Proteins linking APOE ɛ4 with Alzheimer's disease

Abstract

Introduction: The ɛ4 allele of the apolipoprotein E gene (APOE ɛ4) is the strongest genetic risk factor for Alzheimer's disease (AD), but the mechanisms connecting APOE ɛ4 to AD are not clear.

Methods: Participants (n = 596) were from two clinical-pathological studies. Tissues from dorsolateral prefrontal cortex were examined to identify 8425 proteins. Post mortem pathological assessment used immunohistochemistry to obtain amyloid beta (Aβ) load and tau tangle density.

Results: In separate models, APOE ɛ4 was associated with 18 proteins, which were associated with Aβ and tau tangles. Examining the proteins in a single model identified Netrin-1 and secreted frizzled-related protein 1 (SFRP1) as the two proteins linking APOE ɛ4 with Aβ with the largest effect sizes and Netrin-1 and testican-3 linking APOE ɛ4 with tau tangles.

Discussion: We identified Netrin-1, SFRP1, and testican-3 as the most promising proteins that link APOE ɛ4 with Aβ and tau tangles.

Highlights: Of 8425 proteins extracted from prefrontal cortex, 18 were related to APOE ɛ4. The 18 proteins were also related to amyloid beta (Aβ) and tau. The 18 proteins were more related to APOE ɛ4 than other AD genetic risk variants. Netrin-1 and secreted frizzled-related protein 1 were the two most promising proteins linking APOE ɛ4 with Aβ. Netrin-1 and testican-3 were two most promising proteins linking APOE ɛ4 with tau.

Keywords: Alzheimer's disease; amyloid; apolipoprotein ε4; proteins; tau proteins.

FIGURE 1

Chicago plot of proteome‐wide association of APOE ɛ4 with proteins in dorsolateral prefrontal cortex.

FIGURE 2

Associations of APOE ɛ4‐related proteins with AD pathological indices and rate of cognitive decline. The circles and bars illustrate estimates and their 95% confidence intervals (CIs) of the associations between the 18 APOE ɛ4‐related proteins and different outcomes. The estimates and 95% CIs are derived from analyzing proteins in separate models. The estimates of the associations with APOE ɛ4 were derived from separate linear regression models where each of the 18 proteins was the outcome and APOE ɛ4 was the model term (A). The associations between the proteins and Aβ or tau tangles were derived from separate linear regression models where Aβ or tau tangle was the outcome and each of the proteins was the model term (A). The association with the rate of cognitive decline is derived from separate mixed‐effects models with repeated measurements of global cognition or the five cognitive domains as the outcome (B). Each mixed‐effects model term was one of the proteins, time (i.e., the years in the study), and interaction of the protein with time. All the linear regression models were controlled for age at death and sex, and the mixed‐effects models were controlled for age at death, sex, education, and their interaction with time. Crossed circles indicate the associations that were not significant after Bonferroni adjustment.

FIGURE 3

Pseudo‐bulk snRNA‐seq gene expression data for the 18 proteins related to APOE ɛ4.

FIGURE 4

A heatmap plot illustrating correlations of the 18 proteins associated with APOE ɛ4. The gray squares denote missing in the levels of Cellular Communication Network family member 1 (O00622) and collagen alpha‐1(XXV) chain (Q9BXS0) as there were no participants having non‐missing levels of both proteins.

FIGURE 5

Associations of five and two APOE ɛ4‐related proteins independently associated with Aβ and tau tangles, respectively. In two separate models including 15 APOE ɛ4‐related proteins, only five proteins (A–E) remained associated with Aβ and two proteins (F–G) with tau tangles.

FIGURE 6

Associations of APOE ɛ4 with Aβ and tau tangles with and without adjustment for APOE ɛ4‐related proteins. The left panel illustrates associations of APOE ɛ4 with Aβ (upper panel) and tau tangles (lower panel) where levels of Aβ and tau tangles were adjusted for age at death and sex. The right panels illustrate the same associations where levels of Aβ (upper panel) and tau tangles (lower panel) were further adjusted for the related proteins, which were Netrin‐1 and secreted frizzled‐related protein 1 for Aβ and netrin‐1 and testican‐3 for tau tangles. The figure illustrates attenuation of the association between APOE ɛ4 and Aβ or tau tangles after adjustment for the proteins.