Chemparathy A, LeGuen Y, Chen S, Lee E-G, Leong L, Gorzynski J, Xu G, Belloy M, Kasireddy N, Pena-Tauber A, Williams K, Stewart I, Wingo T, Lah J, Jayadev S, Hales C, Peskind E, Child DD, Keene CD, Cong L, Ashley E, Yu C-E, Greicus M. APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology. 2023 Jul 24 10.1101/2023.07.20.23292771 (version 1) medRxiv.

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  1. Congratulations on a very nice paper confirming in humans what Thomas Wisniewski's and our labs have been study for decades in vitro and in mice, that is, the catalytic activity of apoE4 on amyloid formation and consequent cognitive decline.

    We and colleagues have also used a repurposed drug screen to identify two human drugs, imipramine and olanzapine, that block the catalytic activity of apoE4 on Aβ polymerization into neurotoxic filaments. Both these drugs reversed cognitive decline and clinical diagnosis of AD patients in the NACC database, when they were prescribed for their normal indications. No other anti-depressant or antipsychotic was identified by our screen, or benefitted AD patients in the NACC database, confirming that the common beneficial function of imipramine and olanzapine is in blocking the effect of apoE4. Clinical trials are planned.

    References:

    Ma J, Yee A, Brewer HB, Das S, Potter H. Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature. 1994 Nov 3;372(6501):92-4. PubMed.

    Potter H, Wisniewski T. Apolipoprotein e: essential catalyst of the Alzheimer amyloid cascade. Int J Alzheimers Dis. 2012;2012:489428. PubMed.

    Johnson NR, Wang AC, Coughlan C, Sillau S, Lucero E, Viltz L, Markham N, Allen C, Dhanasekaran AR, Chial HJ, Potter H. Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer's disease cognition. Alzheimers Res Ther. 2022 Jun 29;14(1):88. PubMed.

    View all comments by Noah Johnson

  2. I thoroughly enjoyed reading this elegant study. It nicely addresses the question of whether APOE4 exerts a gain-of-function role in the development of AD pathology and gives hope to the notion that therapeutically reducing APOE4 might be tolerated without significant metabolic or lipidomic side effects. The observation that the loss of functional APOE4 expression so remarkably affected the development of amyloid pathology or cognitive decline in APOE4/APOE3 individuals is a powerful indication that APOE4 protein exerts some deleterious gain-of-function relative to APOE3.

    Of course the role of APOE4 in promoting amyloid pathology is well established, and results from animal models suggest that reducing or removing APOE expression reduces amyloid deposition. Nonetheless, it is a pretty amazing, and very satisfying, result to see such a remarkable protection against amyloid in humans due to loss of APOE4 protein expression.

    Moreover, the fact that the individuals lived rather long lives with only one functional APOE allele suggests that at least reduction of APOE4 or partial reduction of APOE levels could both alleviate AD pathology and be well tolerated in regard to effects on systemic lipid metabolism.

    In our previous studies in mouse models of amyloid or tau pathology we found that about 50 percent reduction of APOE4 expression via anti-sense oligonucleotides could reduce amyloid pathology or tau pathology and tau-dependent neurodegeneration (Litvinchuk et al., 2021; Huynh et al., 2017). In the case of tauopathy, an assessment of plasma lipids found no significant differences resulting from CNS-delivery of ApoE ASOs. One caveat, translationally speaking, is that administration of APOE ASOs after amyloid pathology had begun to develop did not significantly impact amyloid burden in mouse models, although reductions in axonal dystrophy around plaques was noted. Other studies using divalent siRNA knockdown of mouse Apoe reported reductions in plaque burden both before and after the onset of pathology, perhaps due to the more robust level of knockdown reported (about 95 percent; Ferguson et al., 2022). Therapeutic efforts to target APOE4 for reduction will thus need to consider carefully the proper patient population in terms of pathology stage and level of APOE reduction that might yield a therapeutic effect.

    References:

    Litvinchuk A, Huynh TV, Shi Y, Jackson RJ, Finn MB, Manis M, Francis CM, Tran AC, Sullivan PM, Ulrich JD, Hyman BT, Cole T, Holtzman DM. Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model. Ann Neurol. 2021 May;89(5):952-966. Epub 2021 Feb 24 PubMed.

    Huynh TV, Liao F, Francis CM, Robinson GO, Serrano JR, Jiang H, Roh J, Finn MB, Sullivan PM, Esparza TJ, Stewart FR, Mahan TE, Ulrich JD, Cole T, Holtzman DM. Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis. Neuron. 2017 Dec 6;96(5):1013-1023.e4. PubMed.

    Ferguson C, Hildebrand S, Godinho BM, Buchwald J, Echeverria D, Coles A, Grigorenko A, Vanjielli L, Sousa J, McHugh N, Hassler M, Santarelli F, Heneka MT, Rogaev E, Khvorova A. Silencing of ApoE with Divalent siRNAs Drives Activation of Immune Clearance Pathways and Improves Amyloid Pathology in Mouse Models of Alzheimer's Disease. 2022 Jul 02 10.1101/2022.06.28.498012 (version 1) bioRxiv.

    View all comments by Jason Ulrich

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  1. Goodbye, APOE4. Hello, Healthy Brain?