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

Objective: The new criteria for preclinical Alzheimer disease (AD) proposed 3 stages: abnormal levels of β-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 β-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 ε4 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 α-synucleinopathy, or physical findings of parkinsonism. Interpretation: Cognitively normal persons with brain injury biomarker abnormalities, with or without abnormal levels of β-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 β-amyloidosis.