Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease

Abstract

Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-β (Aβ) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aβ40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aβ40/Aβ42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aβ40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aβ42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aβ40 and apoE.

Keywords: APOE; Alzheimer’s disease; Amyloid-β; Cerebral amyloid angiopathy; Sex.

Figure 1. Morphologies of CAA with different scores in AD brains

Cerebral amyloid angiopathy (CAA) was evaluated using thioflavin-S fluorescent microscopy. (a) Cases with no CAA were given a score of 0. Cases found to have CAA only in leptomeninges were given a score of 0.5. (b) Scattered amyloid deposition in both leptomeningeal and cortical vessels was given a score of 1. (c) Strong, circumferential amyloid deposition in some, but not all vessels was given a score of 2. (d) Widespread, strong amyloid deposition in leptomeningeal and cortical vessels was given a score of 3. (e) Cases with more severe CAA than score 3 were given a score of 4. (a'-e ') Higher magnification views from each image are shown. Scale bar= 200 μm.

Figure 2. CAA severity in different cortical regions

The distribution of CAA scores in inferior parietal cortex, middle frontal cortex, motor cortex, superior temporal cortex and visual cortex are shown as they relate to sex and APOE4 status.

Figure 3. Sex- and APOE4-dependent differences in CAA severity

The overall averaged CAA scores from the five cortical regions were plotted as they relate to sex and APOE4 status. Horizontal lines are medians and boxes are interquartile ranges (IQRs).

Figure 4. CAA-, Sex- and APOE4-dependent differences in Aβ40 levels and Aβ40/Aβ42 ratios

The levels of Aβ40 in TBS (a), TX (b) and GuHCl (c) fractions and Aβ40/Aβ42 ratio in GuHCl fraction (d) from temporal cortex of AD cases with or without CAA were plotted as they relate to sex and APOE4 status. Horizontal lines are medians and boxes are interquartile ranges (IQRs).

Figure 5. Associations between the levels of apoE and Aβ as a function of CAA

The regression plots for insoluble levels of apoE vs. Aβ40 (a) and apoE vs. Aβ42 (b) were shown.