TY - JOUR
T1 - ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias
AU - Martens, Yuka A.
AU - Zhao, Na
AU - Liu, Chia Chen
AU - Kanekiyo, Takahisa
AU - Yang, Austin J.
AU - Goate, Alison M.
AU - Holtzman, David M.
AU - Bu, Guojun
N1 - Funding Information:
This work is supported by NIH grant U19AG069701 to all listed authors with G.B., D.M.H., and A.M.G. as Co-Principal Investigators. The authors also receive other NIH grants that relate to studies on apoE. G.B. and D.M.H. are further supported by grants from the Cure Alzheimer’s Fund . A.M.G. is supported by grants from the JPB Foundation and the Neurodegeneration Consortium . The authors would like to thank Dr. Ana-Caroline Raulin and Ms. Shelby Ross for critical reading of the manuscript.
Funding Information:
This work is supported by NIH grant U19AG069701 to all listed authors with G.B. D.M.H. and A.M.G. as Co-Principal Investigators. The authors also receive other NIH grants that relate to studies on apoE. G.B. and D.M.H. are further supported by grants from the Cure Alzheimer's Fund. A.M.G. is supported by grants from the JPB Foundation and the Neurodegeneration Consortium. The authors would like to thank Dr. Ana-Caroline Raulin and Ms. Shelby Ross for critical reading of the manuscript. Y.A.M. and T.K. led the initial drafting of the manuscript, created figures, and edited the manuscript. N.Z. C.-C.L. A.J.Y. A.M.G. and D.M.H. co-edited the manuscript. G.B. supervised the writing and edited the manuscript. All authors have read and agreed on the final manuscript. G.B. consults for SciNeuro and Lexeo, has consulted for Vida Ventures, AbbVie, E-Scape, and Eisai, is on the scientific advisory board of Kisbee Therapeutics, and serves as a Co-Editor-in-Chief for Molecular Neurodegeneration. D.M.H. is as an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. C2N Diagnostics has licensed certain anti-tau antibodies to AbbVie for therapeutic development. D.M.H. is on the scientific advisory board of Denali, Genentech, and Cajal Neurosciences and consults for Eli Lilly. D.M.H. receives sponsored research agreements to Washington University from NextCure, C2N Diagnostics, Yumanity, Eli Lilly, and Novartis. A.M.G. is on the scientific advisory board of Genentech and has consulted for Cognition Therapeutics and AbbVie. The other authors declare no competing interests.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/4/20
Y1 - 2022/4/20
N2 - The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD). The three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel “ApoE Cascade Hypothesis” in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.
AB - The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD). The three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel “ApoE Cascade Hypothesis” in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.
UR - http://www.scopus.com/inward/record.url?scp=85128328584&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2022.03.004
DO - 10.1016/j.neuron.2022.03.004
M3 - Review article
C2 - 35298921
AN - SCOPUS:85128328584
SN - 0896-6273
VL - 110
SP - 1304
EP - 1317
JO - Neuron
JF - Neuron
IS - 8
ER -