Perioperative neurocognitive and functional neuroimaging trajectories in older APOE4 carriers compared with non-carriers: secondary analysis of a prospective cohort study

Abstract

Background: Cognitive dysfunction after surgery is a major issue in older adults. Here, we determined the effect of APOE4 on perioperative neurocognitive function in older patients.

Methods: We enrolled 140 English-speaking patients ≥60 yr old scheduled for noncardiac surgery under general anaesthesia in an observational cohort study, of whom 52 underwent neuroimaging. We measured cognition; Aβ, tau, p-tau levels in CSF; and resting-state intrinsic functional connectivity in six Alzheimer's disease-risk regions before and 6 weeks after surgery.

Results: There were no significant APOE4-related differences in cognition or CSF biomarkers, except APOE4 carriers had lower CSF Aβ levels than non-carriers (preoperative median CSF Aβ [median absolute deviation], APOE4 305 pg ml^-1 [65] vs 378 pg ml^-1 [38], respectively; P=0.001). Controlling for age, APOE4 carriers had significantly greater preoperative functional connectivity than non-carriers between several brain regions implicated in Alzheimer's disease, including between the left posterior cingulate cortex and left angular gyrus (β [95% confidence interval, CI], 0.218 [0.137-0.230]; P_FWE=0.016). APOE4 carriers, but not non-carriers, experienced significant connectivity decreases from before to 6 weeks after surgery between several brain regions including between the left posterior cingulate cortex and left angular gyrus (β [95% CI], -0.196 [-0.256 to -0.136]; P_FWE=0.001). Most preoperative and postoperative functional connectivity differences did not change after controlling for preoperative CSF Aβ levels.

Conclusions: Postoperative change trajectories for cognition and CSF Aβ, tau or p-tau levels did not differ between community dwelling older APOE4 carriers and non-carriers. APOE4 carriers showed greater preoperative functional connectivity and greater postoperative decreases in functional connectivity in key Alzheimer's disease-risk regions, which occur via Aβ-independent mechanisms.

Keywords: APOE4; Alzheimer's disease; cerebrospinal fluid; functional MRI; intrinsic functional connectivity; neuroimaging; perioperative neurocognitive disorders; surgery.

Fig 1

MADCO-PC surgical patients consort diagram. Of the 109 patients who returned for 6 week cognitive testing and had APOEε4 genotyping, 52 patients had preoperative and 6 week postoperative neuroimaging and CSF samples obtained at all three time points. APOE4, apolipoprotein E4; fMRI, functional MRI; MADCO-PC, Markers of Alzheimer's Disease and neuroCognitive Outcomes after Perioperative Care.

Fig 2

Perioperative neurocognitive trajectories by APOE4 genotype. (a) Perioperative CSF AD biomarker trajectories. ∗P<0.05. (b) Indicated cognitive trajectories. AD, Alzheimer's disease.

Fig 2

Perioperative neurocognitive trajectories by APOE4 genotype. (a) Perioperative CSF AD biomarker trajectories. ∗P<0.05. (b) Indicated cognitive trajectories. AD, Alzheimer's disease.

Fig 3

Postoperative resting-state functional connectivity changes in APOE4 carriers and non-carriers for Alzheimer's disease-associated brain regions. (a.1) A priori left posterior cingulate cortex Alzheimer's disease-risk seed region-of-interest (SPM12 Neuromorphometrics ROI Atlas). (a.2) Left angular/supramarginal gyrus region demonstrating statistically significant (peak P<0.001; cluster P_FWE<0.05) resting-state functional connectivity change from preoperative baseline to 6 weeks postoperatively between APOE e4 carrier and non-carrier groups for a.1 seed ROI. (a.3) Distribution of resting-state functional connectivity contrast values (i.e. β, standardised regression coefficient) for APOE groups between a.1 and a.2 regions at preoperative baseline and postoperatively at 6 weeks. (See Table 2, Postoperative Change section.). (b.1) A priori right entorhinal cortex Alzheimer's disease-risk seed region-of-interest (SPM12 Neuromorphometrics ROI Atlas). (b.2) Left dorsolateral prefrontal cortex region demonstrating statistically significant (peak P<0.001; cluster P_FWE<0.05) resting-state functional connectivity change from preoperative baseline to 6 weeks postoperatively between APOE e4 carrier and non-carrier groups for b.1 seed ROI. (b.3) Distribution of resting-state functional connectivity contrast values (i.e. β, standardised regression coefficient) for APOE groups between b.1 and b.2 regions at preoperative baseline and postoperatively at 6 weeks. (See Table 2, Postoperative Change section.). P_FWE, family-wise error probability.