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

Abstract

Background and objectives: Plasma β-amyloid₄₂ (Aβ₄₂)/Aβ₄₀ levels have shown promise in identifying Aβ-PET positive individuals. This study explored the concordance and discordance of plasma Aβ₄₂/Aβ₄₀ positivity (Plasma±) with CSF Aβ₄₂/Aβ₄₀ positivity (CSF±) and Aβ-PET positivity (PET±) in older adults without dementia. Associations of Aβ deposition, cortical thickness, glucose metabolism, and microglial activation were also investigated.

Methods: We selected participants without dementia who had concurrent plasma Aβ₄₂/Aβ₄₀ and Aβ-PET scans from the Alzheimer's Disease Neuroimaging Initiative cohort. Participants were categorized into Plasma±/PET± based on thresholds of composite ¹⁸F-florbetapir (FBP) standardized uptake value ratio (SUVR) ≥1.11 and plasma Aβ₄₂/Aβ₄₀ ≤0.1218. Aβ-PET-negative individuals were further divided into Plasma±/CSF± (CSF Aβ₄₂/Aβ₄₀ ≤0.138), and the concordance and discordance of Aβ₄₂/Aβ₄₀ 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 Aβ-PET-negative individuals. Besides, Plasma+/PET- individuals exhibited faster (p < 0.05) Aβ 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 Aβ accumulation (standardized β (β_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 Aβ₄₂/Aβ₄₀ abnormalities may predate CSF Aβ₄₂/Aβ₄₀ and Aβ-PET abnormalities. Higher sTREM2-related microglial activation is linked to thicker cortical thickness and higher metabolism in early amyloidosis stages but tends to mitigate Aβ accumulation primarily at relatively advanced stages.