Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred A Cross-sectional Study

IMPORTANCE Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and noncarriers from the world's largest known autosomal dominant Alzheimer disease (AD) kindred. OBJECTIVE To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional measures of F-18-florbetapir positron emission tomography, F-18-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). MAIN OUTCOMES AND MEASURES We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine F-18-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF A beta 1-42, total tau and phosphorylated tau(181), and plasma A beta measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. RESULTS Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF A beta 1-42, higher CSF total tau and phosphorylated tau(181), and higher plasma A beta 1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF A beta 1-42, age 16 years (95% CI, 11-24 years) for the mean cortical F-18-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau, age 13 years (95% CI, 8-19 years) for phosphorylated tau181, and age 6 years (95% CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindred's estimated median age of 44 years (95% CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma A beta 1-42 or A beta 1-40. CONCLUSIONS AND RELEVANCE This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD.