Sleep Fragmentation and Alzheimer’s Disease - Chronic sleep disruption, resulting from work schedules, noise exposure, family obligations, sleep disorders, or
lifestyle choices, is a pervasive feature of contemporary life. Sleep problems affect up to 40% of AD patients,
may precede cognitive impairments by more than a decade, and worsen as the disease progresses. As well as
affecting mood and well-being, sleep disruption may drive the development of AD neuropathology for instance,
by reducing clearance of amyloid-β (Aβ) and by promoting a neurotoxic proinflammatory state involving
astrocytes and microglia. Sleep disruption can include reduced total sleep (sleep restriction [SR]), loss of deep
sleep (also known as slow-wave sleep [SWS], marked by large amplitude, low frequency electrical activity),
and fragmentation of sleep (SF) into shorter bouts. Fragmentation of the daily sleep-wake rhythm is associated
with greater risk of incident AD and earlier cognitive decline in older humans. In spite of these correlative
studies, whether or how chronic SF impacts the progression of AD has not been experimentally investigated.
SF may be a better model of the sleep disruption associated with AD than the traditional approach of SR. Our
studies of AD mouse models show that spontaneously occurring SF is associated with more severe Aβ
accumulation and that experimentally-induced SF leads to Aβ accumulation and neuroinflammation. Besides
SF, loss of SWS may exacerbate AD, and improving SWS may be beneficial in mild cognitive impairment
(MCI) or even in AD. Since sleep disruption adversely affects the development of AD-related neuropathology, it
is surprising that sleep enhancement (SE) strategies to consolidate sleep and increase SWS have not been
adequately explored to slow or reverse these effects. Our overall working hypothesis is that a change in the
quality of sleep, especially sleep fragmentation and loss of SWS, is more important than the quantity of sleep.
Further, we hypothesize that the mechanism underlying these effects is primarily neuroinflammation, at least in
part mediated by Aβ peptide deposition. We will use a unique, well-characterized mouse model, that exhibits
AD-related Aβ pathology, neuroinflammation, and cognitive deficits. This project has three specific aims: (1)
that SF will accelerate (and SE decelerate) AD progression; (2) that increases in Aβ accumulation mediates
SF-induced neuroinflammation, neuropathology, and cognitive decline; and (3) that increases in
neuroinflammation mediate SF-induced neuropathology and cognitive decline. We will use multiple novel
approaches, including thermoneutral temperature manipulation, and a unique anti-inflammatory compound that
has recently entered early stage clinical trials. Thus, these studies will elucidate the underlying mechanisms by
which sleep disruption is linked to AD and will lay the groundwork for new therapeutic strategies.
