Browsing by Author "Martins, Ralph N."
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Item APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies(Wiley, 2022) Wang, Tingting; Huynh, Kevin; Giles, Corey; Mellett, Natalie A.; Duong, Thy; Nguyen, Anh; Lim, Wei Ling Florence; Smith, Alex At; Olshansky, Gavriel; Cadby, Gemma; Hung, Joseph; Hui, Jennie; Beilby, John; Watts, Gerald F.; Chatterjee, Pratishtha; Martins, Ian; Laws, Simon M.; Bush, Ashley I.; Rowe, Christopher C.; Villemagne, Victor L.; Ames, David; Masters, Colin L.; Taddei, Kevin; Doré, Vincent; Fripp, Jürgen; Arnold, Matthias; Kastenmüller, Gabi; Nho, Kwangsik; Saykin, Andrew J.; Baillie, Rebecca; Han, Xianlin; Martins, Ralph N.; Moses, Eric K.; Kaddurah-Daouk, Rima; Meikle, Peter J.; Radiology and Imaging Sciences, School of MedicineIntroduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.Item Awareness of Genetic Risk in the Dominantly Inherited Alzheimer Network (DIAN)(Wiley, 2020-01) Aschenbrenner, Andrew J.; James, Bryan D.; McDade, Eric; Wang, Guoqiao; Lim, Yen Ying; Benzinger, Tammie L.S.; Cruchaga, Carlos; Goate, Alison; Xiong, Chengjie; Perrin, Richard; Buckles, Virginia; Allegri, Ricardo; Berman, Sarah B.; Chhatwal, Jasmeer P.; Fagan, Anne; Farlow, Martin; O'Connor, Antoinette; Ghetti, Bernardino; Graff-Radford, Neill; Goldman, Jill; Gräber, Susanne; Karch, Celeste M.; Lee, Jae-Hong; Levin, Johannes; Martins, Ralph N.; Masters, Colin; Mori, Hiroshi; Noble, James; Salloway, Stephen; Schofield, Peter; Morris, John C.; Bateman, Randall J.; Hassenstab, Jason; Neurology, School of MedicineIntroduction: Although some members of families with autosomal dominant Alzheimer's disease mutations learn their mutation status, most do not. How knowledge of mutation status affects clinical disease progression is unknown. This study quantifies the influence of mutation awareness on clinical symptoms, cognition, and biomarkers. Methods: Mutation carriers and non-carriers from the Dominantly Inherited Alzheimer Network (DIAN) were stratified based on knowledge of mutation status. Rates of change on standard clinical, cognitive, and neuroimaging outcomes were examined. Results: Mutation knowledge had no associations with cognitive decline, clinical progression, amyloid deposition, hippocampal volume, or depression in either carriers or non-carriers. Carriers who learned their status mid-study had slightly higher levels of depression and lower cognitive scores. Discussion: Knowledge of mutation status does not affect rates of change on any measured outcome. Learning of status mid-study may confer short-term changes in cognitive functioning, or changes in cognition may influence the determination of mutation status.Item Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease(American Academy of Neurology, 2015-09) Wang, Fen; Gordon, Brian A.; Ryman, Davis C.; Ma, Shengmei; Xiong, Chengjie; Hassenstab, Jason; Goate, Alison; Fagan, Anne M.; Cairns, Nigel J.; Marcus, Daniel S.; McDade, Eric; Ringman, John M.; Graff-Radford, Neill R.; Ghetti, Bernardino; Farlow, Martin R.; Sperling, Reisa; Salloway, Steve; Schofield, Peter R.; Masters, Colin L.; Martins, Ralph N.; Rossor, Martin N. N.; Jucker, Mathias; Danek, Adrian; Förster, Stefan; Lane, Christopher A.S.; Morris, John C.; Benzinger, Tammie L. S.; Bateman, Randall J.; Department of Neurology, IU School of MedicineOBJECTIVE: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD). METHODS: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years ± 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE ε4 allelic status, and education. RESULTS: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination. CONCLUSIONS: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials.Item Comparison of amyloid accumulation