Microglial responses partially mediate the effect of Aβ on cognition in Alzheimer's disease

Abstract

Introduction: Microglial responses are an integral part of Alzheimer's disease (AD) pathology and are associated with amyloid beta (Aβ) deposition. This study aimed to investigate the effects of Aβ and microglial responses on global cognitive impairment.

Methods: In this longitudinal study, 28 patients with mild cognitive impairment and 11 healthy controls underwent ¹¹C-PK11195 and ¹¹C-Pittsburgh compound B positron emission tomography (PET), structural magnetic resonance imaging scans, and global cognitive ratings at baseline and 2-year follow-up. Correlations between PET uptake and global cognition were assessed. Additionally, the mediation effect of the microglial response on the association between Aβ load and global cognition was assessed.

Results: Aβ load and the microglial response were both independently detrimental to global cognitive performance at baseline; however, at 2-year follow-up the association between Aβ load and global cognitive ratings was partially mediated by the microglial response.

Discussion: As AD progresses, the associated microglial response partially mediates the detrimental effect of aggregated Aβ on cognition.

Highlights: This was a longitudinal study of amyloid beta (Aβ), microglial responses, and global cognitive performance. Aβ and microglial responses both affect cognition in early Alzheimer's disease. Microglial response partially mediates the effect of Aβ on cognition in later stages.

Keywords: Alzheimer's disease; PK11195; amyloid beta; cognition; mild cognitive impairment; position emission tomography; translocator protein.

FIGURE 1

Mean PET uptake and group differences. A, Group means of ¹¹C‐PiB SUVR, ¹¹C‐PK11195 BP, and ¹⁸F‐FTP SUVR in healthy controls (n = 11, n = 9, and n = 8) and MCI patients with raised cortical amyloid beta load at baseline and 2‐year follow‐up (n = 28, n = 28, and n = 17). B, Group differences between healthy controls and baseline MCI (left panel), and 2‐year longitudinal change in the MCI group (right panel). Positive t values (red colors) indicate a significantly higher uptake in the MCI group (left panel) and a significant increase in mean PET signal over the 2‐year follow‐up period, and vice versa for negative t values (blue colors). Statistical maps were family‐wise error rate–corrected (α = 0.05) using cluster‐extent–based thresholding with two levels of primary cluster‐defining threshold: P < 0.05 (*) and P < 0.01 (**). †Unpaired t test adjusted for age and sex, ‡Paired t test. BP, binding potential; FTP, flortaucipir; MCI, mild cognitive impairment; PET, positron emission tomography; PiB, Pittsburgh compound B; SUVR, standardized uptake value ratio

FIGURE 2

Correlation between ¹¹C‐PiB (n = 28), ¹¹C‐PK11195 (n = 28), and ¹⁸F‐FTP (n = 17) PET scans and the Montreal Cognitive Assessment. Baseline (left) and 2‐year follow‐up (right) correlations in patients with mild cognitive impairment and raised cortical amyloid beta load. Statistical tests were adjusted for age and sex and family‐wise error rate–corrected (α = 0.05) using cluster‐extent–based thresholding with two levels of primary cluster‐defining threshold: P < 0.05 (*) and P < 0.01 (**). Negative t values (blue colors) indicate a significant negative correlation. FTP, flortaucipir; PET, positron emission tomography; PiB, Pittsburgh compound B;

FIGURE 3

Mediation analyses results. Mediation analyses for the relationship between ¹¹C‐PiB PET and the MoCA as mediated by ¹¹C‐PK11195 PET in 28 patients with mild cognitive impairment and raised cortical amyloid beta load. The mediation analyses were adjusted for age and sex. A, Baseline mediation results in cortical areas where both ¹¹C‐PiB PET and ¹¹C‐PK11195 PET negatively correlated with the MoCA scores at baseline (P < 0.05). Overlapping regions are presented on the right. B, Two‐year follow‐up mediation results in cortical areas where both ¹¹C‐PiB PET and ¹¹C‐PK11195 PET negatively correlated with the MoCA scores at follow‐up (P < 0.05). Overlapping regions are presented on the right. Regression coefficients are presented with 95% confidence intervals. Solid lines indicate a statistically significant effect (P < 0.05). FTP, flortaucipir; MCI, mild cognitive impairment; PET, positron emission tomography; MoCA, Montreal Cognitive Assessment; PiB, Pittsburgh compound B