Systematic review of the relationship between amyloid-β levels and measures of transgenic mouse cognitive deficit in Alzheimer's disease

Abstract

Amyloid-β (Aβ) is believed to directly affect memory and learning in Alzheimer's disease (AD). It is widely suggested that there is a relationship between Aβ40 and Aβ42 levels and cognitive performance. In order to explore the validity of this relationship, we performed a meta-analysis of 40 peer-reviewed, published AD transgenic mouse studies that quantitatively measured Aβ levels in brain tissue after assessing cognitive performance. We examined the relationship between Aβ levels (Aβ40, Aβ42, or the ratio of Aβ42 to Aβ40) and cognitive function as measured by escape latency times in the Morris water maze or exploratory preference percentage in the novel object recognition test. Our systematic review examined five mouse models (Tg2576, APP, PS1, 3xTg, APP(OSK)-Tg), gender, and age. The overall result revealed no statistically significant correlation between quantified Aβ levels and experimental measures of cognitive function. However, enough of the trends were of the same sign to suggest that there probably is a very weak qualitative trend visible only across many orders of magnitude. In summary, the results of the systematic review revealed that mice bred to show elevated levels of Aβ do not perform significantly worse in cognitive tests than mice that do not have elevated Aβ levels. Our results suggest two lines of inquiry: 1) Aβ is a biochemical "side effect" of the AD pathology; or 2) learning and memory deficits in AD are tied to the presence of qualitatively "high" levels of Aβ but are not quantitatively sensitive to the levels themselves.

Keywords: Amyloid-β; Morris water maze; Tg2576; cognitive deficit; memory; mouse model; novel object recognition.

Fig. 1

The log of raw Aβ₄₀ and Aβ₄₂ soluble and insoluble levels per area of tissue in the brain is plotted versus Morris water maze escape latency in Tg2576 mice. Only the insoluble level of Aβ₄₂ was found to be significantly correlated with Morris water maze escape latency. No correlation was found between escape latency and insoluble Aβ₄₀, soluble Aβ₄₀, or soluble Aβ₄₂. A) Insoluble levels of Aβ₄₀, r² = 0.049, p-value = 0.24. B) Insoluble levels of Aβ₄₂, r² = 0.125, p-value = 0.0043. C) Soluble levels of Aβ₄₀, r² = 0.0017, p-value = 0.80. D) Soluble levels of Aβ42, r² = 0.027, p-value = 0.281.

Fig. 2

Extracted and pooled Tg2576 data from 21 studies showed no statistical correlation between Morris water maze escape latency and the log of Aβ₄₂ to Aβ₄₀ ratio in the brain tissue of transgenic mice. A) soluble ratio between levels of Aβ₄₂ to Aβ₄₀, r² = 0.039, p-value = 0.206. B) insoluble ratio, r² = 0.118, p-value = 0.0625.

Fig. 3

Age and Gender Separation data showed no statistical correlation between Morris water maze escape latency and the log of Aβ₄₂ to Aβ₄₀ ratio in the brain tissue of transgenic mice. Extracted data for the Tg2576 mice were separated into groups based on age and gender differences used in the included studies. A) All female mice, r² = 0.02, p-value = 0.6. B) Mice ages 6–11 months, r² = 0.31, p-value = 0.33. Mice ages 12–14 months, r² = 0.001, p-value = 0.88. Mice ages 15–20 months, r² = 0.093, p-value = 0.25.

Fig. 4

APP, APP(OSK)-Tg, 3xTg, and PS1 mice showed no correlation between Morris water maze escape latency and the log of Aβ₄₂ to Aβ₄₀ ratio in brain tissue. Extracted data for A) APP mice, r² = 0.65, p-value = 0.098. B) APP(OSK)-Tg mice, too few points. C) 3xTg mice, r² = 0.072, p-value = 0.73. D) PS1 mice, r² = 0.10, p-value = 0.60.

Fig. 5

Extracted data for Tg2576 mice subjected to the novel object recognition test showed no correlation between exploratory preference percentage and the log Aβ₄₂ to Aβ₄₀ ratio in brain tissue, r² = 0.19, p-value = 0.19.