APOE genotype moderates the relationship between LRP1 polymorphism and cognition across the Alzheimer's disease spectrum via disturbing default mode network

Abstract

Aims: This study aims to investigate the mechanisms by which apolipoprotein E (APOE) genotype modulates the relationship between low-density lipoprotein receptor-related protein 1 (LRP1) rs1799986 variant on the default mode network (DMN) and cognition in Alzheimer's disease (AD) spectrum populations.

Methods: Cross-sectional 168 subjects of AD spectrum were obtained from Alzheimer's Disease Neuroimaging Initiative database with resting-state fMRI scans and neuropsychological scores data. Multivariable linear regression analysis was adopted to investigate the main effects and interaction of LRP1 and disease on the DMN. Moderation and interactive analyses were performed to assess the relationships among APOE, LRP1, and cognition. A support vector machine model was used to classify AD spectrum with altered connectivity as an objective diagnostic biomarker.

Results: The main effects and interaction of LRP1 and disease were mainly focused on the core hubs of frontal-parietal network. Several brain regions with altered connectivity were correlated with cognitive scores in LRP1-T carriers, but not in non-carriers. APOE regulated the effect of LRP1 on cognitive performance. The functional connectivity of numerous brain regions within LRP1-T carriers yielded strong power for classifying AD spectrum.

Conclusion: These findings suggested LRP1 could affect DMN and provided a stage-dependent neuroimaging biomarker for classifying AD spectrum populations.

Keywords: Alzheimer's disease; apolipoprotein E; default mode network; low-density lipoprotein receptor-related protein 1.

FIGURE 1

Main effect and interaction between disease status and LRP1 genotype on the DMN across all subjects. (A) Brain regions with main effect of disease status on the DMN were identified and presented with node map. (B) Numerical representations of significant main effect of disease status on the DMN were illustrated in bar charts. (C) Brain regions significantly affected by LRP1 genotypes on the DMN in LRP1‐T carriers (LRP1 T⁺) compared with LRP1‐T non‐carriers (LRP1 T⁻) were plotted with node map. (D) Numerical representations of the significant main effect of LRP1 genotype on the DMN were described in bar charts. (E) Brain regions with significant interactive effects between LRP1 genotype and disease on the DMN. (F) Linear trend of functional connectivity (FC) drawn via line charts represents the significant interactive effects of LRP1 genotype and disease status on the DMN. Notably, the trajectory changes of mean FC in LRP1‐T carriers are opposite to LRP1‐T non‐carriers. Nodes’ colors and sizes in Figure A, C, and E indicate the plus and minus sign and variance of F value. Bar represents mean and standard error of mean, and each dot represents averaged functional connectivity of each participant within significant brain regions in Figure B and D. LRP1, low‐density lipoprotein receptor‐related protein 1; DMN, default mode network; CN, cognitively normal; SCD, subjective cognitive decline; MCI, mild cognitive impairment; AD, Alzheimer's disease; FC, functional connectivity; LTPJ, left temporoparietal junction; LIPC, left inferior parietal cortex; LPCC, left posterior cingulate cortex; LRSC, left retrosplenial cortex; LPCUN/LCUN, left precuneus and left cuneus; RPCC, right posterior cingulate cortex; RPCUN/RCUN, right precuneus and right cuneus; LMFG, left middle frontal gyrus; RDLPFC, right dorsal lateral prefrontal cortex.

FIGURE 2

Linear regression analyses between functional connectivity and cognitive performance in the LRP1‐T carriers. (A) Brain nodes diagrams represented altered functional connectivity (FC) values in the regions of LMFG, RPCC, and LIPC. (B) Brain regions of LMFG, RPCC, and LIPC with altered FC could significantly affect the MMSE scores in the LRP1‐T carriers but not in LRP1‐T non‐carriers. The individual raw scores of MMSE were transformed to z scores to assure data normally distributed. Z transformation formula is z = (x ‐ μ) / σ, where x is a specific value, μ is the mean value, and σ is the standard deviation. The significance level was set at p < 0.05. LMFG, left middle frontal gyrus; RPCC, right posterior cingulate cortex; LIPC, left inferior parietal cortex; MMSE, mini‐mental state examination.

FIGURE 3

The relationships between LRP1, APOE, and MMSE across all subjects. (A) The moderation model of APOE genotype influencing the effect of LRP1 genotype on MMSE scores. (B) The statistical diagram presents the effects of LRP1 genotype, APOE genotype, and interaction of LRP1 and APOE on MMSE scores. Moderation effect analysis revealed that APOE could modulate the relationship between LRP1 and cognitive performance. (C) The moderation model of LRP1 genotype influencing the effect of APOE genotype on MMSE scores. (D) The statistical diagram presents the effects of APOE genotype, LRP1 genotype, and interaction of LRP1 and APOE on MMSE scores. Moderation effect analysis revealed that LRP1 could modulate the relationship between APOE and cognitive performance. (E) The interaction of LRP1 genotype (T⁻/T⁺) and APOE genotype (ε4⁻/ε4⁺) on z‐transformed MMSE values. Bar represents mean and standard error of mean, and each dot represents z‐transformed MMSE scores of each participant within every genotype group. The main effect of LRP1 on MMSE was insignificant (F = 0.510, p = 0.476), but that of APOE was significant (F = 6.877, p = 0.010). *p < 0.05. (F) The interactive effect of LRP1 genotype (T⁻/T⁺) and APOE genotype (ε4⁻/ε4⁺) on MMSE scores was significant (F = 8.546, p = 0.004). Interactive effect analysis revealed that the effect of LRP1 on MMSE was dependent on different levels of APOE genotype. APOE, apolipoprotein E; LRP1, low‐density lipoprotein receptor‐related protein 1; MMSE, mini‐mental state examination.

FIGURE 4

Stage‐dependent neuroimaging biomarker for classifying AD spectrum population in the LRP1‐T carriers. Only in the LRP1‐T carriers, functional connectivity (FC) values of numerous brain regions were found to be predictive variables in classifying SCD from CN (AUC = 0.744, p = 0.040 for LMFG), MCI from CN (AUC = 0.771, p = 0.020 for LMFG), AD from CN (AUC = 0.891, p = 0.002 for LMFG), AD from SCD (AUC = 0.756, p = 0.030 for LMFG), AD from MCI (AUC = 0.762, p = 0.020 for LIPC), MCI from CN (AUC = 0.753, p = 0.030 for RPCC). ROC, receiver operating characteristic; AUC, area under curve; LMFG, left middle frontal gyrus; LIPC, left inferior parietal cortex; RPCC, right posterior cingulate cortex; CN, cognitively normal; SCD, subjective cognitive decline; MCI, mild cognitive impairment; AD, Alzheimer's disease.