Association of β-Amyloid, Microglial Activation, Cortical Thickness, and Metabolism in Older Adults Without Dementia

Background and Objectives Plasma beta-amyloid(42) (A beta(42))/A beta(40) levels have shown promise in identifying A beta-PET positive individuals. This study explored the concordance and discordance of plasma A beta(42)/A beta(40) positivity (Plasma +/-) with CSF A beta(42)/A beta(40) positivity (CSF +/-) and A beta-PET positivity (PET +/-) in older adults without dementia. Associations of A beta deposition, cortical thickness, glucose metabolism, and microglial activation were also investigated. Methods We selected participants without dementia who had concurrent plasma A beta(42)/A beta(40) and A beta-PET scans from the Alzheimer's Disease Neuroimaging Initiative cohort. Participants were categorized into Plasma +/-/PET +/- based on thresholds of composite F-18-florbetapir (FBP) standardized uptake value ratio (SUVR) >= 1.11 and plasma A beta(42)/A beta(40) <= 0.1218. A beta-PET-negative individuals were further divided into Plasma +/-/CSF +/- (CSF A beta(42)/A beta(40) <= 0.138), and the concordance and discordance of A beta(42)/A beta(40) in the plasma and CSF were investigated. Baseline and slopes of regional FBP SUVR were compared among Plasma +/-/PET +/- groups, and associations of regional FBP SUVR, FDG SUVR, cortical thickness, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) levels were analyzed. Results One hundred eighty participants (mean age 72.7 years, 51.4% female, 96 cognitively unimpaired, and 84 with mild cognitive impairment) were included. We found that the proportion of Plasma+/PET- individuals was 6.14 times higher (odds ratio (OR) = 6.143, 95% confidence interval (CI) 2.740-16.185, p < 0.001) than that of Plasma-/PET+ individuals, and Plasma+/CSF- individuals showed 8.5 times larger percentage (OR = 8.5, 95% CI: 3.031-32.974, p < 0.001) than Plasma-/CSF+ individuals in A beta-PET-negative individuals. Besides, Plasma+/PET- individuals exhibited faster (p < 0.05) A beta accumulation predominantly in bilateral banks of superior temporal sulcus (BANKSSTS) and supramarginal, and superior parietal cortices compared with Plasma-/PET- individuals, despite no difference in baseline FBP SUVRs. In Plasma+/PET+ individuals, higher CSF sTREM2 levels correlated with slower BANKSSTS A beta accumulation (standardized beta (beta(std)) = -0.418, 95% CI -0.681 to -0.154, p = 0.002). Conversely, thicker cortical thickness and higher glucose metabolism in supramarginal and superior parietal cortices were associated with faster (p < 0.05) CSF sTREM2 increase in Plasma+/PET- individuals rather than in Plasma+/PET+ individuals. Discussion These findings suggest that plasma A beta(42)/A beta(40) abnormalities may predate CSF A beta(42)/A beta(40) and A beta-PET abnormalities. Higher sTREM2-related microglial activation is linked to thicker cortical thickness and higher metabolism in early amyloidosis stages but tends to mitigate A beta accumulation primarily at relatively advanced stages.