Annals of Neurology | February 7, 2021

Litvinchuk A, Huynh TV, Shi Y, Jackson RJ, Finn MB, Manis M, Francis CM, Tran A, Sullivan PM, Ulrich JD, Hyman BT, Cole T and Holtzman DM

Ann Neurol. 2021

DOI: https://doi.org/10.1002/ana.26043

Abstract

Objective

Apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late‐onset Alzheimer’s disease with the ε4 allele increasing risk in a dose‐dependent fashion. In addition to ApoE4 playing a crucial role in amyloid‐β deposition, recent evidence suggests that it also plays an important role in tau pathology and tau‐mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau‐mediated neurodegeneration.

Methods

Herein, we utilized antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 months and 7.5 months of age and performed brain pathological assessments at 9 months of age.

Results

Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO‐treated mice.

Interpretation

We conclude that reducing ApoE4 levels should be further explored as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer’s disease.