Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by the accumulation of tau tangles and amyloid plaques. Current consensus is that the AD pathological process begins decades before overt clinical symptoms occur. Emerging evidence suggests that sleep disruption may be an important factor in both early cognitive deterioration leading to AD and in the metabolism of amyloid and tau. Obstructive sleep apnea (OSA) is the most common sleep disorder in the US with an estimated prevalence of 40-50% in the cognitively normal elderly. We have previously shown that OSA severity is associated with longitudinal increase in brain amyloid load, but less is known about the long-term effects of OSA on tau and its hyperphosphorylation, a crucial step in the formation of tangles, as well as the effects of OSA on spatial navigational memory, perhaps the earliest form of memory affected in AD. Our preliminary cross-sectional data suggest that higher OSA severity is associated with higher levels of total tau (T-tau) and phosphorylated tau (P-tau) in the cerebrospinal fluid (CSF) and poorer overnight processing of spatial navigational memory in cognitively normal elderly. Further, self-reported presence of OSA is associated with greater longitudinal increase in CSF T-tau and P-tau over 3 years. Although these observations implicate OSA in aberrant memory processing and regulation of tau in the brain, a causal role for OSA in these processes would be strengthened by additional analyses. By measuring behavioral readouts of both the encoding and processing of spatial navigation memory, and quantifying brain tau burden with precise anatomical resolution by adding tau PET brain imaging at baseline and 2.5 years later in 60 asymptomatic, cognitively normal older individuals with a wide range of OSA severity who are already being followed with polysomnography (PSG), actigraphy, and structural brain MRI as part of R01AG056031, we can test the expectations that overnight processing of spatial memory declines longitudinally (Aim 1) and that brain tau burden increases longitudinally (Aim 2) in a way that is dependent on measured OSA severity. A role for OSA in the metabolism of tau also would be strengthened by treating OSA with positive airway pressure (PAP). Whereas CSF A?42 levels can change in a matter of hours depending on sleep condition, CSF tau levels are thought to change over several weeks. Therefore, we aim to examine T-tau and P-tau in CSF and T-tau in plasma prior to treatment and 8 weeks later in 80 cognitively normal older individuals with OSA and subjective sleepiness prescribed PAP treatment for the first time at the Mount Sinai Integrative Sleep Center (MSISC). Satisfactory PAP adherence occurs in typically 50% of patients at the MSISC, and we will monitor adherence through downloads from users' machines. Measuring CSF and plasma tau as a function of PAP adherence serves as the basis for Aim 3.
Alzheimer's disease is the most common neurodegenerative disease and its current lack of effective treatment makes determining factors that may modify the disease course of paramount importance. Sleep disruption is one such factor, and obstructive sleep apnea (OSA), the most common clinical form of sleep disruption, is highly prevalent in the aged. The current proposal addresses the longitudinal impact of untreated OSA on both memory and brain tau accumulation as well as the impact of OSA treatment on tau in cerebrospinal fluid.
