Non-linear Relationship Between Plasma Amyloid-β 40 Level and Cognitive Decline in a Cognitively Normal Population

Recent studies regarding the relationships between plasma amyloid-β (Aβ) levels and cognitive performance had inconsistent results. In this study, we aimed to characterize the relationship between cognitive decline and plasma Aβ levels in a large-sample cognitively normal population.

This population-based, prospective cohort study included 1,240 participants with normal cognition. The Mini-Mental State Examination (MMSE) was used to assess cognitive function at baseline and 2 years later. Restricted cubic splines, multivariate logistic regression, and multivariate linear regression models were used to evaluate the type of relationship between cognitive decline during the 2-year follow-up period and plasma Aβ levels (Aβ₄₀, Aβ₄₂, and Aβ_{42 / 40}).

Participants with moderate Aβ₄₀ levels had the highest risk of cognitive decline during a 2-year follow-up relative to individuals with low Aβ₄₀ [odds ratio (OR): 0.60, 95% confidence interval (CI): 0.45-0.81, p < 0.001] or high Aβ₄₀ (OR: 0.65, 95% CI: 0.49-0.87, p = 0.004) levels. The association between Aβ₄₀ and cognitive decline did not depend on sex, education level, or APOE ε4 status. There was an interaction found between age (≤ 65 and > 65 years) and Aβ₄₀ (p for interaction = 0.021). In individuals older than 65 years, there was a positive linear relationship between plasma Aβ₄₀ and cognitive decline (OR: 1.02, 95% CI: 1.00-1.04, p = 0.027). For participants ≤ 65 years old, the lower Aβ₄₀ and higher Aβ₄₀ groups had a lower risk of cognitive decline than the medium Aβ₄₀ group (OR: 0.69, 95% CI: 0.50-0.94, p = 0.02; OR: 0.63, 95% CI: 0.45-0.86, p = 0.004). None of relationship between plasma Aβ₄₂, Aβ_{42 / 40} and cognitive decline was found during a 2-year follow-up.

The relationship between plasma Aβ₄₀ and cognitive decline was not linear, but an inverted-U shape in a cognitively normal population. The underlying mechanism requires further investigation.