Orexin (hypocretin) and tau pathology in cognitively normal elderly: a new prevention strategy for Alzheimer's disease

New York University School Of Medicine, New York NY

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Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Current consensus is that the AD pathological process begins decades before clinical symptoms occur. This long ?preclinical? phase of AD might first become detectable in middle-age as deposits of hyperphosphorylated tau (P-tau) in the transentorhinal cortex and subcortical nuclei such as the locus coeruleus (LC) and the nucleus basalis of Meynert. We have strong preliminary evidence showing that cerebrospinal fluid (CSF) levels of orexin-A (OxA) are associated with increased P-tau (r=.52, p<.01) and total-tau (T-tau) (r=.42, p<.01) in cognitively normal older adults (mean age: 69.6±8.6 years). Our study model poses that onset of tauopathy in the LC results in downregulation of orexin receptors, leading to a homeostatic increase of OxA production by the hypothalamus, which results in changes in core body temperature (CBT ) and sleep disruption that cause further neurodegeneration. We propose to test this hypothesis first by demonstrating that increases in CSF P-tau are associated in vivo with tau PET uptake, and that tau binding in the LC is associated with increases in CSF OxA (Aim 1); and second, by analyzing the downstream consequences of increased central nervous system (CNS) OxA on sleep architecture and CBT (Aim 2). To test these hypotheses, 30 older adults (age 55-75) balanced by sex, will first perform a full clinical evaluation and MRI (visits 1-2). Subjects will later undergo 7 days of actigraphy followed by nocturnal polysomnography (NPSG) for 2 consecutive nights (N1 -2) during which we will measure CBT (visits 3-4). A morning lumbar puncture (LP) will be performed after N2 to obtain CSF. Tau burden will be analyzed by PET- MR using 1 8F-T HK5351, which will be performed 1 -4 weeks after the LP (visit 5). There is the potential to identify : 1) an association between CSF P-tau and in vivo 1 8F-T HK5351 uptake; 2) a mechanism by which tau pathology may contribute to orexin dysfunction; 3) evidence that orexin dysfunction disrupts sleep and CBT rhythm; and, 4) CNS orexin dysfunction as a new therapeutic target for AD prevention.