Sleep Disturbance May Predict Rapid Cognitive Decline in AD

Deborah Brauser

May 22, 2020

Excessive sleep disturbances are linked to increased cognitive decline in patients with Alzheimer's disease (AD), new research suggests.

Records from the National AD Coordinating Center (NACC) datasets for more than 400 patients with autopsy-confirmed AD, all of whom were initially cognitively intact, showed that those who experienced nighttime behaviors (NTB) at baseline had a significantly greater rate of cognitive decline than those without NTB.

NTB, as reported by caregivers on the Neuropsychiatric Inventory Questionnaire Quick Version (NPI-Q), include frequent awakenings during the night, rising too early in mornings, and/or taking an excessive number of daytime naps.

Interestingly, the between-group difference in cognitive decline was enhanced in patients who carried the APOE e4 known risk genotype or had cerebral amyloid angiopathy.

Because no difference was found between those with and without NTB in prevalence of cognitive-decline risk factors, the results suggest "that NTB itself is responsible for the effect observed," the investigators note.

Adrienne L. Atayde

"Given what we know, we should be a little bit more aware that sleep has an effect on cognitive status," lead investigator Adrienne L. Atayde, a research student at St. Michael's Hospital, Toronto, Ontario, Canada, told Medscape Medical News.

"This is speculative and more research needs to be done, but there is a potential" that sleep patterns could eventually be used as a predictor for AD and cognitive decline and may even help in determining treatment options, Atayde said.

The current research is being presented on as part of the American Academy of Neurology (AAN) 2020 Science Highlights. Because of the COVID-19 pandemic, the AAN cancelled its 2020 annual meeting.

Debates and Controversy

"The temporal relationship between sleep disturbances, AD pathology, and related cognitive impairment remains controversial," the researchers note.

There has been some debate as to whether sleep disturbance is a symptom of AD or if it's a potential factor in disease progression; and there has been speculation as to whether treating sleep disturbances early could slow development of AD, they add.

"There's growing evidence related to brain health. We were really curious to see how these factors were interrelated and whether we were able to identify a link between sleep and Alzheimer's," Atayde said.

The investigators assessed NACC datasets for 404 patients who had caregiver-reported information on a clinician-administered NPI-Q.

Atayde noted that behaviors that are common in an older population, such as light nighttime awakenings, are not considered NTBs. Rather, they are ones that are so excessive that they negatively affect the caretaker.

Upon first visit to an NACC, patients had a Mini-Mental Status Examination (MMSE) total score of 24 or greater. Cognitive decline rate was determined by change in MMSE score throughout total clinical visits.

All participants had an autopsy-confirmed primary pathologic diagnosis of AD, based on neurofibrillary tangles through Braak staging and plaque load on CERAD. Further assessment determined APOE genotype and presence or absence of cerebral amyloid angiopathy.

'A Good Start'

Demographics for the groups with NTB (n = 74) and without NTB (n = 330) were similar, including mean age at baseline (78 vs 79 years, respectively), sex (61% vs 56% male), age at death (83 vs 84 years), time between baseline and last visit (3.4 vs 3.5 years), percentage of APOE e4 carriers (45% vs 47%), and percentage of those with cerebral amyloid angiopathy (68% vs 72%).

Results showed that, overall, the patients with NTB had a significantly greater rate of cognitive decline than those without NTB (–3.3 vs –2.45 points per year; P = .016).

"This significant difference was restricted to APOE e4 carriers" (P = .049), as well as those with cerebral amyloid angiopathy (P = .02) and/or vascular, ischemic, or hemorrhagic pathology (P = .015), the researchers report.

Atayde noted that using the NACC database was a limitation because "it's a clinical case series of volunteers. So that might limit the generalizability of this particular study."

Still, "it's a very good start to learning more about what we need to look into and what clinicians should be more aware of," she said.

She added that the investigators are continuing to assess the NACC data and look forward to continuing their research in this area.

Screen for Sleep Patterns?

Rebecca L. Edelmayer, PhD

Commenting on the study for Medscape Medical News, Rebecca L. Edelmayer, PhD, director of scientific engagement at the Alzheimer's Association, noted that the overall findings were not surprising.

"We've known from previous research, including some that we've even seen reported at our Alzheimer's Association International Conference, that problems with sleep may be associated with an increased risk of Alzheimer's or even other dementias," Edelmayer said. "So this research would align with what we've already seen."

She added that sleep disturbances at night could be caused by a number of different factors and can be characterized as disordered breathing/sleep apnea, insomnia, and circadian rhythm disruptions.

A study limitation Edelmayer cited was that all of these were grouped into one NTB "bucket."

Still, she pointed out the findings in patients with CAA and other pathologies were interesting.

"It's very common for people who have Alzheimer's pathology to also have vascular-related pathology in their brains. We've seen that through a lot of neuropathological reports recently. I think when you start compounding some of these [conditions] in the brain, it could make people more at risk for developing cognitive symptoms of dementia," Edelmayer said.

"I think there's a body of evidence building that sleep disturbances are related to some kind of dementia. At this time, though, whether or not it could be used as a predictor or whether it's something that is potentially another type of disease pathology that's occurring in the brain that's inducing sleep disturbances is something that still needs to be teased out by further research," she added.

However, Edelmayer noted that "we do know today" that patients with AD experience changes in their sleep that can cause stress and may worsen AD symptoms.

Asked whether clinicians should ask about sleep for all older patients, she said "if a patient is experiencing problems with their memory or thinking, we would absolutely advocate that physicians ask questions about cognitive health, including sleep that helps to build someone's medical history."

Atayde and Edelmayer have reported no relevant financial relationships.

American Academy of Neurology (AAN) 2020 Annual Meeting. Abstract S23.010.

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