Search

Your search keyword '"The Dominantly Inherited Alzheimer Network"' showing total 125 results
Start Over Author "The Dominantly Inherited Alzheimer Network"
125 results on '"The Dominantly Inherited Alzheimer Network"'

1. Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort

Author

Reddy Peera Kommaddi, Aditi Verma, Graciela Muniz-Terrera, Vivek Tiwari, Keerthana Chithanathan, Latha Diwakar, Ruturaj Gowaikar, Smitha Karunakaran, Palash Kumar Malo, Neill R. Graff-Radford, Gregory S. Day, Christoph Laske, Jonathan Vöglein, Georg Nübling, Takeshi Ikeuchi, Kensaku Kasuga, the Dominantly Inherited Alzheimer Network (DIAN), and Vijayalakshmi Ravindranath

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Women carry a higher burden of Alzheimer’s disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler’s logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.

Published
2023
Full Text
View/download PDF

2. Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease

Author

Muhammad Ali, Derek B. Archer, Priyanka Gorijala, Daniel Western, Jigyasha Timsina, Maria V. Fernández, Ting-Chen Wang, Claudia L. Satizabal, Qiong Yang, Alexa S. Beiser, Ruiqi Wang, Gengsheng Chen, Brian Gordon, Tammie L. S. Benzinger, Chengjie Xiong, John C. Morris, Randall J. Bateman, Celeste M. Karch, Eric McDade, Alison Goate, Sudha Seshadri, Richard P. Mayeux, Reisa A. Sperling, Rachel F. Buckley, Keith A. Johnson, Hong-Hee Won, Sang-Hyuk Jung, Hang-Rai Kim, Sang Won Seo, Hee Jin Kim, Elizabeth Mormino, Simon M. Laws, Kang-Hsien Fan, M. Ilyas Kamboh, Prashanthi Vemuri, Vijay K. Ramanan, Hyun-Sik Yang, Allen Wenzel, Hema Sekhar Reddy Rajula, Aniket Mishra, Carole Dufouil, Stephanie Debette, Oscar L. Lopez, Steven T. DeKosky, Feifei Tao, Michael W. Nagle, Knight Alzheimer Disease Research Center (Knight ADRC), the Dominantly Inherited Alzheimer Network (DIAN), Alzheimer’s Disease Neuroimaging Initiative (ADNI), ADNI-DOD, A4 Study Team, the Australian Imaging Biomarkers, Lifestyle (AIBL) Study, Timothy J. Hohman, Yun Ju Sung, Logan Dumitrescu, and Carlos Cruchaga

Subjects
Brain amyloidosis, Amyloid PET, Alzheimer’s disease, Multi-ethnic, Meta-analysis, GWAS, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10–311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10–09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10–10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10–09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10–08, MAF = 0.006, sex-interaction P = 9.8 × 10–07) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10–08, MAF = 0.004, sex-interaction P = 1.3 × 10–03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.

Published
2023
Full Text
View/download PDF

3. Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study

Author

Peter R Millar, Brian A Gordon, Patrick H Luckett, Tammie LS Benzinger, Carlos Cruchaga, Anne M Fagan, Jason J Hassenstab, Richard J Perrin, Suzanne E Schindler, Ricardo F Allegri, Gregory S Day, Martin R Farlow, Hiroshi Mori, Georg Nübling, The Dominantly Inherited Alzheimer Network, Randall J Bateman, John C Morris, and Beau M Ances

Subjects
brain aging, Alzheimer disease, structural MRI, resting-state functional connectivity, machine learning, Medicine, Science, Biology (General), QH301-705.5
Abstract

Background: Estimates of ‘brain-predicted age’ quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. Methods: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A−) participants (18–89 years old). In independent samples of 144 CN/A−, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite. Results: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A−. In CI participants only, elevated S-BAG and S+FC BAG were associated with more advanced AD pathology and lower cognitive performance. Conclusions: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences. Funding: This work was supported by the National Institutes of Health (P01-AG026276, P01- AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, and U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimer’s Association (SG-20-690363-DIAN).

Published
2023
Full Text
View/download PDF

4. CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2, neurodegeneration and cognitive decline

Author

Marc Suárez‐Calvet, Anja Capell, Miguel Ángel Araque Caballero, Estrella Morenas‐Rodríguez, Katrin Fellerer, Nicolai Franzmeier, Gernot Kleinberger, Erden Eren, Yuetiva Deming, Laura Piccio, Celeste M Karch, Carlos Cruchaga, Katrina Paumier, Randall J Bateman, Anne M Fagan, John C Morris, Johannes Levin, Adrian Danek, Mathias Jucker, Colin L Masters, Martin N Rossor, John M Ringman, Leslie M Shaw, John Q Trojanowski, Michael Weiner, Michael Ewers, Christian Haass, the Dominantly Inherited Alzheimer Network, and the Alzheimer's Disease Neuroimaging Initiative

Subjects
Alzheimer's disease, biomarker, microglia, progranulin, TREM2, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity‐specific manner in AD. We measured PGRN in cerebrospinal fluid (CSF) in two of the best‐characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross‐sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non‐carriers 10 years before the expected symptom onset. In late‐onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.

Published
2018
Full Text
View/download PDF

5. Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network

Author

Celeste M. Karch, Damián Hernández, Jen-Chyong Wang, Jacob Marsh, Alex W. Hewitt, Simon Hsu, Joanne Norton, Denise Levitch, Tamara Donahue, Wendy Sigurdson, Bernardino Ghetti, Martin Farlow, Jasmeer Chhatwal, Sarah Berman, Carlos Cruchaga, John C. Morris, Randall J. Bateman, the Dominantly Inherited Alzheimer Network (DIAN), Alice Pébay, and Alison M. Goate

Subjects
Dominantly Inherited Alzheimer Network, Amyloid precursor protein, Presenilin 1, Presenilin 2, Fibroblasts, Induced pluripotent stem cells, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. However, understanding of the basic biological mechanisms that drive the disease are limited. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease. Results We generated a library of 98 dermal fibroblast lines from 42 ADAD families enrolled in DIAN. We have reprogrammed a subset of the DIAN fibroblast lines into patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized for pluripotency markers. Conclusions This library represents a comprehensive resource that can be used for disease modeling and the development of novel therapeutics.

Published
2018
Full Text
View/download PDF

6. Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure

Author

Zeran Li, Jorge L. Del-Aguila, Umber Dube, John Budde, Rita Martinez, Kathleen Black, Qingli Xiao, Nigel J. Cairns, The Dominantly Inherited Alzheimer Network (DIAN), Joseph D. Dougherty, Jin-Moo Lee, John C. Morris, Randall J. Bateman, Celeste M. Karch, Carlos Cruchaga, and Oscar Harari

Subjects
Digital deconvolution, Alzheimer’s disease, Brain cellular composition, Bulk RNA-sequencing, Autosomal dominant AD, TREM2, Medicine, Genetics, QH426-470
Abstract

Abstract Background Alzheimer’s disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the specific effects that pathological mutations and coding variants associated with AD have on the cellular composition of the brain are often ignored. Methods We developed and optimized a cell-type-specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies. Results We found that neuronal and astrocyte relative proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1, or PSEN2 presented lower neuron and higher astrocyte relative proportions compared to sporadic AD. Similarly, the APOE ε4 allele also showed decreased neuronal and increased astrocyte relative proportions compared to AD non-carriers. In contrast, carriers of variants in TREM2 risk showed a lower degree of neuronal loss compared to matched AD cases in multiple independent studies. Conclusions These findings suggest that genetic risk factors associated with AD etiology have a specific imprinting in the cellular composition of AD brains. Our digital deconvolution reference panel provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-sequencing studies for cell composition and suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD.

Published
2018
Full Text
View/download PDF

7. Deep Learning in current Neuroimaging: a multivariate approach with power and type I error control but arguable generalization ability

Author

Jiménez-Mesa, Carmen, Ramírez, Javier, Suckling, John, Vöglein, Jonathan, Levin, Johannes, Górriz, Juan Manuel, ADNI, Alzheimer's Disease Neuroimaging Initiative, and DIAN, Dominantly Inherited Alzheimer Network

Subjects
Statistics - Machine Learning, Computer Science - Machine Learning, Electrical Engineering and Systems Science - Image and Video Processing, Statistics - Applications
Abstract

Discriminative analysis in neuroimaging by means of deep/machine learning techniques is usually tested with validation techniques, whereas the associated statistical significance remains largely under-developed due to their computational complexity. In this work, a non-parametric framework is proposed that estimates the statistical significance of classifications using deep learning architectures. In particular, a combination of autoencoders (AE) and support vector machines (SVM) is applied to: (i) a one-condition, within-group designs often of normal controls (NC) and; (ii) a two-condition, between-group designs which contrast, for example, Alzheimer's disease (AD) patients with NC (the extension to multi-class analyses is also included). A random-effects inference based on a label permutation test is proposed in both studies using cross-validation (CV) and resubstitution with upper bound correction (RUB) as validation methods. This allows both false positives and classifier overfitting to be detected as well as estimating the statistical power of the test. Several experiments were carried out using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, the Dominantly Inherited Alzheimer Network (DIAN) dataset, and a MCI prediction dataset. We found in the permutation test that CV and RUB methods offer a false positive rate close to the significance level and an acceptable statistical power (although lower using cross-validation). A large separation between training and test accuracies using CV was observed, especially in one-condition designs. This implies a low generalization ability as the model fitted in training is not informative with respect to the test set. We propose as solution by applying RUB, whereby similar results are obtained to those of the CV test set, but considering the whole set and with a lower computational cost per iteration., Comment: 26 pages, 10 figures, 13 tables

Published
2021

8. Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease.

Author

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 LS, 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, and Dominantly Inherited Alzheimer Network

Subjects
Dominantly Inherited Alzheimer Network, autosomal dominant Alzheimer's disease, brain atrophy, preclinical Alzheimer's disease, Prevention, Genetics, Dementia, Patient Safety, Neurodegenerative, Brain Disorders, Aging, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Neurosciences, Neurological
Abstract

IntroductionAsymptomatic 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.MethodsWe 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.ResultsOur 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.DiscussionIndividualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.

Published
2021

9. Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease

Author

Dincer, Aylin, Gordon, Brian A, Hari-Raj, Amrita, Keefe, Sarah J, Flores, Shaney, McKay, Nicole S, Paulick, Angela M, Lewis, Kristine E Shady, Feldman, Rebecca L, Hornbeck, Russ C, Allegri, Ricardo, Ances, Beau M, Berman, Sarah B, Brickman, Adam M, Brooks, William S, Cash, David M, Chhatwal, Jasmeer P, Farlow, Martin R, la Fougère, Christian, Fox, Nick C, Fulham, Michael J, Jack, Clifford R, Joseph-Mathurin, Nelly, Karch, Celeste M, Lee, Athene, Levin, Johannes, Masters, Colin L, McDade, Eric M, Oh, Hwamee, Perrin, Richard J, Raji, Cyrus, Salloway, Stephen P, Schofield, Peter R, Su, Yi, Villemagne, Victor L, Wang, Qing, Weiner, Michael W, Xiong, Chengjie, Yakushev, Igor, Morris, John C, Bateman, Randall J, Benzinger, Tammie LS, and DIAN, for the Dominantly Inherited Alzheimer Network

Subjects
Neurodegenerative, Dementia, Clinical Research, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Aging, Acquired Cognitive Impairment, Alzheimer's Disease, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Atrophy, Hippocampus, Humans, Magnetic Resonance Imaging, Positron-Emission Tomography, Alzheimer disease, Autosomal dominant Alzheimer disease, Preclinical, Cortical signature, Amyloid, Cortical thickness, Dominantly Inherited Alzheimer Network DIAN
Abstract

Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (nADRC = 381; nDIAN = 145), preclinical (nADRC = 153; nDIAN = 76), and cognitively impaired (nADRC = 54; nDIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11C-Pittsburgh compound B or 18F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.

Published
2020

10. An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations.

Author

Dube, Umber, Del-Aguila, Jorge L, Li, Zeran, Budde, John P, Jiang, Shan, Hsu, Simon, Ibanez, Laura, Fernandez, Maria Victoria, Farias, Fabiana, Norton, Joanne, Gentsch, Jen, Wang, Fengxian, Dominantly Inherited Alzheimer Network (DIAN), Salloway, Stephen, Masters, Colin L, Lee, Jae-Hong, Graff-Radford, Neill R, Chhatwal, Jasmeer P, Bateman, Randall J, Morris, John C, Karch, Celeste M, Harari, Oscar, and Cruchaga, Carlos

Subjects
Dominantly Inherited Alzheimer Network, Parietal Lobe, Humans, Alzheimer Disease, MicroRNAs, RNA, Messenger, Severity of Illness Index, Case-Control Studies, Gene Expression Profiling, Sequence Analysis, RNA, Atlases as Topic, RNA, Circular, RNA, Messenger, Sequence Analysis, Circular, Neurology & Neurosurgery, Neurosciences, Psychology, Cognitive Sciences
Abstract

Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA-AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis.

Published
2019

11. Autosomal dominantly inherited alzheimer disease: Analysis of genetic subgroups by machine learning

Author

Castillo-Barnes, Diego, Su, Li, Ramírez, Javier, Salas-Gonzalez, Diego, Martinez-Murcia, Francisco J., Illan, Ignacio A., Segovia, Fermin, Ortiz, Andres, Cruchaga, Carlos, Farlow, Martin R., Xiong, Chengjie, Graff-Radford, Neil R., Schofield, Peter R., Masters, Colin L., Salloway, Stephen, Jucker, Mathias, Mori, Hiroshi, Levin, Johannes, Gorriz, Juan M., and (DIAN), Dominantly Inherited Alzheimer Network

Published
2020
Full Text
View/download PDF

12. Autosomal Dominant Alzheimer's Disease Mutations in Human Microglia Are Not Sufficient to Trigger Amyloid Pathology in WT Mice but Might Affect Pathology in 5XFAD Mice.

Author

Romero-Molina, C, Neuner, SM, Ryszawiec, M, Pébay, A, Dominantly Inherited Alzheimer Network, Marcora, E, Goate, A, Romero-Molina, C, Neuner, SM, Ryszawiec, M, Pébay, A, Dominantly Inherited Alzheimer Network, Marcora, E, and Goate, A

Abstract

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer's Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or the presenilin (PSEN1/2) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk.

Published
2024

13. Generation of a gene-corrected human isogenic iPSC line from an Alzheimer's disease iPSC line carrying the PSEN1 H163R mutation

Author

Hernández, D, Morgan Schlicht, S, Clarke, JE, Daniszewski, M, Karch, CM, Dominantly Inherited Alzheimer Network (DIAN), Goate, AM, Pébay, A, Hernández, D, Morgan Schlicht, S, Clarke, JE, Daniszewski, M, Karch, CM, Dominantly Inherited Alzheimer Network (DIAN), Goate, AM, and Pébay, A

Abstract

We report the generation of a gene-edited human induced pluripotent stem cell (iPSC) line from an Alzheimer's disease patient-derived iPSC line harbouring the PSEN1 H163R mutation. This line demonstrates pluripotent stem cell morphology, expression of pluripotency markers, and maintains a normal karyotype.

Published
2024

15. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease

Author

Preische, Oliver, Schultz, Stephanie A., Apel, Anja, Kuhle, Jens, Kaeser, Stephan A., Barro, Christian, Gräber, Susanne, Kuder-Buletta, Elke, LaFougere, Christian, Laske, Christoph, Vöglein, Jonathan, Levin, Johannes, Masters, Colin L., Martins, Ralph, Schofield, Peter R., Rossor, Martin N., Graff-Radford, Neill R., Salloway, Stephen, Ghetti, Bernardino, Ringman, John M., Noble, James M., Chhatwal, Jasmeer, Goate, Alison M., Benzinger, Tammie L. S., Morris, John C., Bateman, Randall J., Wang, Guoqiao, Fagan, Anne M., McDade, Eric M., Gordon, Brian A., Jucker, Mathias, and Dominantly Inherited Alzheimer Network

Published
2019
Full Text
View/download PDF

16. This title is unavailable for guests, please login to see more information.

Author

Chatterjee, Pratishtha, Vermunt, Lisa, Gordon, Brian A., Pedrini, Steve, Boonkamp, Lynn, Armstrong, Nicola J., Xiong, Chengjie, Singh, Abhay K., Li, Yan, Sohrabi, Hamid R., Taddei, Kevin, Molloy, Mark, Benzinger, Tammie L. S., Morris, John C., Karch, Celeste, Berman, Sarah, Chhatwal, Jasmeer, Cruchaga, Carlos, Graff-Radford, Neill R., Day, Gregory S., Farlow, Martin, Fox, Nick, Goate, Alison, Hassenstab, Jason, Lee, Jae-Hong, Levin, Johannes, McDade, Eric, Mori, Hiroshi, Perrin, Richard, Sanchez-Valle, Raquel, Schofield, Peter R., Levey, Allan, Jucker, Mathias, Masters, Colin L., Fagan, Anne M., Bateman, Randall J., Martins, Ralph N., Teunissen, Charlotte, Dominantly Inherited Alzheimer Network, Chatterjee, Pratishtha, Vermunt, Lisa, Gordon, Brian A., Pedrini, Steve, Boonkamp, Lynn, Armstrong, Nicola J., Xiong, Chengjie, Singh, Abhay K., Li, Yan, Sohrabi, Hamid R., Taddei, Kevin, Molloy, Mark, Benzinger, Tammie L. S., Morris, John C., Karch, Celeste, Berman, Sarah, Chhatwal, Jasmeer, Cruchaga, Carlos, Graff-Radford, Neill R., Day, Gregory S., Farlow, Martin, Fox, Nick, Goate, Alison, Hassenstab, Jason, Lee, Jae-Hong, Levin, Johannes, McDade, Eric, Mori, Hiroshi, Perrin, Richard, Sanchez-Valle, Raquel, Schofield, Peter R., Levey, Allan, Jucker, Mathias, Masters, Colin L., Fagan, Anne M., Bateman, Randall J., Martins, Ralph N., Teunissen, Charlotte, and Dominantly Inherited Alzheimer Network

Abstract

Background: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. Methods: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (A ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished A -positive from A -negative ADAD participants and showed a stronger relationship with A load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion: Our findings support a role for plasma GFAP as a clinical biomarker of A -related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights: Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer's disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not.

Published
2023

17. Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease

Author

Schultz, Stephanie A., Shirzadi, Zahra, Schultz, Aaron P., Liu, Lei, Fitzpatrick, Colleen D., McDade, Eric, Barthelemy, Nicolas R., Renton, Alan, Esposito, Bianca, Joseph-Mathurin, Nelly, Cruchaga, Carlos, Chen, Charles D., Goate, Alison, Allegri, Ricardo F., Benzinger, Tammie L. S., Berman, Sarah, Chui, Helena C., Fagan, Anne M., Farlow, Martin R., Fox, Nick C., Gordon, Brian A., Day, Gregory S., Graff-Radford, Neill R., Hassenstab, Jason J., Hanseeuw, Bernard J., Hofmann, Anna, Jack Jr, Clifford R., Jucker, Mathias, Karch, Celeste M., Koeppe, Robert A., Lee, Jae-Hong, Levey, Allan I., Levin, Johannes, Martins, Ralph, Mori, Hiroshi, Morris, John C., Noble, James, Perrin, Richard J., Rosa-Neto, Pedro, Salloway, Stephen P., Sanchez-Valle, Raquel, Schofield, Peter R., Xiong, Chengjie, Johnson, Keith A., Bateman, Randall J., Sperling, Reisa A., Chhatwal, Jasmeer P., Dominantly Inherited Alzheimer Network Investigators, Schultz, Stephanie A., Shirzadi, Zahra, Schultz, Aaron P., Liu, Lei, Fitzpatrick, Colleen D., McDade, Eric, Barthelemy, Nicolas R., Renton, Alan, Esposito, Bianca, Joseph-Mathurin, Nelly, Cruchaga, Carlos, Chen, Charles D., Goate, Alison, Allegri, Ricardo F., Benzinger, Tammie L. S., Berman, Sarah, Chui, Helena C., Fagan, Anne M., Farlow, Martin R., Fox, Nick C., Gordon, Brian A., Day, Gregory S., Graff-Radford, Neill R., Hassenstab, Jason J., Hanseeuw, Bernard J., Hofmann, Anna, Jack Jr, Clifford R., Jucker, Mathias, Karch, Celeste M., Koeppe, Robert A., Lee, Jae-Hong, Levey, Allan I., Levin, Johannes, Martins, Ralph, Mori, Hiroshi, Morris, John C., Noble, James, Perrin, Richard J., Rosa-Neto, Pedro, Salloway, Stephen P., Sanchez-Valle, Raquel, Schofield, Peter R., Xiong, Chengjie, Johnson, Keith A., Bateman, Randall J., Sperling, Reisa A., Chhatwal, Jasmeer P., and Dominantly Inherited Alzheimer Network Investigators

Published
2023

18. Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN).

Author

McKay, NS, Gordon, BA, Hornbeck, RC, Dincer, A, Flores, S, Keefe, SJ, Joseph-Mathurin, N, Jack, CR, Koeppe, R, Millar, PR, Ances, BM, Chen, CD, Daniels, A, Hobbs, DA, Jackson, K, Koudelis, D, Massoumzadeh, P, McCullough, A, Nickels, ML, Rahmani, F, Swisher, L, Wang, Q, Allegri, RF, Berman, SB, Brickman, AM, Brooks, WS, Cash, DM, Chhatwal, JP, Day, GS, Farlow, MR, la Fougère, C, Fox, NC, Fulham, M, Ghetti, B, Graff-Radford, N, Ikeuchi, T, Klunk, W, Lee, J-H, Levin, J, Martins, R, Masters, CL, McConathy, J, Mori, H, Noble, JM, Reischl, G, Rowe, C, Salloway, S, Sanchez-Valle, R, Schofield, PR, Shimada, H, Shoji, M, Su, Y, Suzuki, K, Vöglein, J, Yakushev, I, Cruchaga, C, Hassenstab, J, Karch, C, McDade, E, Perrin, RJ, Xiong, C, Morris, JC, Bateman, RJ, Benzinger, TLS, Dominantly Inherited Alzheimer Network, McKay, NS, Gordon, BA, Hornbeck, RC, Dincer, A, Flores, S, Keefe, SJ, Joseph-Mathurin, N, Jack, CR, Koeppe, R, Millar, PR, Ances, BM, Chen, CD, Daniels, A, Hobbs, DA, Jackson, K, Koudelis, D, Massoumzadeh, P, McCullough, A, Nickels, ML, Rahmani, F, Swisher, L, Wang, Q, Allegri, RF, Berman, SB, Brickman, AM, Brooks, WS, Cash, DM, Chhatwal, JP, Day, GS, Farlow, MR, la Fougère, C, Fox, NC, Fulham, M, Ghetti, B, Graff-Radford, N, Ikeuchi, T, Klunk, W, Lee, J-H, Levin, J, Martins, R, Masters, CL, McConathy, J, Mori, H, Noble, JM, Reischl, G, Rowe, C, Salloway, S, Sanchez-Valle, R, Schofield, PR, Shimada, H, Shoji, M, Su, Y, Suzuki, K, Vöglein, J, Yakushev, I, Cruchaga, C, Hassenstab, J, Karch, C, McDade, E, Perrin, RJ, Xiong, C, Morris, JC, Bateman, RJ, Benzinger, TLS, and Dominantly Inherited Alzheimer Network

Abstract

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.

Published
2023

19. Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease

Author

Ali, Muhammad, Archer, Derek B., Gorijala, Priyanka, Western, Daniel, Timsina, Jigyasha, Fernández, Maria V., Wang, Ting Chen, Satizabal, Claudia L., Yang, Qiong, Beiser, Alexa S., Wang, Ruiqi, Chen, Gengsheng, Gordon, Brian, Benzinger, Tammie L.S., Xiong, Chengjie, Morris, John C., Bateman, Randall J., Karch, Celeste M., McDade, Eric, Goate, Alison, Seshadri, Sudha, Mayeux, Richard P., Sperling, Reisa A., Buckley, Rachel F., Johnson, Keith A., Won, Hong-Hee, Jung, Sang-Hyuk, Kim, Hang-Rai, Seo, Sang W., Kim, Hee J., Mormino, Elizabeth, Laws, Simon M., Fan, Kang-Hsien, Kamboh, M. Ilyas, Vemuri, Prashanthi, Ramanan, Vijay K., Yang, Hyun-Sik, Wenzel, Allen, Rajula, Hema S. R., Mishra, Aniket, Dufouil, Carole, Debette, Stephanie, Lopez, Oscar L., DeKosky, Steven T., Tao, Feifei, Nagle, Michael W., Hohman, Timothy J., Sung, Yun J., Dumitrescu, Logan, Cruchaga, Carlos, Knight Alzheimer Disease Research Center (Knight ADRC), the Dominantly Inherited Alzheimer Network (DIAN), Alzheimer's Disease Neuroimaging Initiative (ADNI), ADNI-DOD, A4 Study Team, the Australian Imaging Biomarkers, Lifestyle (AIBL) Study, Ali, Muhammad, Archer, Derek B., Gorijala, Priyanka, Western, Daniel, Timsina, Jigyasha, Fernández, Maria V., Wang, Ting Chen, Satizabal, Claudia L., Yang, Qiong, Beiser, Alexa S., Wang, Ruiqi, Chen, Gengsheng, Gordon, Brian, Benzinger, Tammie L.S., Xiong, Chengjie, Morris, John C., Bateman, Randall J., Karch, Celeste M., McDade, Eric, Goate, Alison, Seshadri, Sudha, Mayeux, Richard P., Sperling, Reisa A., Buckley, Rachel F., Johnson, Keith A., Won, Hong-Hee, Jung, Sang-Hyuk, Kim, Hang-Rai, Seo, Sang W., Kim, Hee J., Mormino, Elizabeth, Laws, Simon M., Fan, Kang-Hsien, Kamboh, M. Ilyas, Vemuri, Prashanthi, Ramanan, Vijay K., Yang, Hyun-Sik, Wenzel, Allen, Rajula, Hema S. R., Mishra, Aniket, Dufouil, Carole, Debette, Stephanie, Lopez, Oscar L., DeKosky, Steven T., Tao, Feifei, Nagle, Michael W., Hohman, Timothy J., Sung, Yun J., Dumitrescu, Logan, Cruchaga, Carlos, Knight Alzheimer Disease Research Center (Knight ADRC), the Dominantly Inherited Alzheimer Network (DIAN), Alzheimer's Disease Neuroimaging Initiative (ADNI), ADNI-DOD, A4 Study Team, and the Australian Imaging Biomarkers, Lifestyle (AIBL) Study

Abstract

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (AB) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE 4; rs429358; = 0.35, SE = 0.01, P = 6.2 × 10–311, MAF = 0.19), driven by APOE 4, and five additional novel associations (APOE 2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE 4. APOE 4 and 2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; = 0.07, SE = 0.01, P = 9.2 × 10–09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; = 0.1, SE = 0.02, P = 2.4 × 10–10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; = 0.16, SE = 0.03, P = 1.1 × 10–09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, = 0.79, SE = 0.14, P = 1.4 × 10–08, MAF = 0.006, sex-interaction P = 9.8 × 10–07) and chr11p.15.2 (rs192346166, = 0.94, SE = 0.17, P = 3.7 × 10–08, MAF = 0.004, sex-interaction P = 1.3 × 10–03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.

Published
2023

20. Positron emission tomography and magnetic resonance imaging methods and datasets within the dominantly inherited Alzheimer network (DIAN)

Author

McKay, Nicole S., Gordon, Brian A., Hornbeck, Russ C., Dincer, Aylin, Flores, Shaney, Keefe, Sarah J., Joseph-Mathurin, Nelly, Jack, Clifford R., Koeppe, Robert, Millar, Peter R., Ances, Beau M., Chen, Charles D., Daniels, Alisha, Hobbs, Diana A., Jackson, Kelley, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, Nickels, Michael L., Rahmani, Farzaneh, Swisher, Laura, Wang, Qing, Allegri, Ricardo F., Berman, Sarah B., Brickman, Adam M., Brooks, William S., Cash, David M., Chhatwal, Jasmeer P., Day, Gregory S., Farlow, Martin R., la Fougère, Christian, Fox, Nick C., Fulham, Michael, Ghetti, Bernardino, Graff-Radford, Neill, Ikeuchi, Takeshi, Klunk, William, Lee, Jae-Hong, Levin, Johannes, Martins, Ralph, Masters, Colin L., McConathy, Jonathan, Mori, Hiroshi, Noble, James M., Reischl, Gerald, Rowe, Christopher, Salloway, Stephen, Sanchez-Valle, Raquel, Schofield, Peter R., Shimada, Hiroyuki, Shoji, Mikio, Su, Yi, Suzuki, Kazushi, Vöglein, Jonathan, Yakushev, Igor, Cruchaga, Carlos, Hassenstab, Jason, Karch, Celeste, McDade, Eric, Perrin, Richard J., Xiong, Chengjie, Morris, John C., Bateman, Randall J., Benzinger, Tammie L. S., Dominantly Inherited Alzheimer Network, McKay, Nicole S., Gordon, Brian A., Hornbeck, Russ C., Dincer, Aylin, Flores, Shaney, Keefe, Sarah J., Joseph-Mathurin, Nelly, Jack, Clifford R., Koeppe, Robert, Millar, Peter R., Ances, Beau M., Chen, Charles D., Daniels, Alisha, Hobbs, Diana A., Jackson, Kelley, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, Nickels, Michael L., Rahmani, Farzaneh, Swisher, Laura, Wang, Qing, Allegri, Ricardo F., Berman, Sarah B., Brickman, Adam M., Brooks, William S., Cash, David M., Chhatwal, Jasmeer P., Day, Gregory S., Farlow, Martin R., la Fougère, Christian, Fox, Nick C., Fulham, Michael, Ghetti, Bernardino, Graff-Radford, Neill, Ikeuchi, Takeshi, Klunk, William, Lee, Jae-Hong, Levin, Johannes, Martins, Ralph, Masters, Colin L., McConathy, Jonathan, Mori, Hiroshi, Noble, James M., Reischl, Gerald, Rowe, Christopher, Salloway, Stephen, Sanchez-Valle, Raquel, Schofield, Peter R., Shimada, Hiroyuki, Shoji, Mikio, Su, Yi, Suzuki, Kazushi, Vöglein, Jonathan, Yakushev, Igor, Cruchaga, Carlos, Hassenstab, Jason, Karch, Celeste, McDade, Eric, Perrin, Richard J., Xiong, Chengjie, Morris, John C., Bateman, Randall J., Benzinger, Tammie L. S., and Dominantly Inherited Alzheimer Network

Abstract

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case–control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual’s point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of ‘sporadic’ AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.

Published
2023

21. Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Author

Johnson, Erik C. B., Bian, Shijia, Haque, Rafi U., Carter, E. Kathleen, Watson, Caroline M., Gordon, Brian A., Ping, Lingyan, Duong, Duc M., Epstein, Michael P., McDade, Eric, Barthélemy, Nicolas R., Karch, Celeste M., Xiong, Chengjie, Cruchaga, Carlos, Perrin, Richard J., Wingo, Aliza P., Wingo, Thomas S., Chhatwal, Jasmeer P., Day, Gregory S., Noble, James M., Berman, Sarah B., Martins, Ralph, Graff-Radford, Neill R., Schofield, Peter R., Ikeuchi, Takeshi, Mori, Hiroshi, Levin, Johannes, Farlow, Martin, Lah, James J., Haass, Christian, Jucker, Mathias, Morris, John C., Benzinger, Tammie L. S., Roberts, Blaine R., Bateman, Randall J., Fagan, Anne M., Seyfried, Nicholas T., Levey, Allan I., Dominantly Inherited Alzheimer Network, Johnson, Erik C. B., Bian, Shijia, Haque, Rafi U., Carter, E. Kathleen, Watson, Caroline M., Gordon, Brian A., Ping, Lingyan, Duong, Duc M., Epstein, Michael P., McDade, Eric, Barthélemy, Nicolas R., Karch, Celeste M., Xiong, Chengjie, Cruchaga, Carlos, Perrin, Richard J., Wingo, Aliza P., Wingo, Thomas S., Chhatwal, Jasmeer P., Day, Gregory S., Noble, James M., Berman, Sarah B., Martins, Ralph, Graff-Radford, Neill R., Schofield, Peter R., Ikeuchi, Takeshi, Mori, Hiroshi, Levin, Johannes, Farlow, Martin, Lah, James J., Haass, Christian, Jucker, Mathias, Morris, John C., Benzinger, Tammie L. S., Roberts, Blaine R., Bateman, Randall J., Fagan, Anne M., Seyfried, Nicholas T., Levey, Allan I., and Dominantly Inherited Alzheimer Network

Abstract

Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid- (A ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of A plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with A plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than A and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with A and tau.

Published
2023

22. Patterns and implications of neurological examination findings in autosomal dominant Alzheimer disease

Author

Vöglein, Jonathan, Franzmeier, Nicolai, Morris, John C., Dieterich, Marianne, McDade, Eric, Simons, Mikael, Preische, Oliver, Hofmann, Anna, Hassenstab, Jason, Benzinger, Tammie L., Fagan, Anne, Noble, James M., Berman, Sarah B., Graff-Radford, Neill R., Ghetti, Bernardino, Farlow, Martin R., Chhatwal, Jasmeer P., Salloway, Stephen, Xiong, Chengjie, Karch, Celeste M., Cairns, Nigel, Perrin, Richard J., Day, Gregory, Martins, Ralph, Sanchez-Valle, Raquel, Mori, Hiroshi, Shimada, Hiroyuki, Ikeuchi, Takeshi, Suzuki, Kazushi, Schofield, Peter R., Masters, Colin L., Goate, Alison, Buckles, Virginia, Fox, Nick C., Chrem, Patricio, Allegri, Ricardo, Ringman, John M., Yakushev, Igor, Laske, Christoph, Jucker, Mathias, Höglinger, Günter, Bateman, Randall L., Danek, Adrian, Levin, Johannes, Dominantly Inherited Alzheimer Network, Vöglein, Jonathan, Franzmeier, Nicolai, Morris, John C., Dieterich, Marianne, McDade, Eric, Simons, Mikael, Preische, Oliver, Hofmann, Anna, Hassenstab, Jason, Benzinger, Tammie L., Fagan, Anne, Noble, James M., Berman, Sarah B., Graff-Radford, Neill R., Ghetti, Bernardino, Farlow, Martin R., Chhatwal, Jasmeer P., Salloway, Stephen, Xiong, Chengjie, Karch, Celeste M., Cairns, Nigel, Perrin, Richard J., Day, Gregory, Martins, Ralph, Sanchez-Valle, Raquel, Mori, Hiroshi, Shimada, Hiroyuki, Ikeuchi, Takeshi, Suzuki, Kazushi, Schofield, Peter R., Masters, Colin L., Goate, Alison, Buckles, Virginia, Fox, Nick C., Chrem, Patricio, Allegri, Ricardo, Ringman, John M., Yakushev, Igor, Laske, Christoph, Jucker, Mathias, Höglinger, Günter, Bateman, Randall L., Danek, Adrian, Levin, Johannes, and Dominantly Inherited Alzheimer Network

Abstract

Introduction: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. Methods: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. Results: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1 %. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. Discussion: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.

