What Threshold of Amyloid Reduction Is Necessary to Meaningfully Improve Cognitive Function in Transgenic Alzheimer's Disease Mice?

ABSTRACT

Background: Amyloid-ß plaques (Aß) are associated with Alzheimer's disease (AD). Pooled assessment of amyloid reduction in transgenic AD mice is critical for expediting anti-amyloid AD therapeutic research. Objective: The mean threshold of Aß reduction necessary to achieve cognitive improvement was measured via pooled assessment (n = 594 mice) of Morris water maze (MWM) escape latency of transgenic AD mice treated with substances intended to reduce Aß via reduction of beta-secretase cleaving enzyme (BACE). Methods: Machine learning and statistical methods identified necessary amyloid reduction levels using mouse data (e.g., APP/PS1, LPS, Tg2576, 3xTg-AD, control, wild type, treated, untreated) curated from 22 published studies. Results: K-means clustering identified 4 clusters that primarily corresponded with level of Aß untreated transgenic AD control mice, wild type mice, and two clusters of transgenic AD mice treated with BACE inhibitors that had either an average 25% "medium reduction" of Aß or 50% "high reduction" of Aß compared to untreated control. A 25% Aß reduction achieved a 28% cognitive improvement, and a 50% Aß reduction resulted in a significant 32% improvement compared to untreated transgenic mice (p < 0.05). Comparatively, wild type mice had a mean 41% MWM latency improvement over untreated transgenic mice (p < 0.05). BACE reduction had a lesser impact on the ratio of Aß42 to Aß40. Supervised learning with an 80% -20% train-test split confirmed Aß reduction was a key feature for predicting MWM escape latency (R2 = 0.8 to 0.95). Conclusions: Results suggest a 25% reduction in Aß as a meaningful treatment threshold for improving transgenic AD mouse cognition.