Abstract Increased reactivity of microglia and astrocytes is known to be present at various stages of the Alzheimer’s continuum but their relationship with core Alzheimer’s disease pathology in the preclinical stages is less clear. We investigated glial reactivity and β-amyloid pathology in cognitively unimpaired APOE ε4 homozygotes, heterozygotes and non-carriers using 11 C-PK11195 PET (targeting 18-kDa translocator protein), 11 C-PiB PET (targeting β-amyloid), brain MRI, and a preclinical cognitive composite (APCC). Plasma glial fibrillary acidic protein (GFAP) by and plasma Aβ 1-42/1-40 were measured using single molecule array and immunoprecipitation combined with mass spectrometry, respectively. We observed that (i) 11 C-PiB-binding was significantly higher in APOE ε4 homozygotes compared with non-carriers in all evaluated regions, (ii) regional 11 C-PK11195-binding did not differ between the APOE ε4 gene doses or between Aβ-positive and -negative individuals, and (iii) higher 11 C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, and elevated 11 C-PiB-binding and plasma GFAP concentration with lower APCC scores. Increased glial reactivity might emerge in later stages of preclinical Alzheimer’s disease in parallel with early neurodegenerative changes.

APOE ε4 gene dose effect on imaging and blood biomarkers of glial reactivity and β-amyloid pathology