BOTH FULL-LENGTH AND PYROGLUTAMATE AMYLOID-BETA ARE ASSOCIATED WITH PITTSBURGH COMPOUND-B BINDING IN THE PRECUNEUS ACROSS CLINICAL STAGES OF ALZHEIMER’S DISEASE

Positron emission tomography (PET) imaging demonstrates high [C-11] Pittsburgh compound-B (PiB) retention in the default mode network (DMN), including precuneus cortex (PreC, BA7), which reflects accumulation of fibrillar amyloid-beta (Abeta) in Alzheimer's disease (AD). N-truncated and pyroglutamate-modified Abeta forms [e.g., Abeta(pE3-42)], are particularly fibrillogenic. We hypothesized that Abeta(pE3-42) concentration corresponds to regional PiB binding in the PreC cortex. We quantified [H-3]PiB binding and concentrations of formic acid-extracted Abeta(pE3-42) and full-length Abeta1-42 in PreC from the Rush Religious Order Study cases with a premortem clinical diagnosis of no cognitive impairment (NCI, n=11), mild cognitive impairment (MCI, n=14), or mild AD (mAD, n=15). [H-3]PiB binding, Abeta(pE3-42) and Abeta1-42 concentrations differed across clinical diagnostic groups, with significantly higher levels in mAD compared to NCI and MCI. Higher PreC [H-3]PiB binding correlated strongly with higher Abeta(pE3-42) (r2=0.82) and higher Abeta1-42 (r2=0.81) concentrations. Worse antemortem MMSE scores correlated with higher concentrations of both Abeta(pE3-42) and Abeta1-42 forms (r2=0.23 and r2=0.18, respectively). Across clinical diagnostic stages of AD, changes in full-length Abeta42 are paralleled by increasing concentrations of post-translationally modified pyroglutamate Abeta in PreC cortex. The strong association of PreC PiB binding with regional concentrations of insoluble Abeta(pE3-42) and Abeta1-42 indicates that both forms may contribute to in vivo PiB PET retention. Weak associations of Abeta forms with MMSE indicate that other pathological molecules (e.g., tau) are more relevant to global cognitive decline in AD. Characterization of pyroglutamate-modified and full-length Abeta forms in other DMN regions will clarify their relation to AD pathogenesis and regional [C-11]PiB PET signal.