Nerve growth factor (NGF) metabolic dysfunction as a marker of cognitive decline in autosomal dominant Alzheimer's disease

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PROJECT SUMMARY Alzheimer’s disease (AD) progresses slowly over several decades preceding its clinical diagnosis, at which point the brain compromise is most likely irreversible. Consequently, there is a growing realization that future therapeutic interventions should be applied at earlier AD preclinical stages with the assistance of reliable and accessible biomarkers signaling such “clinically silent” stages. The nerve growth factor (NGF) metabolic pathway has been found to be disrupted in postmortem brain samples along the continuum of AD, starting at preclinical stages. The brain’s NGF metabolism is compromised in non-cognitively impaired (NCI) individuals with incipient AD pathology, but not in NCI individuals devoid of AD pathology. Importantly, in Down syndrome (DS) individuals, also known to develop AD dementia, the brain’s NGF dysmetabolism is reflected in plasma and cerebrospinal fluid (CSF) at asymptomatic stages. We propose the hypothesis that changes in proteins related to NGF metabolism in plasma and CSF should assist in the early detection of preclinical AD. This hypothesis will be tested in individuals carrying familial AD mutations, as this patient population undergoes a predictable disease course, that limits the heterogeneity and comorbidity characteristic of sporadic AD. We propose to study the levels of NGF pathway proteins in biofluids from carriers and non-carriers of pathogenic mutations in the presenilin1 (PSEN1) gene, causing autosomal dominant early-onset Alzheimer's disease. NGF metabolism related putative biomarkers of preclinical AD will be correlated with established biomarkers of Aβ (amyloid) and tau, brain structure, and cognitive assessments in cross-sectional and longitudinal analyses. Towards this objective we have assembled an ambitious research project involving an international collaboration between Massachusetts General Hospital/Harvard Medical School (Boston, USA), University of Antioquia (Medellin, Colombia) and McGill University (Montreal, Canada). Given that NGF metabolism-related proteins are altered in DS individuals at preclinical AD stages, we are confident that this multidisciplinary study will yield novel biomarkers, which should assist in the identification of individuals at preclinical AD stages in the general population. Towards such goals, we have outlined the following aims: 1) To determine whether baseline abnormalities in the NGF metabolic pathway biomarkers, as measured in plasma and CSF, can distinguish cognitively unimpaired PSEN1 mutation carriers from non- carriers, and whether such NGF biomarkers are differentially associated with baseline brain volume and cognitive performance; 2) To evaluate the extent to which changes in the NGF metabolic biomarkers improves prediction of future cognitive decline, neurodegeneration, and clinical progression over and above predictions based only on established biomarkers (e.g. amyloid markers) and baseline cognitive measures in PSEN1 mutation carriers.