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

Research output: Contribution to journalReview articlepeer-review

61 Scopus citations


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.

Original languageEnglish
Pages (from-to)1304-1317
Number of pages14
Issue number8
StatePublished - Apr 20 2022


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