17 August 2012. Like the ebb and flow of ocean tides, Aβ levels in cerebrospinal fluid (CSF) and plasma seem to rise and fall considerably during a single day. One presentation at this year’s Alzheimer’s Association International Conference held 14-19 July in Vancouver showed that age and amyloid status may affect those fluctuations, while another suggested that Aβ accumulation is a culprit in the amplitude of those changes.

“We don’t know for sure what the mechanisms are, but there are really interesting data, including the data presented here, that there is a link between circadian rhythms and Aβ production,” said Francine Grodstein, Brigham and Women's Hospital, Boston, Massachusetts, who chaired a symposium at which some of these findings were presented.

Every healthy adult has a steady, daily rise and fall of CSF Aβ levels (see Bateman et al., 2007). But how do age and amyloid status alter Aβ oscillations? To address this question, Yafei Huang, a member of Randall Bateman’s lab at the Washington University School of Medicine, St. Louis, Missouri, took hourly plasma and cerebrospinal fluid (CSF) samples from three groups of research volunteers over a 36-hour sampling period: amyloid-positive Alzheimer’s disease (AD) patients, age-matched amyloid-negative controls, and young healthy controls with an average age of 36. Each group contained about 10 people. For almost everyone, CSF Aβ42 and Aβ40 levels rose continuously over the total 36-hour sampling period, while plasma levels did not. This rise in CSF levels is a previously observed finding that puzzles researchers. It could be due to a redirection of concentrated CSF Aβ from the brain to a lower area in the spinal cord from the repeated CSF draws, Bateman told ARF. Or it may be from lack of sleep and heightened stress during this study, he said.

Curiously, in this side-by-side comparison of the groups, the rise was pronounced in healthy controls and in older controls without amyloid, but weak for amyloid-positive patients. In fact, for Aβ42, the upward climb was absent altogether. It could be that once plaques are present in the brain, Aβ42 sticks to them rather than crossing into the CSF. This would explain the lack of a CSF Aβ42 rise in the amyloid-positive AD patients, said Huang.

The group also looked at the fluctuations of plasma and CSF Aβ levels over the course of the 36 hours. Canceling out any ascending linear trend, Huang saw cosine curves that fluctuated over 24 hours. The curves' amplitude was highest in young healthy controls, and dropped by about half for both groups of elderly participants. CSF levels were highest around 6 p.m., and plasma levels peaked about midnight, with lows around 12 hours later. “This tells us that it is very important to control for the sampling time when we estimate Aβ levels,” said Huang. “From peak to trough, there can be as much as a 40 percent difference.” Further, given the discordance in Aβ rise and peak times, “we think plasma Aβ levels are not good surrogate markers for CSF levels,” she said.

What causes the circadian rhythm amplitude to shrink in the elderly? