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

Author

Damián Hernández, Stephanie Morgan Schlicht, Jordan Elli Clarke, Maciej Daniszewski, Celeste M. Karch, Alison M. Goate, Alice Pébay, Sarah Adams, Ricardo Allegri, Aki Araki, Nicolas Barthelemy, Randall Bateman, Jacob Bechara, Tammie Benzinger, Sarah Berman, Courtney Bodge, Sus Brandon, William (Bill) Brooks, Jared Brosch, Jill Buck, Virginia Buckles, Kathleen Carter, Lisa Cash, Charlie Chen, Jasmeer Chhatwal, Patricio Chrem Mendez, Jasmin Chua, Helena Chui, Laura Courtney, Carlos Cruchaga, Gregory S Day, Chrismary DeLaCruz, Darcy Denner, Anna Diffenbacher, Aylin Dincer, Tamara Donahue, Jane Douglas, Duc Duong, Noelia Egido, Bianca Esposito, Anne Fagan, Marty Farlow, Becca Feldman, Colleen Fitzpatrick, Shaney Flores, Nick Fox, Erin Franklin, Nelly Joseph-Mathurin, Hisako Fujii, Samantha Gardener, Bernardino Ghetti, Alison Goate, Sarah Goldberg, Jill Goldman, Alyssa Gonzalez, Brian Gordon, Susanne Gr¨aber-Sultan, Neill Graff-Radford, Morgan Graham, Julia Gray, Emily Gremminger, Miguel Grilo, Alex Groves, Christian Haass, Lisa H¨asler, Jason Hassenstab, Cortaiga Hellm, Elizabeth Herries, Laura Hoechst-Swisher, Anna Hofmann, David Holtzman, Russ Hornbeck, Yakushev Igor, Ryoko Ihara, Takeshi Ikeuchi, Snezana Ikonomovic, Kenji Ishii, Clifford Jack, Gina Jerome, Erik Johnson, Mathias Jucker, Celeste Karch, Stephan K¨aser, Kensaku Kasuga, Sarah Keefe, William Klunk, Robert Koeppe, Deb Koudelis, Elke Kuder-Buletta, Christoph Laske, Allan Levey, Johannes Levin, Yan Li, Oscar Lopez, Jacob Marsh, Ralph Martins, Neal Scott Mason, Colin Masters, Kwasi Mawuenyega, Austin McCullough, Eric McDade, Arlene Mejia, Estrella Morenas-Rodriguez, John Morris, James Mountz, Cath Mummery, Neelesh Nadkarni, Akemi Nagamatsu, Katie Neimeyer, Yoshiki Niimi, James Noble, Joanne Norton, Brigitte Nuscher, Ulricke Obermüller, Antoinette O’Connor, Riddhi Patira, Richard Perrin, Lingyan Ping, Oliver Preische, Alan Renton, John Ringman, Stephen Salloway, Peter Schofield, Michio Senda, Nicholas T Seyfried, Kristine Shady, Hiroyuki Shimada, Wendy Sigurdson, Jennifer Smith, Lori Smith, Beth Snitz, Hamid Sohrabi, Sochenda Stephens, Kevin Taddei, Sarah Thompson, Jonathan V¨oglein, Peter Wang, Qing Wang, Elise Weamer, Chengjie Xiong, Jinbin Xu, and Xiong Xu

Subjects
Biology (General), QH301-705.5
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
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2. Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease

