P2‐288: Pyroglutamate and Full‐Length Amyloid‐B Concentrations in the Superior Frontal Cortex Across Clinical Stages of Alzheimer's Disease

Pyroglutamate-modified amyloid-β (AβNpE) peptides are present in amyloid deposits in Alzheimer's disease (AD). The relationship of AβNpE peptides with amyloid PET ligands such as Pittsburgh Compound-B (PiB) and with cognitive status in preclinical and clinical AD is not fully understood. We reported that AβNpE3-42 and Aβ1-42 dominated the insoluble Aβ pool in the posterior cingulate and precuneus cortical association areas and correlated with antemortem cognition in subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. The present study quantified AβNpE3 and full-length Aβ concentrations in the superior frontal cortex (SFC) and examined their relationship with [H-3]PiB binding and global cognition across the clinical-pathological spectrum of NCI, MCI, and AD. Frozen SFC was obtained postmortem from 49 participants in the Rush Religious Order Study with clinical diagnosis of NCI, MCI, or mild-moderate AD. Concentrations of formic acid-extracted (insoluble) AβNpE3-42, AβNpE3-40, Aβ1-42, and Aβ1-40 were measured using commercially available ELISA kits and correlated with [H-3]PiB binding, assessed in the same tissue homogenates, and with the last pre-mortem Mini Mental State Examination (MMSE) score. Clinical groups were heterogeneous pathologically, consisting of low-pathology NCI (LP-NCI, CERAD=3,4; n=10), high-pathology NCI (HP-NCI, CERAD=1,2; n=11), MCI (CERAD=1,2; n=11), and mild-moderate AD (CERAD=1,2; n=17). Groups differed significantly by SFC AβNpE3-42 (p=0.02; LP-NCI