between Down syndrome and autosomal-dominant Alzheimer disease(Wiley, 2022) Boerwinkle, Anna H.; Gordon, Brian A.; Wisch, Julie K.; Flores, Shaney; Henson, Rachel L.; Butt, Omar Hameed; Chen, Charles D.; Benzinger, Tammie L. S.; Fagan, Anne M.; Handen, Benjamin L.; Christian, Bradley T.; Head, Elizabeth; Mapstone, Mark; Klunk, William E.; Rafii, Michael S.; O’Bryant, Sid E.; Price, Julie C.; Schupf, Nicole; Laymon, Charles M.; Krinsky-McHale, Sharon J.; Lai, Florence; Rosas, H. Diana; Hartley, Sigan L.; Zaman, Shahid; Lott, Ira T.; Silverman, Wayne; Brickman, Adam M.; Lee, Joseph H.; Allegri, Ricardo Francisco; Berman, Sarah; Chhatwal, Jasmeer P.; Chui, Helena C.; Cruchaga, Carlos; Farlow, Martin R.; Fox, Nick C.; Goate, Alison; Day, Gregory S.; Graff-Radford, Neill R.; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Martins, Ralph N.; Mori, Hiroshi; Perrin, Richard J.; Salloway, Stephen P.; Sanchez-Valle, Raquel; Schofield, Peter R.; Xiong, Chengjie; Karch, Celeste M.; Hassenstab, Jason J.; McDade, Eric; Bateman, Randall J.; Ances, Beau M.; Neurology, School of MedicineBackground: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)-like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method: We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) and 265 mutation-carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated-years-to-symptom-onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC-DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result: The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ -23 but was not elevated in DS until EYO ≥ -15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5). Conclusion: These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5-10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.Item Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease(Springer Nature, 2022-06-06) Cadby, Gemma; Giles, Corey; Melton, Phillip E.; Huynh, Kevin; Mellett, Natalie A.; Duong, Thy; Nguyen, Anh; Cinel, Michelle; Smith, Alex; Olshansky, Gavriel; Wang, Tingting; Brozynska, Marta; Inouye, Mike; McCarthy, Nina S.; Ariff, Amir; Hung, Joseph; Hui, Jennie; Beilby, John; Dubé, Marie-Pierre; Watts, Gerald F.; Shah, Sonia; Wray, Naomi R.; Lim, Wei Ling Florence; Chatterjee, Pratishtha; Martins, Ian; Laws, Simon M.; Porter, Tenielle; Vacher, Michael; Bush, Ashley I.; Rowe, Christopher C.; Villemagne, Victor L.; Ames, David; Masters, Colin L.; Taddei, Kevin; Arnold, Matthias; Kastenmüller, Gabi; Nho, Kwangsik; Saykin, Andrew J.; Han, Xianlin; Kaddurah-Daouk, Rima; Martins, Ralph N.; Blangero, John; Meikle, Peter J.; Moses, Eric K.; Radiology and Imaging Sciences, School of MedicineWe integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.Item Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease(Nature, 2020-11-10) Huynh, Kevin; Lim, Wei Ling Florence; Giles, Corey; Jayawardana, Kaushala S.; Salim, Agus; Mellett, Natalie A.; Smith, Adam Alexander T.; Olshansky, Gavriel; Drew, Brian G.; Chatterjee, Pratishtha; Martins, Ian; Laws, Simon M.; Bush, Ashley I.; Rowe, Christopher C.; Villemagne, Victor L.; Ames, David; Masters, Colin L.; Arnold, Matthias; Nho, Kwangsik; Saykin, Andrew J.; Baillie, Rebecca; Han, Xianlin; Kaddurah-Daouk, Rima; Martins, Ralph N.; Meikle, Peter J.; BioHealth Informatics, School of Informatics and ComputingChanges to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation., The onset and pathology of Alzheimer’s disease (AD) is associated with changes to lipid metabolism. Here, the authors analysed 569 lipids from 32 classes and subclasses in two independent patient cohorts to identify key lipid pathways to link the plasma lipidome with AD and the future onset of AD.Item Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer's disease(SpringerNature, 