New Insight into Amyloid Deposition and Sleep–Wake Cycle

Pauline Anderson

January 16, 2017

Results of a new study shed fresh light on the relationships between amyloid beta (Aβ) production and clearance throughout the day and night.

Among other things, the study uncovered an age-dependent effect of amyloid on Aβ42 amplitude and linear rise.

"It's interesting to note that you don't see this effect to the same extent in Aβ40," said lead author Brendan P Lucey, MD, assistant professor of neurology, Washington University School of Medicine, St Louis, Missouri.

Because factors that affect Aβ concentration through changes in production and clearance are potential therapeutic targets, the study results could have important implications for future secondary Alzheimer's Disease (AD) prevention trials.

The study was published online December 19 in JAMA Neurology.

Previous research shows the concentration of Aβ in the central nervous system fluctuates with the sleep–wake cycle as a diurnal pattern and that the amplitude of this pattern changes with age and amyloid deposition. It's hypothesized that decreased Aβ production and increased clearance during sleep drive the day/night oscillation.

The current study included 77 volunteers with a mean age of 72.6 years who were assessed with a standard protocol. This included the Clinical Dementia Rating (CDR) Sum of Boxes score, which ranges from 0 (no impairment) to 18 (maximal impairment).

Amyloid status was determined using positron emission tomography (PET) and carbon II-labeled Pittsburgh compound B scans (where amyloid positive was a mean cortical binding potential > 0.18) or Aβ42:Aβ40 ratio (where amyloid positive was a ratio < 0.12 in the cerebrospinal fluid [CSF]).

Of the 77 participants, 39 were classified as amyloid-negative, and of these, only 12 had a CDR greater than 0. There were 38 amyloid-positive participants, and 32 had a CDR greater than 0.

Researchers measured Aβ40 and Aβ42 in serial CSF over 48 hours. They converted concentration values to percentages of the mean for all participants and then averaged that for the amyloid-negative and amyloid-positive groups.

Investigators used mass spectrometry (MS), a novel assay that simultaneously measures absolute Aβ concentration and Aβ stable isotope labeling kinetics (SILK). They also used enzyme-linked immunosorbent assay (ELISA).

They then compared these methods using Cosinor analysis (which uses the least-squares method to fit a cosine wave to a time series) to determine which best fit the day/night oscillation of Aβ42 and Aβ40.

Age-Dependent Decline

The analysis showed that day/night patterns in Aβ concentrations were more sharply defined by MS than ELISA with a mean difference of SD of residuals: Aβ40, −7.42 pM [picomolars] (P < .001); Aβ42, −3.72 pM (P < .001).

"We looked at different parameters, such as amplitude, from the fit of the cosine wave, and it appeared that the parameters were more precisely defined by the MS data; there wasn't as much error," said Dr Lucey.

Because of this finding, researchers used only Aβ concentrations measured by MS for the remainder of the study.

Further analysis showed that amyloid deposition diminished day/night linear increase and amplitude of Aβ42, but not Aβ40.

"We showed that there is this linear increase when you sample CSF every hour or every 2 hours where the concentration goes up over time, but we don't know why this occurs," said Dr Lucey.

Previous research showed this linear increase is tied to the sampling frequency, he added. "So the more you sample, the faster the linear rise."

This could be because CSF is "shifted" towards the lumbar catheter, he said.

The researchers observed "a very similar phenomenon" with amplitude. "We think it's the same thing that's going on; the Aβ concentration doesn't oscillate because, as it's produced in the brain, it gets locked away in the plaque."

They looked at the difference in the amplitude and linear rise between the amyloid-positive and amyloid-negative groups by age.

Amyloid-positive participants had no linear increase, regardless of age. Aβ42 amplitude declined with age in amyloid-negative participants.

"Once someone is above 73 years of age, they basically look like someone who's amyloid positive," said Dr Lucey.

It's not clear why amyloid-negative individuals would have this age-dependent decline, he said.

The study also found novel associations between Aβ concentration and production rates to Aβ amplitude and linear rise, as well as Aβ turnover and linear rise, independent of amyloid deposition.