Published
2023

23. Unique genetic architecture of CSF and brain metabolites pinpoints the novel targets for the traits of human wellness

Author

Wang, Ciyang, primary, Western, Dan, additional, Yang, Chengran, additional, Ali, Muhammad, additional, Wang, Lihua, additional, Gorijala, Priyanka, additional, Timsina, Jigyasha, additional, Ruiz, Agustín, additional, Pastor, Pau, additional, Fernandez, Maria, additional, Panyard, Daniel, additional, Engelman, Corinne, additional, Deming, Yuetiva, additional, Boada, Merce, additional, Cano, Amanda, additional, García-González, Pablo, additional, Graff-Radford, Neill, additional, Mori, Hiroshi, additional, Lee, Jae-Hong, additional, Perrin, Richard, additional, Sung, Yun Ju, additional, (DIAN), Dominantly Inherited Alzheimer Network, additional, (ADNI), Alzheimer’s Disease Neuroimaging Initiative, additional, and Cruchaga, Carlos, additional

Published
2023
Full Text
View/download PDF

24. Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

Author

Jesse Nicholas Cochran, Juliana Acosta‐Uribe, Bianca T. Esposito, Lucia Madrigal, David Aguillón, Margarita M. Giraldo, Jared W. Taylor, Joseph Bradley, Brian Fulton‐Howard, Shea J. Andrews, Natalia Acosta‐Baena, Diana Alzate, Gloria P. Garcia, Francisco Piedrahita, Hugo E. Lopez, Ashlyn G. Anderson, Ivan Rodriguez‐Nunez, Kevin Roberts, null Dominantly Inherited Alzheimer Network, Devin Absher, Richard M. Myers, Gary W. Beecham, Christiane Reitz, Lindsay F. Rizzardi, Maria Victoria Fernandez, Alison M. Goate, Carlos Cruchaga, Alan E. Renton, Francisco Lopera, and Kenneth S. Kosik

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2023
Full Text
View/download PDF

25. Effects of Resilience-Related Life Experiences on Interindividual Variability in Age at Symptom Onset in Participants with Dominantly Inherited Alzheimer's Disease: A Prospective Observational Cohort Study

Author

Hye Joo Son, Jae Seung Kim, Randall J. Bateman, Seonok Kim, Jorge J. Llibre Guerra, Gregory S. Day, Jasmeer P. Chhatwal, Sarah B. Berman, Peter R. Schofield, Mathias Jucker, Johannes Levin, Jae-Hong Lee, Richard Perrin, John C. Morris, Carlos Cruchaga, Jason Hassenstab, Stephen Salloway, Jai-Hyuen Lee, Alisha Daniels, and Dominantly Inherited Alzheimer Network (DIAN)

Published
2023
Full Text
View/download PDF

26. Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP

Author

Jiang, Shan, Wen, Natalie, Li, Zeran, Dube, Umber, Del Aguila, Jorge, Budde, John, Martinez, Rita, Hsu, Simon, Fernandez, Maria V., Cairns, Nigel J., Dominantly Inherited Alzheimer Network (DIAN), International FTD-Genomics Consortium (IFGC), Harari, Oscar, Cruchaga, Carlos, and Karch, Celeste M.

Published
2018
Full Text
View/download PDF

27. The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease

Author

Twohig, Daniel, Rodriguez-Vieitez, Elena, Sando, Sigrid B., Berge, Guro, Lauridsen, Camilla, Møller, Ina, Grøntvedt, Gøril R., Bråthen, Geir, Patra, Kalicharan, Bu, Guojun, Benzinger, Tammie L. S., Karch, Celeste M., Fagan, Anne, Morris, John C., Bateman, Randall J., Nordberg, Agneta, White, Linda R., Nielsen, Henrietta M., and for the Dominantly Inherited Alzheimer Network (DIAN)

Published
2018
Full Text
View/download PDF

28. Discovery and validation of autosomal dominant Alzheimer’s disease mutations

Author

Hsu, Simon, Gordon, Brian A., Hornbeck, Russ, Norton, Joanne B., Levitch, Denise, Louden, Adia, Ziegemeier, Ellen, Laforce, Jr., Robert, Chhatwal, Jasmeer, Day, Gregory S., McDade, Eric, Morris, John C., Fagan, Anne M., Benzinger, Tammie L. S., Goate, Alison M., Cruchaga, Carlos, Bateman, Randall J., Dominantly Inherited Alzheimer Network (DIAN), and Karch, Celeste M.

Published
2018
Full Text
View/download PDF

29. Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease

Author

Phoebe Valdes, Andrew B Caldwell, Qing Liu, Michael Q Fitzgerald, Srinivasan Ramachandran, Celeste M Karch, Dominantly Inherited Alzheimer Network (DIAN), Douglas R Galasko, Shuana H Yuan, Steven L Wagner, and Shankar Subramaniam

Abstract

Background Mutations in PSEN1, PSEN2, and APP can lead to Alzheimer’s disease (AD) with an early age at onset (AAO) and hallmark progressive cognitive decline. These mutations are highly penetrant. Although mutations in PSEN1 are more common and usually have an earlier AAO, certain mutations in PSEN1 cause a later AAO, similar to PSEN2 and APP mutations. We sought to determine whether common disease endotypes exist across these mutations with a relatively late AAO. Methods We generated hiPSC-derived neurons from patients harboring autosomal-dominant, familial Alzheimer’s disease (FAD) mutations in PSEN1, PSEN2, and APP with a documented age at onset (AAO) around 55 years: PSEN1A79V, PSEN2N141I, and APPV717I. We carried out RNA-seq and ATAC-seq to mechanistically characterize the gene expression and chromatin accessibility changes, respectively. Differential expression analysis, enrichment analysis, TF activity identification, and co-expression module detection were performed for RNA-seq. Differential peak analysis and annotation, TF motif footprinting and differential motif accessibility, and peak functional enrichment were performed for ATAC-seq. This approach allowed us to identify the correlation between gene expression and chromatin accessibility associated with key disease endotypes. Results Using a multiomics approach, we identify and characterize common endotypes in mutations across all three FAD genes: dedifferentiation of a mature neuron to a less differentiated quasi-neuron state, dysregulation of synaptic signaling, repression of mitochondrial function and metabolism, and inflammation. The integrativeanalysis allowed us to ascertain the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), as well as NRF1 (repression). Conclusions Our findings characterize the common regulatory changes within endotypes across these FAD mutations. However, the severity of dysregulation often differs between PSEN1, PSEN2, and APP mutations both in magnitude and direction. The overarching common link between mutations in FAD genes is the reversion to a less-differentiated neuron state. The transcriptional regulatory mechanisms described within disease endotypes offer potential targets for therapeutic interventions.

Published
2022
Full Text
View/download PDF

31. Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease

Author

Valdes, Phoebe, primary, Caldwell, Andrew B, additional, Liu, Qing, additional, Fitzgerald, Michael Q, additional, Ramachandran, Srinivasan, additional, Karch, Celeste M, additional, (DIAN), Dominantly Inherited Alzheimer Network, additional, Galasko, Douglas R, additional, Yuan, Shuana H, additional, Wagner, Steven L, additional, and Subramaniam, Shankar, additional

Published
2022
Full Text
View/download PDF

32. Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease

Author

Joseph-Mathurin, Nelly, Llibre-Guerra, Jorge J, Gordon, Brian A, Chen, Charles D, Flores, Shaney, Aggarwal, Neelum T, Berman, Sarah B, Bird, Thomas D, Black, Sandra E, Borowski, Bret, Brooks, William S, Chhatwal, Jasmeer P, Li, Yan, Clarnette, Roger, Cruchaga, Carlos, Fagan, Anne M, Farlow, Martin, Fox, Nick C, Gauthier, Serge, Hassenstab, Jason, Hobbs, Diana A, Holdridge, Karen C, Honig, Lawrence S, McCullough, Austin A, Hornbeck, Russ C, Hsiung, Ging-Yuek R, Jack, Clifford R, Jimenez-Velazquez, Ivonne Z, Jucker, Mathias, Klein, Gregory, Levin, Johannes, Mancini, Michele, Masellis, Mario, McKay, Nicole S, Hofmann, Carsten, Mummery, Catherine J, Ringman, John M, Shimada, Hiroyuki, Snider, B Joy, Suzuki, Kazushi, Wallon, David, Xiong, Chengjie, Yaari, Roy, McDade, Eric, Perrin, Richard J, Wojtowicz, Jakub, Bateman, Randall J, Salloway, Stephen P, Benzinger, Tammie L S, Clifford, David B, Dominantly Inherited Alzheimer Network Trials Unit., Park, Ethan, Wang, Guoqiao, Preboske, Gregory M, and Wang, Qing

Subjects
Amyloid, Amyloid beta-Peptides, gantenerumab, genetics [Alzheimer Disease], Cross-Sectional Studies, Apolipoproteins E, Neurology, Alzheimer Disease, drug therapy [Alzheimer Disease], Humans, ddc:610, Neurology (clinical), diagnostic imaging [Alzheimer Disease], Biomarkers
Abstract

To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD).142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors.Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR 0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E.In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Published
2022
Full Text
View/download PDF

33. Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

Author

Cochran, Jesse Nicholas, Acosta‐Uribe, Juliana, Esposito, Bianca T., Madrigal, Lucia, Aguillón, David, Giraldo, Margarita M., Taylor, Jared W., Bradley, Joseph, Fulton‐Howard, Brian, Andrews, Shea J., Acosta‐Baena, Natalia, Alzate, Diana, Garcia, Gloria P., Piedrahita, Francisco, Lopez, Hugo E., Anderson, Ashlyn G., Rodriguez‐Nunez, Ivan, Roberts, Kevin, Dominantly Inherited Alzheimer Network, and Absher, Devin

Abstract

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early‐onset AD study and four late‐onset AD studies. RESULTS: 13 variants had p<1×10−7 or p<1×10−5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

34. Comparative analysis of Alzheimer’s disease Cerebrospinal fluid biomarkers measurement by multiplex SOMAscan platform and immunoassay-based approach

Author

Timsina, Jigyasha, Gomez-Fonseca, Duber, Xiong, Chengjie, Schindler, Suzanne E, Fagan, Anne M, Bateman, Randall J, Farlow, Martin, Morris, John C, Perrin, Richard J, Moulder, Krista, Hassenstab, Jason, Vöglein, Jonathan, Wang, Lihua, Chhatwal, Jasmeer, Mori, Hiroshi, Initiative, Alzheimer’s Disease Neuroimaging, Consortia, Dominantly Inherited Alzheimer Network, Sung, Yun Ju, Cruchaga, Carlos, Do, Anh, Western, Dan, Alvarez, Ignacio, Aguilar, Miquel, Pastor, Pau, Henson, Rachel L, and Herries, Elizabeth

Subjects
Immunoassay, Amyloid beta-Peptides, assays, diagnosis [Alzheimer Disease], tau Proteins, cerebrospinal fluid [Amyloid beta-Peptides], Article, cerebrospinal fluid [Alzheimer Disease], cerebrospinal fluid [Biomarkers], cerebrospinal fluid [tau Proteins], ROC Curve, Alzheimer Disease, correlation, Humans, Neurogranin, ddc:610, cerebrospinal fluid [Neurogranin], SOMAscan, cerebrospinal fluid biomarkers, Alzheimer’s disease, Biomarkers
Abstract

BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer’s disease (AD) and neurodegeration: NfL, Neurogranin, sTREM2, VILIP-1 and SNAP-25. METHODS: We compared biomarkers measured in ADNI (N=689), Knight-ADRC (N=870), DIAN (N=115), and Barcelona-1 (N=92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson’s correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. RESULTS: Neurogranin, VILIP-1 and NfL showed high correlation between SOMAscan and immunoassay measures (r > 0.9). sTREM2 had a fair correlation (r > 0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1 and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers.

Published
2022
Full Text
View/download PDF

36. Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort.

Author

Kommaddi, Reddy Peera, Verma, Aditi, Muniz-Terrera, Graciela, Tiwari, Vivek, Chithanathan, Keerthana, Diwakar, Latha, Gowaikar, Ruturaj, Karunakaran, Smitha, Malo, Palash Kumar, Graff-Radford, Neill R., Day, Gregory S., Laske, Christoph, Vöglein, Jonathan, Nübling, Georg, Ikeuchi, Takeshi, Kasuga, Kensaku, the Dominantly Inherited Alzheimer Network (DIAN), and Ravindranath, Vijayalakshmi

Published
2023
Full Text
View/download PDF

37. Accelerated functional brain aging in pre-clinical familial Alzheimer's disease

Author

Gonneaud, Julie, Baria, Alex T, Pichet Binette, Alexa, Gordon, Brian A, Chhatwal, Jasmeer P, Cruchaga, Carlos, Jucker, Mathias, Levin, Johannes, Salloway, Stephen, Farlow, Martin, Gauthier, Serge, Benzinger, Tammie LS, Morris, John C, Bateman, Randall J, Breitner, John CS, Poirier, Judes, Vachon-Presseau, Etienne, Villeneuve, Sylvia, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Dominantly Inherited Alzheimer Network (DIAN) Study Group, and Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT-AD) Research Group

Subjects
Adult, Male, Aging, Neurodegenerative, Alzheimer's Disease, Young Adult, Alzheimer Disease, Clinical Research, Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT-AD) Research Group, 80 and over, Acquired Cognitive Impairment, Humans, Genetic Predisposition to Disease, Cognitive Dysfunction, Longitudinal Studies, Aged, Brain Mapping, Amyloid beta-Peptides, Neurosciences, Brain, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer’s Disease Neuroimaging Initiative, Dominantly Inherited Alzheimer Network (DIAN) Study Group, Middle Aged, Magnetic Resonance Imaging, Brain Disorders, Positron-Emission Tomography, Mutation, Neurological, Female, Dementia
Abstract

Resting 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.

Published
2021

38. Neuropsychiatric symptoms are early indicators of an upcoming metabolic decline in Alzheimer’s disease

Author

Kok Pin Ng, Tharick A. Pascoal, Sulantha Mathotaarachchi, Yiong Huak Chan, Lai Jiang, Joseph Therriault, Andrea L. Benedet, Monica Shin, Nagaendran Kandiah, Celia M. T. Greenwood, Pedro Rosa-Neto, Serge Gauthier, and Dominantly Inherited Alzheimer Network

Subjects
Adult, Male, Oncology, Heterozygote, medicine.medical_specialty, Neurology, Cognitive Neuroscience, Diad, Disease, Neuropsychological Tests, Irritability, lcsh:RC346-429, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Mutation Carrier, Alzheimer Disease, Fluorodeoxyglucose F18, Internal medicine, medicine, Humans, Longitudinal Studies, Age of Onset, lcsh:Neurology. Diseases of the nervous system, Dominantly inherited Alzheimer’s disease, Aged, 030214 geriatrics, business.industry, Mental Disorders, Research, Middle Aged, Metabolic correlates, Penetrance, Neuropsychiatric symptoms, Disinhibition, Positron-Emission Tomography, Posterior cingulate, Mutation, Disease Progression, Female, Neurology (clinical), Nervous System Diseases, Radiopharmaceuticals, medicine.symptom, Factor Analysis, Statistical, business, 030217 neurology & neurosurgery
Abstract

Background Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer’s disease (AD) continuum. However, the role of NPS as an early marker of pathophysiological progression in AD remains unclear. Dominantly inherited AD (DIAD) mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation. Hence, the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies. In this longitudinal study, we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers. Methods We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer’s Network according to their mutation carrier status. The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q), age, and estimated years to symptom onset (EYO) as a function of metabolism measured by [18F]flurodeoxyglucose ([18F]FDG) positron emission tomography, were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers. Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q sub-components. Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model. Results A total of 119 mutation carriers and 102 non-carriers were studied. The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional [18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices, the bilateral parietal lobes and the right insula in DIAD mutation carriers. The neuropsychiatric subsyndromes of agitation, disinhibition, irritability and depression interacted with the EYO to drive the [18F]FDG uptake decline in the DIAD mutation carriers. The interaction of NPI and EYO was not associated with [18F]FDG uptake in DIAD mutation non-carriers. Conclusions The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD, which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD. Further studies using different methodological approaches to identify NPS in preclinical AD are needed to validate our findings.