2017-04-27) Müller, Stephan; Preische, Oliver; Sohrabi, Hamid R.; Gräber, Susanne; Jucker, Mathias; Dietzsch, Janko; Ringman, Ralph N.; Martins, Ralph N.; McDade, Eric; Schofield, Peter R.; Ghetti, Bernardino; Rossor, Martin; Graff-Radford, Neill R.; Levin, Johannes; Galasko, Douglas; Quaid, Kimberly A.; Salloway, Stephen; Xiong, Chengjie; Benzinger, Tammie; Buckles, Virginia; Masters, Colin L.; Sperling, Reisa; Bateman, Randall J.; Morris, John C.; Laske, Christoph; Department of Pathology and Laboratory Medicine, School of MedicineThe relationship between body-mass index (BMI) and Alzheimer´s disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time.Item Diagnostic Value of Subjective Memory Complaints Assessed with a Single Item in Dominantly Inherited Alzheimer’s Disease: Results of the DIAN Study(Hindawi, 2015) Laske, Christoph; Sohrabi, Hamid R.; Jasielec, Mateusz S.; Müller, Stephan; Koehler, Niklas K.; Gräber, Susanne; Förster, Stefan; Drzezga, Alexander; Mueller-Sarnowski, Felix; Danek, Adrian; Jucker, Mathias; Bateman, Randall J.; Buckles, Virginia; Saykin, Andrew J.; Martins, Ralph N.; Morris, John C.; Indiana Alzheimer Disease Center, Indiana University School of MedicineObjective. We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimer’s disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN). Methods. The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: ; NCs: ), early symptomatic (CDR 0.5; MCs: ; NCs: ), and dementia stage (CDR ≥ 1; MCs: ; NCs: ). These groups were subdivided by the presence or absence of SMCs. Results. At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs . At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs . At CDR ≥ 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset. Conclusions. The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials.Item First presentation with neuropsychiatric symptoms in autosomal dominant Alzheimer's disease: the Dominantly Inherited Alzheimer's Network Study(BMJ, 2023) O'Connor, Antoinette; Rice, Helen; Barnes, Josephine; Ryan, Natalie S.; Liu, Kathy Y.; Allegri, Ricardo Francisco; Berman, Sarah; Ringman, John M.; Cruchaga, Carlos; Farlow, Martin R.; Hassenstab, Jason; Lee, Jae-Hong; Perrin, Richard J.; Xiong, Chengjie; Gordon, Brian; Levey, Allan I.; Goate, Alison; Graff-Radford, Neil; Levin, Johannes; Jucker, Mathias; Benzinger, Tammie; McDade, Eric; Mori, Hiroshi; Noble, James M.; Schofield, Peter R.; Martins, Ralph N.; Salloway, Stephen; Chhatwal, Jasmeer; Morris, John C.; Bateman, Randall; Howard, Rob; Reeves, Suzanne; Fox, Nick C.; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineItem Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease(Wiley, 2021-07-05) Keret, Ophir; Staffaroni, Adam M.; Ringman, John M.; Cobigo, Yann; Goh, Sheng-Yang M.; Wolf, Amy; Allen, Isabel Elaine; Salloway, Stephen; Chhatwal, Jasmeer; Brickman, Adam M.; Reyes-Dumeyer, Dolly; Bateman, Randal J.; Benzinger, Tammie L.S.; Morris, John C.; Ances, Beau M.; Joseph-Mathurin, Nelly; Perrin, Richard J.; Gordon, Brian A.; Levin, Johannes; Vöglein, Jonathan; Jucker, Mathias; la Fougère, Christian; Martins, Ralph N.; Sohrabi, Hamid R.; Taddei, Kevin; Villemagne, Victor L.; Schofield, Peter R.; Brooks, William S.; Fulham, Michael; Masters, Colin L.; Ghetti, Bernardino; Saykin, Andrew J.; Jack, Clifford R.; Graff-Radford, Neill R.; Weiner, Michael; Cash, David M.; Allegri, Ricardo F.; Chrem, Patricio; Yi, Su; Miller, Bruce L.; Rabinovici, Gil D.; Rosen, Howard J.; Pathology and Laboratory Medicine, School of MedicineIntroduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment. Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally. Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset. Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.