After controlling for amyloid deposition, amplitude of Aβ40 was positively associated with production rates (P < .001), while the linear rise was associated with turnover rates (P < .05).

The amplitude and linear rise of Aβ42 were both associated with turnover (P < .001) and production (P < .05) rates.

No Immediate Clinical Impact

"Although longitudinal follow-up studies are needed, our results suggest that amyloid deposition leads to premature loss of Aβ42 day/night patterns associated with aging, in contrast to Aβ40, which is largely driven by production rates," the authors write.

Dr Lucey said the results won't have an immediate impact on clinical practice, but they could affect the design of AD prevention trials targeting Aβ production (for example, β-secretase 1 inhibitors) and using CSF Aβ as a marker of target engagement.

The findings may also affect the timing of a therapeutic intervention.

"In amyloid-negative individuals, timing of anti-amyloid intervention and age of participants may be critical factors," the authors note.

"Adults younger than 73 years may benefit from anti-amyloid therapy during the day or waking hours when production and concentrations are highest. For amyloid-positive individuals, the timing of anti-amyloid therapy may be irrelevant because there are no significant time-of-day differences for Aβ to aggregate into insoluble plaque."

Improving sleep quality or treating sleep disorders to reduce Aβ production and increase clearance could decrease the growth of amyloids. Already studies have shown that amyloid concentrations can be manipulated in mice by changing their sleep patterns. Dr Lucey said, "This finding awaits translation to humans."

But changing sleep patterns to try to drive down the amyloid concentration, lessen plaque deposition, and prevent AD may not be an effective approach in amyloid-positive individuals of any age or adults older than 73 years.

"I hypothesize that if there's no oscillation of Aβ42 in amyloid-positive individuals, and the whole point of manipulating sleep is trying to alter Aβ oscillation, then it's probably not going to be effective," said Dr Lucey.

He also noted that in older amyloid-negative individuals, there's not a lot of variability.

"Since older adults are already getting really low Aβ amplitudes, you may not be able to manipulate it much, but with someone who is 60 years old, you might be able to intervene and potentially change their course of Alzheimer's disease."

A limitation of the study was that information on sleep–wake monitoring was unavailable. Having this information for younger patients may have been helpful, said Dr Lucey. It might, for example, have addressed questions surrounding what's driving the variability in these patients.

"Did the individuals with low amplitude not have good sleep–wake demarcation, so did they nap all day? And were the people with high Aβ amplitudes awake all day and sleep all night and have good consolidation of their sleep? Were there changes in sleep across the population with age, which might have explained the changes?"

Further Aβ studies in participants under different sleep conditions are needed to determine the sleep parameters that can manipulate Aβ production, clearance, and concentrations, said the authors.

"Understanding the factors that influence Aβ physiology throughout the sleep/wake cycle could establish potential approaches and targets for the prevention or treatment of AD."

Cause or Consequence?

Commenting on the findings for Medscape Medical News, James A Hendrix, PhD, director, Global Science Initiatives, Alzheimer’s Association, said he found the article interesting.

The study is important, said Dr Hendrix, because it helps further knowledge of circadian rhythms and the association with AD. This, he added, is an area of increasing research focus.

Patients with dementia tend to have sleep problems, such as insomnia, but it's still not clear whether these issues are a cause or consequence of AD, said Dr Hendrix.

He agreed with the study authors that changing sleep patterns to try to prevent AD may not be an effective intervention in older patients.

Circadian rhythm disruptions may be a "modern day" phenomenon that may relate to the constant bombardment of lights, noise, and other disruptions, said Dr Hendrix.

The impact of circadian rhythm patterns on AD needs further study, he said.

Dr Lucey has consulted for AbbVie and Neurim Pharmaceuticals, and owns stock (less than $5000) in Cardinal Health. Dr Lucey also receives research support from the National Institutes of Health, BrightFocus Foundation, and McDonnell Center for Systems Neuroscience.

JAMA Neurology. Published online December 19, 2016. Full text

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