Genetic resilience to amyloid-related neurodegeneration in older adulthood

Abstract

Background: Biomarkers are the only feasible approach to diagnose Alzheimer’s disease (AD) in its presymptomatic stages, when a disease-modifying agent will have the greatest impact. Blood-based markers, that are inexpensive and easily obtainable, could become useful for presymptomatic diagnosis. Pittsburgh compound B is a positron emission tomography (PET) radiotracer that binds to fibrillar A b in the brains of symptomatic and presymptomatic AD subjects. Here we examined the association between several AD-relevant blood plasma proteins and PIB binding in the brain. Methods: Our dataset consisted of 18 AD, 56 mild cognitive impairment and 3 normal control Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects with available [11 C] PIB and peripheral blood protein data. MRI-coregistered PET data was smoothed with a 15 mm kernel and convected onto the 3D hemispheric models along the warping deformations computed in cortical pattern matching of the associated MRI scans. We applied linear regression to examine in 3D the associations between apolipoprotein E (ApoE), apolipoprotein J (ApoJ), brain-derived neurotrophic factor (BDNF), interleukin 6 receptor (IL6R), interleukin 13 (IL13) and tumor-necrosis factor a (TNF a) and PIB SUVR, while adjusting for age and sex. We used permutation statistics thresholded at p<0.01, for multiple comparisons correction.Results: Plasma ApoE showed significant negative association with PIB SUVR throughout the brain, except in the sensorimotor and entorhinal cortex (left p corrected 1⁄40.004, right p corrected 1⁄40.008). Plasma BDNF levels showed significant negative associations with left greater than right amyloid burden in the lateral temporal, inferior parietal, inferior frontal, anterior and posterior cingulate, and orbitofrontal regions (left p corrected1⁄40.03). ApoJ, IL6R, IL13 and TNF a failed to show significant associations with PIB SUVR. Conclusions: Lower peripheral blood levels of proteins that are involved in A b degradation and clearance (ApoE) and neuroprotection against A b toxicity (BDNF) showed a significant widespread association with severity of brain amyloidosis. This further establishes the role of these two proteins in AD. The lack of association between IL6R, IL13 and TNF a may be explained by their stronger relevance to the neuroinflammatory aspects of AD, which are not directly measured by amyloid imaging.