Clinical proteomic analysis across the Alzheimer’s disease continuum

Abstract

AbstractBackgroundAlzheimer’s disease (AD), defined by amyloid‐β (Aβ) and neurofibrillary tau tangles, can be viewed as a continuum, starting with an asymptomatic “pre‐clinical” phase that progresses to a symptomatic clinical stage characterized as mild cognitive impairment (MCI), and finally, AD dementia. Identifying biomarkers reflective of the different disease stages is important to detect individuals at risk of developing AD, to monitor disease progression and the effect of treatments, as well as to determine new therapeutic targets.MethodWe present data from a cross‐sectional tandem mass tag (TMT) proteomic study of cerebrospinal fluid (CSF) samples from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (young adults (n = 22), cognitively unimpaired (n = 54), cognitively impaired (n = 26), MCI (n = 19), AD (n = 19), non‐AD (n = 16), frontotemporal dementia (n = 9); total n = 214); a highly profiled cohort across the AD continuum with clinical and neuropsychological assessments, MRI, and Aβ and tau positron emission tomography (PET). To enhance detection of brain‐derived proteins, we evaluated the use of a TMT booster channel consisting of brain protein extract. Planned statistical analyses include linear regression modelling to compare biomarker distributions across groups, covariating for sex and age where appropriate as well as correlation analyses of biomarker levels with Aβ and tau PET measurements.ResultOur preliminary data analysis suggests that a set of proteins differed with high significance between amyloid PET negative and positive individuals (Fig. 1), including proteins that showed changes already at the pre‐clinical stage of AD. We will explore the correlation of the identified biomarker candidates with pathological process and disease progression, as well as with Aβ‐ and tau‐PET measurements. Also, protein changes associated with aging and other neurodegenerative disorders will be evaluated. Finally, the use of a TMT booster based on brain protein extract to enhance identification of CSF biomarkers will be assessed.ConclusionThis study describes the most extensive unbiased proteomic profiling in CSF across the AD continuum, identifying proteins that may serve as novel therapeutic targets and fluid biomarkers for the disease. Additionally, the use of a TMT booster to enhance the detection of brain‐derived proteins was evaluated.