Brain injury biomarkers are not dependent on -amyloid in normal elderly

Objective The new criteria for preclinical Alzheimer disease (AD) proposed 3 stages: abnormal levels of -amyloid (stage 1), stage 1 plus evidence of brain injury (stage 2), and stage 2 plus subtle cognitive changes (stage 3). However, a large group of subjects with normal -amyloid biomarkers have evidence of brain injury; we labeled them as the suspected non-Alzheimer pathophysiology (sNAP) group. The characteristics of the sNAP group are poorly understood. Methods Using the preclinical AD classification, 430 cognitively normal subjects from the Mayo Clinic Study of Aging who underwent brain magnetic resonance (MR), 18fluorodeoxyglucose (FDG), and Pittsburgh compound B positron emission tomography (PET) were evaluated for FDG PET regional volumetrics, MR regional brain volumetrics, white matter hyperintensity volume, and number of infarcts. We examined cross-sectional associations across AD preclinical stages, those with all biomarkers normal, and the sNAP group. Results The sNAP group had a lower proportion (14%) with apolipoprotein E epsilon 4 genotype than the preclinical AD stages 2 + 3. The sNAP group did not show any group differences compared to stages 2 + 3 of the preclinical AD group on measures of FDG PET regional hypometabolism, MR regional brain volume loss, cerebrovascular imaging lesions, vascular risk factors, imaging changes associated with -synucleinopathy, or physical findings of parkinsonism. Interpretation Cognitively normal persons with brain injury biomarker abnormalities, with or without abnormal levels of -amyloid, were indistinguishable on a variety of imaging markers, clinical features, and risk factors. The initial appearance of brain injury biomarkers that occurs in cognitively normal persons with preclinical AD may not depend on -amyloidosis. ANN NEUROL 2013;73:472-480