APOE modifies the association between Aβ load and cognition in cognitively normal older adults

Abstract

Objective: To determine the relationship between β-amyloid (Aβ) load as measured by [(11)C]-Pittsburgh compound B (PiB) PET and cognitive function in cognitively normal older adults.

Methods: We studied 408 cognitively normal older adults who participated in the population-based Mayo Clinic Study of Aging (MCSA) from January 2009 through March 2011. The participants underwent PiB PET and neuropsychometric testing within 6 months. The association between PiB retention and cognitive function was measured by partial correlation and an interaction with APOE status was tested using linear regression after adjusting for age, sex, and education.

Results: Higher PiB retention was associated with cognitive performance (Spearman partial r = -0.18; p < 0.01), specifically the memory, language, attention/executive, and visual-spatial processing domains in the whole group of participants. The association between PiB retention and cognition was modified by the APOE status on linear regression analysis even after controlling for the differences in the distribution of PiB values among APOE ε4 carriers and noncarriers (p = 0.02). Cognitive performance was associated with the Aβ deposition in the frontal, temporal, and parietal lobe association cortices in APOE ε4 carriers on SPM analysis (p < 0.001).

Conclusion: There is a modest association between PiB retention and cognitive function in cognitively normal older adults and this relationship between Aβ load and cognitive function is modified by APOE status. Whereas Aβ load is associated with greater cognitive impairment in APOE ε4 carriers, the cognitive function in APOE ε4 noncarriers is influenced less by the Aβ load, suggesting that APOE isoforms modulate the harmful effects of Aβ on cognitive function.

Figure 1. Global cortical Pittsburgh compound B (PiB) retention by APOE status

Figure 2. Associations between global cortical Pittsburgh compound B (PiB) retention and standardized cognitive scores according to APOE status

The trend lines indicate estimated mean cognition as a function of log-transformed PiB with green representing APOE ϵ2 carriers (n = 51), blue representing APOE ϵ3 homozygotes (n = 254), and orange representing APOE ϵ4 carriers (n = 97). Shaded regions indicate 95% confidence intervals. The p values from the sequential analysis of variance (ANOVA) are listed for each cognitive domain.

Figure 3. Associations between global cortical Pittsburgh compound B (PiB) retention and standardized cognitive scores in APOE ϵ4 carriers and a matched group of APOE ϵ4 noncarriers

The trend lines indicate estimated mean cognition as a function of log-transformed PiB with orange representing APOE ϵ4 carriers (n = 97) and blue representing APOE ϵ4 noncarriers (n = 97) matched to the APOE ϵ4 carriers on age, sex, education, and PiB retention ratio. Shaded regions indicate 95% confidence intervals. The p values from the sequential analysis of variance (ANOVA) are listed for each cognitive domain.

Figure 4. Correlations between cortical Pittsburgh compound B (PiB) retention and global cognitive performance score in APOE ϵ4 carriers

Voxelwise analysis demonstrates that global cognitive performance is associated with PiB retention in the frontal, temporal, and parietal lobe association cortices (p < 0.001).