Author

Peter R. Millar, Patrick H. Luckett, Brian A. Gordon, Tammie L.S. Benzinger, Suzanne E. Schindler, Anne M. Fagan, Carlos Cruchaga, Randall J. Bateman, Ricardo Allegri, Mathias Jucker, Jae-Hong Lee, Hiroshi Mori, Stephen P Salloway, Igor Yakushev, John C. Morris, Beau M. Ances, Sarah Adams, MS, Ricardo Allegri, PhD, Aki Araki, Nicolas Barthelemy, PhD, Randall Bateman, MD, Jacob Bechara, BS, Tammie Benzinger, MD, PhD, Sarah Berman, MD, PhD, Courtney Bodge, PhD, Susan Brandon, BS, William (Bill) Brooks, MBBS,MPH, Jared Brosch, MD, PhD, Jill Buck, BSN, Virginia Buckles, PhD, Kathleen Carter, PhD, Lisa Cash, BFA, Charlie Chen, BA, Jasmeer Chhatwal, MD,PhD, Patricio Chrem Mendez, MD, Jasmin Chua, BS, Helena Chui, MD, Laura Courtney, BS, Carlos Cruchaga, PhD, Gregory S Day, MD, Chrismary DeLaCruz, BA, Darcy Denner, PhD, Anna Diffenbacher, MS, Aylin Dincer, BS, Tamara Donahue, MS, Jane Douglas, MPh, Duc Duong, BS, Noelia Egido, BS, Bianca Esposito, BS, Anne Fagan, PhD, Marty Farlow, MD, Becca Feldman, BS,BA, Colleen Fitzpatrick, MS, Shaney Flores, BS, Nick Fox, MD, Erin Franklin, MS, Nelly Joseph-Mathurin, PhD, Hisako Fujii, PhD, Samantha Gardener, PhD, Bernardino Ghetti, MD, Alison Goate, PhD, Sarah Goldberg, MS,LPC,NCC, Jill Goldman, MS,MPhil,CGC, Alyssa Gonzalez, BS, Brian Gordon, PhD, Susanne Gräber-Sultan, PhD, Neill Graff-Radford, MD, Morgan Graham, BA, Julia Gray, MS, Emily Gremminger, BA, Miguel Grilo, MD, Alex Groves, Christian Haass, PhD, Lisa Häsler, MSc, Jason Hassenstab, PhD, Cortaiga Hellm, BA, Elizabeth Herries, BA, Laura Hoechst-Swisher, MS, Anna Hofmann, MD, Anna Hofmann, David Holtzman, MD, Russ Hornbeck, MSCS, MPM, Yakushev Igor, MD, Ryoko Ihara, MD, Takeshi Ikeuchi, MD, Snezana Ikonomovic, MD, Kenji Ishii, MD, Clifford Jack, MD, Gina Jerome, MS, Erik Johnson, MD, PHD, Mathias Jucker, PhD, Celeste Karch, PhD, Stephan Käser, PHD, Kensaku Kasuga, MD, Sarah Keefe, BS, William Klunk, MD, PHD, Robert Koeppe, PHD, Deb Koudelis, MHS,RN, Elke Kuder-Buletta, RN, Christoph Laske, PhD, Allan Levey, MD, PHD, Johannes Levin, MD, Yan Li, PHD, Oscar Lopez, MD, MD, Jacob Marsh, BA, Ralph Martins, PhD, Neal Scott Mason, PhD, Colin Masters, MD, Kwasi Mawuenyega, PhD, Austin McCullough, PhD Candidate, Eric McDade, DO, Arlene Mejia, MD, Estrella Morenas-Rodriguez, MD, PhD, John Morris, MD, James Mountz, MD, Cath Mummery, PhD, N eelesh Nadkarni, MD, PhD, Akemi Nagamatsu, RN, Katie Neimeyer, MS, Yoshiki Niimi, MD, James Noble, MD, Joanne Norton, MSN, RN, PMHCNS-BC, Brigitte Nuscher, Ulricke Obermüller, Antoinette O'Connor, MRCPI, Riddhi Patira, MD, Richard Perrin, MD, PhD, Lingyan Ping, PhD, Oliver Preische, MD, Alan Renton, PhD, John Ringman, MD, Stephen Salloway, MD, Peter Schofield, PhD, Michio Senda, MD, PhD, Nicholas T Seyfried, D.Phil, Kristine Shady, BA, BS, Hiroyuki Shimada, MD, PhD, Wendy Sigurdson, RN, Jennifer Smith, PhD, Lori Smith, PA-C, Beth Snitz, PhD, Hamid Sohrabi, PhD, Sochenda Stephens, BS, CCRP, Kevin Taddei, BS, Sarah Thompson, PA-C, Jonathan Vöglein, MD, Peter Wang, PhD, Qing Wang, PhD, Elise Weamer, MPH, Chengjie Xiong, PhD, Jinbin Xu, PhD, and Xiong Xu, BS, MS

Subjects
Brain aging, Alzheimer disease, Resting-state functional connectivity, fMRI, Machine learning, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18–89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.

Published
2022
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3. Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Anna H Boerwinkle, Brian A Gordon, Julie Wisch, Shaney Flores, Rachel L Henson, Omar H Butt, Nicole McKay, Charles D Chen, Tammie L S Benzinger, Anne M Fagan, Benjamin L Handen, Bradley T Christian, Elizabeth Head, Mark Mapstone, Michael S Rafii, Sid O'Bryant, Florence Lai, H Diana Rosas, Joseph H Lee, Wayne Silverman, Adam M Brickman, Jasmeer P Chhatwal, Carlos Cruchaga, Richard J Perrin, Chengjie Xiong, Jason Hassenstab, Eric McDade, Randall J Bateman, Beau M Ances, Howard J Aizenstein, Howard F Andrews, Karen Bell, Rasmus M Birn, Peter Bulova, Amrita Cheema, Kewei Chen, Isabel Clare, Lorraine Clark, Ann D Cohen, John N Constantino, Eric W Doran, Eleanor Feingold, Tatiana M Foroud, Sigan L Hartley, Christy Hom, Lawrence Honig, Milos D Ikonomovic, Sterling C Johnson, Courtney Jordan, M Ilyas Kamboh, David Keator, William E Klunk MD, Julia K Kofler, William C Kreisl, Sharon J Krinsky- McHale, Patrick Lao, Charles Laymon, Ira T Lott, Victoria Lupson, Chester A Mathis, Davneet S Minhas, Neelesh Nadkarni, Deborah Pang, Melissa Petersen, Julie C Price, Margaret Pulsifer, Eric Reiman, Batool Rizvi, Marwan N Sabbagh, Nicole Schupf, Dana L Tudorascu, Rameshwari Tumuluru, Benjamin Tycko, Badri Varadarajan, Desiree A White, Michael A Yassa, Shahid Zaman, Fan Zhang, Sarah Adams, Ricardo Allegri, Aki Araki, Nicolas Barthelemy, Jacob Bechara, Sarah Berman, Courtney Bodge, Susan Brandon, William Brooks, Jared Brosch, Jill Buck, Virginia Buckles, Kathleen Carter, Lisa Cash, Patricio C Mendez, Jasmin Chua, Helena Chui, Laura Courtney, Gregory Day, Chrismary DeLaCruz, Darcy Denner, Anna Diffenbacher, Aylin Dincer, Tamara Donahue, Jane Douglas, Duc Duong, Noelia Egido, Bianca Esposito, Marty Farlow, Becca Feldman, Colleen Fitzpatrick, Nick Fox, Erin Franklin, Nelly Joseph-Mathurin, Hisako Fujii, Samantha Gardener, Bernardino Ghetti, Alison Goate, Sarah Goldberg, Jill Goldman, Alyssa Gonzalez, Susanne Gräber-Sultan, Neill Graff-Radford, Morgan Graham, Julia Gray, Emily Gremminger, Miguel Grilo, Alex Groves, Christian Haass, Lisa Häslerc, Cortaiga Hellm, Elizabeth Herries, Laura Hoechst-Swisher, Anna Hofmann, David Holtzman, Russ Hornbeck, Yakushev Igor, Ryoko Ihara, Takeshi Ikeuchi, Snezana Ikonomovic, Kenji Ishii, Clifford Jack, Gina Jerome, Erik Johnson, Mathias Jucker, Celeste Karch, Stephan Käser, Kensaku Kasuga, Sarah Keefe, William Klunk, Robert Koeppe, Deb Koudelis, Elke Kuder-Buletta, Christoph Laske, Allan Levey, Johannes Levin, Yan Li, Oscar Lopez, Jacob Marsh, Ralph Martins, Neal S Mason, Colin Masters, Kwasi Mawuenyega, Austin McCullough, Arlene Mejia, Estrella Morenas-Rodriguez, John C Morris, James Mountz, Catherine Mummery, Akemi Nagamatsu, Katie Neimeyer, Yoshiki Niimi, James Noble, Joanne Norton, Brigitte Nuscher, Ulricke Obermüller, Antoinette O'Connor, Riddhi Patira, Lingyan Ping, Oliver Preische, Alan Renton, John Ringman, Stephen Salloway, Peter Schofield, Michio Senda, Nicholas T Seyfried, Kristine Shady, Hiroyuki Shimada, Wendy Sigurdson, Jennifer Smith, Lori Smith, Beth Snitz, Hamid Sohrabi, Sochenda Stephens, Kevin Taddei, Sarah Thompson, Jonathan Vöglein, Peter Wang, Qing Wang, Elise Weamer, Jinbin Xu, and Xiong Xu

Subjects
Adult, Cerebral Cortex, Amyloid beta-Peptides, Apolipoproteins E, Cross-Sectional Studies, Alzheimer Disease, Positron-Emission Tomography, Humans, Neurology (clinical), Middle Aged, Down Syndrome, Biomarkers, Aged
Abstract

Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p0·0001) and in people with Down syndrome (n=32; r=-0·801; p0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome.Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome.The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Published
2022

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