Gyamfi, Joel K.; Aubé, Jeffrey; Chu, Shaoyou; Conlon, Ivie L.; Frankowski, Kevin J.; Guduru, Shiva K.R.; Hardy, Brian P.; Hopkins, Megan D.; Kinoshita, Chizuru; Kireev, Dmitri B.; Mason, Emily R.; Moerk, Charles T.; Nwogbo, Felix; Pearce, Kenneth H.; Richardson, Timothy I.; Rogers, David A.; Soni, Disha M.; Stashko, Michael; Wang, Xiaodong; Wells, Carrow; Willson, Timothy M.; Frye, Stephen V.; Young, Jessica E.; Axtman, Alison D.; Medicine, School of MedicineIntroduction: The portfolio of novel targets to treat Alzheimer's disease (AD) has been enriched by the Accelerating Medicines Partnership Program for Alzheimer's Disease (AMP AD) program. Methods: Publicly available resources, such as literature and databases, enabled a data-driven effort to identify existing small molecule modulators for many protein products expressed by the genes nominated by AMP AD and suitable positive control compounds to be included in the set. Compounds contained within the set were manually selected and annotated with associated published, predicted, and/or experimental data. Results: We built an annotated set of 171 small molecule modulators targeting 98 unique proteins that have been nominated by AMP AD consortium members as novel targets for the treatment of AD. The majority of compounds included in the set are inhibitors. These small molecules vary in their quality and should be considered chemical tools that can be used in efforts to validate therapeutic hypotheses, but which will require further optimization. A physical copy of the AD Informer Set can be requested on the Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) website. Discussion: Small molecules that enable target validation are important tools for the translation of novel hypotheses into viable therapeutic strategies for AD.Item Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome(Elsevier, 2019-01) MahmoudianDehkordi, Siamak; Arnold, Matthias; Nho, Kwangsik; Ahmad, Shahzad; Jia, Wei; Xie, Guoxiang; Louie, Gregory; Kueider‐Paisley, Alexandra; Moseley, M. Arthur; Thompson, J. Will; St John Williams, Lisa; Tenenbaum, Jessica D.; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Bhattacharyya, Sudeepa; Toledo, Jon B.; Schafferer, Simon; Klein, Sebastian; Koal, Therese; Risacher, Shannon L.; Kling, Mitchel Allan; Motsinger‐Reif, Alison; Rotroff, Daniel M.; Jack, John; Hankemeier, Thomas; Bennett, David A.; De Jager, Philip L.; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; van Duijn, Cornelia M.; Saykin, Andrew J.; Kastenmüller, Gabi; Kaddurah‐Daouk, Rima; Radiology and Imaging Sciences, School of MedicineIntroduction Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut‐brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). Methods Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD‐related genetic variants, adjusting for confounders and multiple testing. Results In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α‐dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response–related genes implicated in AD showed associations with BA profiles. Discussion We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut‐liver‐brain axis in the pathogenesis of AD.Item Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers(Elsevier, 2019-02) Nho, Kwangsik; Kueider-Paisley, Alexandra; MahmoudianDehkordi, Siamak; Arnold, Matthias; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmüller, Gabi; Jia, Wei; Xie, Guoxiang; Ahmad, Shahzad; Hankemeier, Thomas; van Duijn, Cornelia M.; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Radiology and Imaging Sciences, School of MedicineINTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-β deposition. METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.Item Alzheimer's disease and inflammatory biomarkers positively correlate in plasma in the UK‐ADRC cohort(Wiley, 2024) Foley, Kate E.; Winder, Zachary; Sudduth, Tiffany L.; Martin, Barbara J.; Nelson, Peter T.; Jicha, Gregory A.; Harp, Jordan P.; Weekman, Erica M.; Wilcock, Donna M.; Neurology, School of MedicineIntroduction: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. Methods: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. Results: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD-inflammatory biomarker correlations showed significant associations between AD and inflammatory biomarkers suggesting peripheral inflammatory interactions with increasing AD pathology. Biomarker associations parsed out by clinical diagnosis (normal, MCI, and dementia) reveal changes in strength of the correlations across the cognitive continuum. Discussion: Unique AD-inflammatory biomarker correlations in a community-based cohort reveal a new avenue for utilizing plasma-based biomarkers in the assessment of AD and related dementias. Highlights: Large community cohorts studying sex, age, and APOE genotype effects on biomarkers are few. It is unknown how biomarker-biomarker associations vary through aging and dementia. Six AD (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNFα, IL6, IL8, IL10, and GFAP) were used to examine associations between biomarkers. Plasma biomarkers suggesting increasing cerebral AD pathology corresponded to increases in peripheral inflammatory markers, both pro-inflammatory and anti-inflammatory. Strength of correlations, between pairs of classic AD and inflammatory plasma biomarker, changes throughout cognitive progression to dementia.Item Alzheimer's disease and primary open‐angle glaucoma associated with vascular health in patients of African descent(Wiley, 2018-12) Hutchins, Katherine; Harris, Alon; Thomas, Joseph; Alkhairy, Sameerah; Vercellin, Alice Chandra Verticchio; Shah, Aaditya; Siesky, Brent; Ophthalmology, School of MedicineItem Alzheimer's disease genetic risk variants beyond APOE ε4 predict mortality(Elsevier, 2017-08-24) Mez, Jesse; Marden, Jessica R.; Mukherjee, Shubhabrata; Walter, Stefan; Gibbons, Laura E.; Gross, Alden L.; Zahodne, Laura B.; Gilsanz, Paola; Brewster, Paul; Nho, Kwangsik; Crane, Paul K.; Larson, Eric B.; Glymour, M. Maria; Radiology and Imaging Sciences, School of Medicine• A genetic risk score from 21 non-APOE late-onset Alzheimer's disease risk variants predicts mortality. • The genetic risk score likely confers risk for mortality through its effect on dementia incidence. • Late-onset Alzheimer's disease risk loci effect estimates from genome-wide association unlikely suffer from selection bias.