Published
2021
Full Text
View/download PDF

39. Plasma amyloid‐beta levels in a pre‐symptomatic dutch‐type hereditary cerebral amyloid angiopathy pedigree: A cross‐sectional and longitudinal investigation

Author

Chatterjee, Pratishtha, Tegg, Michelle, Pedrini, Steve, Fagan, Anne M., Xiong, Chengjie, Singh, Abhay K., Taddei, Kevin, Gardener, Samantha, Masters, Colin L., Schofield, Peter R., Multhaup, Gerhard, Benzinger, Tammie L. S., Morris, John C., Bateman, Randall J., Greenberg, Steven M., van Buchem, Mark A., Stoops, Erik, Vanderstichele, Hugo, Teunissen, Charlotte E., Hankey, Graeme J., Wermer, Marieke J. H., Sohrabi, Hamid R., Martins, Ralph N., the Dominantly Inherited Alzheimer Network, Chatterjee, Pratishtha, Tegg, Michelle, Pedrini, Steve, Fagan, Anne M., Xiong, Chengjie, Singh, Abhay K., Taddei, Kevin, Gardener, Samantha, Masters, Colin L., Schofield, Peter R., Multhaup, Gerhard, Benzinger, Tammie L. S., Morris, John C., Bateman, Randall J., Greenberg, Steven M., van Buchem, Mark A., Stoops, Erik, Vanderstichele, Hugo, Teunissen, Charlotte E., Hankey, Graeme J., Wermer, Marieke J. H., Sohrabi, Hamid R., Martins, Ralph N., and the Dominantly Inherited Alzheimer Network

Published
2021

40. Plasma amyloid-beta levels in a pre-symptomatic Dutch-type hereditary cerebral amyloid angiopathy pedigree: A cross-sectional and longitudinal investigation

Author

Chatterjee, P., Tegg, M., Pedrini, S., Fagan, A., Xiong, C., Singh, A., Taddei, K., Gardener, S., Masters, C., Schofield, P., Multhaup, G., Benzinger, T., Morris, J., Bateman, R., Greenberg, S., van Buchem, M., Stoops, E., Vanderstichele, H., Teunissen, C., Hankey, G., Wermer, M., Sohrabi, H., Martins, R.N., the Dominantly Inherited Alzheimer Network, Chatterjee, P., Tegg, M., Pedrini, S., Fagan, A., Xiong, C., Singh, A., Taddei, K., Gardener, S., Masters, C., Schofield, P., Multhaup, G., Benzinger, T., Morris, J., Bateman, R., Greenberg, S., van Buchem, M., Stoops, E., Vanderstichele, H., Teunissen, C., Hankey, G., Wermer, M., Sohrabi, H., Martins, R.N., and the Dominantly Inherited Alzheimer Network

Abstract

Plasma amyloid-beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3–4 years later (NC = 8; MC = 9). Plasma Aβ1-40 and Aβ1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aβ1-40: p = 0.001; Aβ1-42: p = 0.0004) and T2 (Aβ1-40: p = 0.001; Aβ1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aβ1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aβ1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aβ may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.

Published
2021

41. Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease

Author

Ewers, Michael, Luan, Ying, Frontzkowski, Lukas, Neitzel, Julia, Rubinski, Anna, Dichgans, Martin, Hassenstab, Jason, Gordon, Brian A., Chhatwal, Jasmeer P., Levin, Johannes, Schofield, Peter, Benzinger, Tammie L. S., Morris, John C., Goate, Alison, Karch, Celeste M., Fagan, Anne M., McDade, Eric, Allegri, Ricardo, Berman, Sarah, Chui, Helena, Cruchaga, Carlos, Farlow, Marty, Graff-Radford, Neill, Jucker, Mathias, Lee, Jae-Hong, Martins, Ralph N., Mori, Hiroshi, Perrin, Richard, Xiong, Chengjie, Rosser, Martin, Fox, Nick C, O'Connor, Antoinette, Salloway, Stephen, Danek, Adrian, Beurger, Katharina, Bateman, Randall J, Habeck, Christian, Stern, Yaakov, Franzmeier, Nicolai, Alzheimer's Disease Neuroimaging Initiative and the Dominantly Inherited Alzheimer Network, Ewers, Michael, Luan, Ying, Frontzkowski, Lukas, Neitzel, Julia, Rubinski, Anna, Dichgans, Martin, Hassenstab, Jason, Gordon, Brian A., Chhatwal, Jasmeer P., Levin, Johannes, Schofield, Peter, Benzinger, Tammie L. S., Morris, John C., Goate, Alison, Karch, Celeste M., Fagan, Anne M., McDade, Eric, Allegri, Ricardo, Berman, Sarah, Chui, Helena, Cruchaga, Carlos, Farlow, Marty, Graff-Radford, Neill, Jucker, Mathias, Lee, Jae-Hong, Martins, Ralph N., Mori, Hiroshi, Perrin, Richard, Xiong, Chengjie, Rosser, Martin, Fox, Nick C, O'Connor, Antoinette, Salloway, Stephen, Danek, Adrian, Beurger, Katharina, Bateman, Randall J, Habeck, Christian, Stern, Yaakov, Franzmeier, Nicolai, and Alzheimer's Disease Neuroimaging Initiative and the Dominantly Inherited Alzheimer Network

Abstract

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of fu

Published
2021

42. Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease

Author

Nelly Joseph‐Mathurin, Yi Su, Tyler M. Blazey, Mateusz Jasielec, Andrei Vlassenko, Karl Friedrichsen, Brian A. Gordon, Russ C. Hornbeck, Lisa Cash, Beau M. Ances, Thomas Veale, David M. Cash, Adam M. Brickman, Virginia Buckles, Nigel J. Cairns, Carlos Cruchaga, Alison Goate, Clifford R. Jack Jr., Celeste Karch, William Klunk, Robert A. Koeppe, Daniel S. Marcus, Richard Mayeux, Eric McDade, James M. Noble, John Ringman, Andrew J. Saykin, Paul M. Thompson, Chengjie Xiong, John C. Morris, Randall J. Bateman, Tammie L.S. Benzinger, and Dominantly Inherited Alzheimer Network

Subjects
FDG, PiB, Neuroimaging, Perfusion scanning, Disease, lcsh:Geriatrics, lcsh:RC346-429, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Neuronal injury, 0302 clinical medicine, medicine, Dementia, lcsh:Neurology. Diseases of the nervous system, medicine.diagnostic_test, business.industry, Disease progression, Alzheimer's disease, medicine.disease, 3. Good health, Perfusion, Radiation exposure, lcsh:RC952-954.6, Psychiatry and Mental health, Positron emission tomography, Neurology (clinical), Nuclear medicine, business, 030217 neurology & neurosurgery
Abstract

Introduction 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11 C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. Methods FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. Results Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. Discussion Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure.

Published
2018
Full Text
View/download PDF

43. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease

Author

Barthélemy, Nicolas R., Li, Yan, Joseph-Mathurin, Nelly, Gordon, Brian A., Hassenstab, Jason, Benzinger, Tammie L.S., Buckles, Virginia, Fagan, Anne M., Perrin, Richard J., Goate, Alison M., Morris, John C., Karch, Celeste M., Xiong, Chengjie, Allegri, Ricardo, Mendez, Patricio Chrem, Berman, Sarah B., Ikeuchi, Takeshi, Mori, Hiroshi, Shimada, Hiroyuki, Shoji, Mikio, Suzuki, Kazushi, Noble, James, Farlow, Martin, Chhatwal, Jasmeer, Graff-Radford, Neill R., Salloway, Stephen, Schofield, Peter R., Masters, Colin L., Martins, Ralph N., O'Connor, Antoinette, Fox, Nick C., Levin, Johannes, Jucker, Mathias, Lehmann, Sylvain, Sato, Chihiro, Bateman, Randall J., McDade, Eric, Dominantly Inherited Alzheimer Network, Barthélemy, Nicolas R., Li, Yan, Joseph-Mathurin, Nelly, Gordon, Brian A., Hassenstab, Jason, Benzinger, Tammie L.S., Buckles, Virginia, Fagan, Anne M., Perrin, Richard J., Goate, Alison M., Morris, John C., Karch, Celeste M., Xiong, Chengjie, Allegri, Ricardo, Mendez, Patricio Chrem, Berman, Sarah B., Ikeuchi, Takeshi, Mori, Hiroshi, Shimada, Hiroyuki, Shoji, Mikio, Suzuki, Kazushi, Noble, James, Farlow, Martin, Chhatwal, Jasmeer, Graff-Radford, Neill R., Salloway, Stephen, Schofield, Peter R., Masters, Colin L., Martins, Ralph N., O'Connor, Antoinette, Fox, Nick C., Levin, Johannes, Jucker, Mathias, Lehmann, Sylvain, Sato, Chihiro, Bateman, Randall J., McDade, Eric, and Dominantly Inherited Alzheimer Network

Abstract

Development of tau-based therapies for Alzheimer’s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer’s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Published
2020

44. Awareness of genetic risk in the Dominantly Inherited Alzheimer Network (DIAN)

Author

Aschenbrenner, Andrew A., 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, Graber, 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, Dominantly Inherited Alzheimer Network, Aschenbrenner, Andrew A., 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, Graber, 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, and Dominantly Inherited Alzheimer Network

Abstract

Introduction: 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. © 2020 the Alzheimer's Association

Published
2020

45. Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients

Author

Projectafdeling VCI, MS Geriatrie, Circulatory Health, Zorglijn AN/AAN Medisch, Brain, Dominantly Inherited Alzheimer Network (DIAN)* DELCODE study group* Alzheimer's Disease Neuroimaging Initiative (ADNI)* Utrecht VCI study group*, Projectafdeling VCI, MS Geriatrie, Circulatory Health, Zorglijn AN/AAN Medisch, Brain, and Dominantly Inherited Alzheimer Network (DIAN)* DELCODE study group* Alzheimer's Disease Neuroimaging Initiative (ADNI)* Utrecht VCI study group*

Published
2020

46. Discovery and validation of autosomal dominant Alzheimer's disease mutations

Author

Simon Hsu, Brian A. Gordon, Russ Hornbeck, Joanne B. Norton, Denise Levitch, Adia Louden, Ellen Ziegemeier, Robert Laforce, Jasmeer Chhatwal, Gregory S. Day, Eric McDade, John C. Morris, Anne M. Fagan, Tammie L. S. Benzinger, Alison M. Goate, Carlos Cruchaga, Randall J. Bateman, Dominantly Inherited Alzheimer Network (DIAN), and Celeste M. Karch

Subjects
0301 basic medicine, Male, DNA Mutational Analysis, Disease, medicine.disease_cause, lcsh:RC346-429, Amyloid beta-Protein Precursor, Neuroblastoma, 0302 clinical medicine, PSEN2, PSEN1, Genetics, Mutation, Aniline Compounds, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Pathogenicity algorithm, Neurology, Female, Alzheimer's disease, Algorithms, Amyloid, Cognitive Neuroscience, Biology, Transfection, Presenilin, lcsh:RC321-571, 03 medical and health sciences, Alzheimer Disease, Cell Line, Tumor, Presenilin-2, medicine, Presenilin-1, Humans, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene, lcsh:Neurology. Diseases of the nervous system, Family Health, Amyloid beta-Peptides, Research, Cell-based assays, Computational Biology, Reproducibility of Results, medicine.disease, Peptide Fragments, Thiazoles, 030104 developmental biology, Autosomal dominant Alzheimer’s disease, Positron-Emission Tomography, Neurology (clinical), APP, 030217 neurology & neurosurgery
Abstract

Background Alzheimer’s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. Methods In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Results We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379_382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. Conclusions In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes.

Published
2018

47. Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study

Author

Kinnunen, Kirsi M, Cash, David M, Poole, Teresa, Frost, Chris, Benzinger, Tammie LS, Ahsan, R Laila, Leung, Kelvin K, Cardoso, M Jorge, Modat, Marc, Malone, Ian B, Morris, John C, Bateman, Randall J, Marcus, Daniel S, Goate, Alison, Salloway, Stephen P, Correia, Stephen, Sperling, Reisa A, Chhatwal, Jasmeer P, Mayeux, Richard P, Brickman, Adam M, Martins, Ralph N, Farlow, Martin R, Ghetti, Bernardino, Saykin, Andrew J, Jack, Clifford R, Schofield, Peter R, McDade, Eric, Weiner, Michael W, Ringman, John M, Thompson, Paul M, Masters, Colin L, Rowe, Christopher C, Rossor, Martin N, Ourselin, Sebastien, Fox, Nick C, and Dominantly Inherited Alzheimer Network (DIAN)

Subjects
Adult, Male, Aging, Time Factors, Nonlinear modeling, Image Processing, Clinical Sciences, Boundary Shift Integral, Neuroimaging, Bioengineering, Neurodegenerative, Alzheimer's Disease, Apolipoproteins E, Computer-Assisted, Alzheimer Disease, Clinical Research, Change-point, Acquired Cognitive Impairment, Humans, Nonparametric, Longitudinal Studies, Psychiatric Status Rating Scales, Statistics, Neurosciences, Brain, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Middle Aged, Magnetic Resonance Imaging, Brain Disorders, Autosomal dominant, Geriatrics, Dominantly Inherited Alzheimer Network, Neurological, Longitudinal, Biomedical Imaging, Female, Dementia, Atrophy, MRI
Abstract

IntroductionIdentifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials.MethodsSerial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point.ResultsAtrophy increased after the change-point, which occurred 1-1.5years (assuming a single step change in atrophy rate) or 3-8years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point.DiscussionAtrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

Published
2018

48. Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study

Author

Kinnunen, Kirsi M, Cash, David M, Poole, Teresa, Frost, Chris, Benzinger, Tammie LS, Ahsan, R Laila, Leung, Kelvin K, Cardoso, M Jorge, Modat, Marc, Malone, Ian B, Morris, John C, Bateman, Randall J, Marcus, Daniel S, Goate, Alison, Salloway, Stephen P, Correia, Stephen, Sperling, Reisa A, Chhatwal, Jasmeer P, Mayeux, Richard P, Brickman, Adam M, Martins, Ralph N, Farlow, Martin R, Ghetti, Bernardino, Saykin, Andrew J, Jack, Clifford R, Schofield, Peter R, McDade, Eric, Weiner, Michael W, Ringman, John M, Thompson, Paul M, Masters, Colin L, Rowe, Christopher C, Rossor, Martin N, Ourselin, Sebastien, Fox, Nick C, and Dominantly Inherited Alzheimer Network (DIAN)

Subjects
sense organs, skin and connective tissue diseases
Abstract

INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

Published
2017

49. [Accepted Manuscript] Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study

Author

Kinnunen, K.M., Cash, D.M., Poole, T., Frost, C., Benzinger, T.L.S., Ahsan, R.L., Leung, K.K., Cardoso, M.J., Modat, M., Malone, I.B., Morris, J.C., Bateman, R.J., Marcus, D.S., Goate, A., Salloway, S., Correia, S., Sperling, R.A., Chhatwal, J.P., Mayeux, R., Brickman, A.M., Martins, R.N., Farlow, M.R., Ghetti, B., Saykin, A.J., Jack, C.R. Jr, Schofield, P.R., McDade, E., Weiner, M.W., Ringman, J.M., Thompson, P.M., Masters, C.L., Rowe, C.C., Rossor, M.N., Ourselin, S., Fox, N.C., and Dominantly Inherited Alzheimer Network (DIAN), .

Subjects
sense organs, skin and connective tissue diseases
Abstract

Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Serial T1-weighed magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

Published
2017

50. A novel cognitive disease progression model for clinical trials in autosomal-dominant Alzheimer's disease.

Author

Wang, Guoqiao, Berry, Scott, Xiong, Chengjie, Hassenstab, Jason, Quintana, Melanie, McDade, Eric M., Delmar, Paul, Vestrucci, Matteo, Sethuraman, Gopalan, Bateman, Randall J., For the Dominantly Inherited Alzheimer Network Trials Unit, and Dominantly Inherited Alzheimer Network Trials Unit

Abstract

Clinical trial outcomes for Alzheimer's disease are typically analyzed by using the mixed model for repeated measures (MMRM) or similar models that compare an efficacy scale change from baseline between treatment arms with or without participants' disease stage as a covariate. The MMRM focuses on a single-point fixed follow-up duration regardless of the exposure for each participant. In contrast to these typical models, we have developed a novel semiparametric cognitive disease progression model (DPM) for autosomal dominant Alzheimer's disease based on the Dominantly Inherited Alzheimer Network (DIAN) observational study. This model includes 3 novel features, in which the DPM (1) aligns and compares participants by disease stage, (2) uses a proportional treatment effect similar to the concept of the Cox proportional hazard ratio, and (3) incorporates extended follow-up data from participants with different follow-up durations using all data until last participant visit. We present the DPM model developed by using the DIAN observational study data and demonstrate through simulation that the cognitive DPM used in hypothetical intervention clinical trials produces substantial gains in power compared with the MMRM. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results