There is a window of time in humans, hypothesized as preclinical Alzheimer's disease (AD) during which amyloid-? (A?) deposition and tauopathy accrues prior to the detection of clinical symptoms and signs of cognitive impairment. By the time of clinical detection of symptomatic AD, there is already significant cell and synaptic loss. An important goal is to determine whether there are changes not only in imaging and fluid biomarkers, but also in brain function, that are associated with preclinical AD that are 1) quantitative;2) predict prognosis;and 3) respond to therapeutic intervention. Sleep in an essential biological function that becomes significantly abnormal during the course of dementia due to AD. We have shown that soluble, monomeric A? in both mice and humans is regulated by the sleep/wake cycle. We have also found that as APP transgenic mice develop A? deposition, sleep, particularly non-REM sleep, is markedly disrupted and that this is secondary to A? accumulation. We have also assessed sleep in a mouse model of tauopathy (P301S Tau transgenic mice) and have noted a marked decline in delta power during non-REM sleep. In recent studies, we have assessed sleep in a cohort of late-middle aged individuals with actigraphy, and found that those with A? deposition have significantly decreased sleep efficiency (% of time sleeping while in bed). Very few of the individuals in our first study had developed neurodegeneration (e.g. increased CSF tau) and we did not assess sleep stages directly by EEG. Herein, we will assess a cohort of individuals who are somewhat older (with mean age ~75);many are cognitively normal with and without different stages of preclinical AD and some have very mild dementia. We hypothesize that decreases in non-REM sleep and delta power will begin during the initial phases of A? deposition and worsen with biomarker evidence of neurodegeneration and tauopathy during preclinical AD and mild cognitive impairment (MCI). In addition, we hypothesize that changes in sleep detected initially and longitudinally will be quantitative diagnostic and prognostic markers of brain injury that have potential to respond to therapeutic intervention (theranostic markers). We predict that progressive changes in sleep will correlate with brain atrophy and dysfunction as assessed by structural MRI, functional connectivity MRI, and certain aspects of longitudinal cognitive performance such as the practice effect.

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As instructed by the funding opportunity announcement for this application (PAR-13-329), only the Overall component contains a project narrative. Cores and projects were instructed not to include this section.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Su, Yi; Blazey, Tyler M; Snyder, Abraham Z et al. (2015) Partial volume correction in quantitative amyloid imaging. Neuroimage 107:55-64
Shim, Yong Soo; Yang, Dong-Won; Roe, Catherine M et al. (2015) Pathological correlates of white matter hyperintensities on magnetic resonance imaging. Dement Geriatr Cogn Disord 39:92-104
Wang, Li-San; Naj, Adam C; Graham, Robert R et al. (2015) Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol 72:209-16
Ghoshal, Nupur; Perry, Arie; McKeel, Daniel et al. (2015) Variably Protease-sensitive Prionopathy in an Apparent Cognitively Normal 93-Year-Old. Alzheimer Dis Assoc Disord 29:173-6
Hurth, Kyle; Tarawneh, Rawan; Ghoshal, Nupur et al. (2015) Whipple's disease masquerades as dementia with Lewy bodies. Alzheimer Dis Assoc Disord 29:85-9
Aschenbrenner, Andrew J; Balota, David A; Tse, Chi-Shing et al. (2015) Alzheimer disease biomarkers, attentional control, and semantic memory retrieval: Synergistic and mediational effects of biomarkers on a sensitive cognitive measure in non-demented older adults. Neuropsychology 29:368-81
Pizzie, Rachel; Hindman, Halley; Roe, Catherine M et al. (2014) Physical activity and cognitive trajectories in cognitively normal adults: the adult children study. Alzheimer Dis Assoc Disord 28:50-7
Lim, Miranda M; Gerstner, Jason R; Holtzman, David M (2014) The sleep-wake cycle and Alzheimer's disease: what do we know? Neurodegener Dis Manag 4:351-62
Harari, Oscar; Cruchaga, Carlos; Kauwe, John S K et al. (2014) Phosphorylated tau-A?42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid. Biol Psychiatry 75:723-31
Fagan, Anne M; Xiong, Chengjie; Jasielec, Mateusz S et al. (2014) Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Sci Transl Med 6:226ra30

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