ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias.

Yuka A Martens, Na Zhao, Chia-Chen Liu, Takahisa Kanekiyo, Austin J Yang, Alison M Goate, David M Holtzman, Guojun Bu

Journal: Neuron 2022;110(8):1304-1317

PMID: 35298921

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Abstract

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.

Address: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Division of Neuroscience, National Institute on Aging, Bethesda, MD, USA.; Ronald M. Loeb Center for Alzheimer's Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: [email protected].

DOI: 10.1016/j.neuron.2022.03.004