TY - JOUR
T1 - Coping with brain amyloid
T2 - genetic heterogeneity and cognitive resilience to Alzheimer’s pathophysiology
AU - for the Alzheimer's Disease Neuroimaging Initiative (ADNI)
AU - Ramanan, Vijay K.
AU - Lesnick, Timothy G.
AU - Przybelski, Scott A.
AU - Heckman, Michael G.
AU - Knopman, David S.
AU - Graff-Radford, Jonathan
AU - Lowe, Val J.
AU - Machulda, Mary M.
AU - Mielke, Michelle M.
AU - Jack, Clifford R.
AU - Petersen, Ronald C.
AU - Ross, Owen A.
AU - Vemuri, Prashanthi
N1 - Funding Information:
Dr. Knopman reported serving on a data safety monitoring board for the DIAN study, serving as an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California, and receiving research support from the National Institutes of Health (NIH) outside of the submitted work. Dr. Graff-Radford reported receiving research support from the National Institute on Aging outside the submitted work. Dr. Lowe reported receiving consulting fees from Bayer Schering Pharma, Piramal Life Sciences, and Merck Research and grants from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH outside the submitted work. Dr. Mielke reported receiving research support from the NIH, Department of Defense, and unrestricted research grants from Biogen outside the submitted work. Dr. Jack reported consulting for Eli Lilly, serving on an independent data monitoring board for Roche, and serving as a speaker for Eisai but receives no personal compensation from any commercial entity; he also reported receiving research support from the NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Dr. Petersen reported receiving consulting fees from Hoffman-La Roche Inc, Merck Inc, Genentech Inc, Biogen Inc, GE Healthcare, and Eisai Inc. outside the submitted work. Dr. Vemuri reported receiving grants from the NIH during the conduct of the study. No other disclosures were reported.
Funding Information:
This work was supported by NIH grants U01 AG006786 (PI: Petersen/Mielke/Jack), R01 NS097495 (PI: Vemuri), R01 AG56366 (PI: Vemuri), P50 AG016574 (PI: Petersen), P30 AG062677 (PI: Petersen), R37 AG011378 (PI: Jack), R01 AG041851 (PIs: Jack and Knopman), RF1 AG55151 (PI: Mielke), U54 NS100693 (PI: Ross), and R01 AG034676 (PI: Rocca); the GHR Foundation, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the Elsie and Marvin Dekelboum Family Foundation, the Schuler Foundation, and Opus Building NIH grant C06 RR018898. Data collection and sharing for the ADNI data utilized in this project was funded by the ADNI NIH grant U01 AG024904, other funding through the the National Institute of Biomedical Imaging and Bioengineering, and private sector contributions from the following (facilitated by the Foundation for the National Institutes of Health with the grantee organization as the Northern California Institute for Research and Education): AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. The study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We would like to greatly thank AVID Radiopharmaceuticals, Inc., for their support in supplying AV-1451 precursor, chemistry production advice and oversight, and FDA regulatory cross-filing permission and documentation needed for this work. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer’s disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10–8, β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.
AB - Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer’s disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10–8, β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.
KW - Alzheimer’s
KW - Amyloid
KW - Cognitive decline
KW - Genome-Wide Association Study
KW - Resilience
UR - http://www.scopus.com/inward/record.url?scp=85102940919&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102940919&partnerID=8YFLogxK
U2 - 10.1186/s40478-021-01154-1
DO - 10.1186/s40478-021-01154-1
M3 - Article
C2 - 33757599
AN - SCOPUS:85102940919
SN - 2051-5960
VL - 9
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
M1 - 48
ER -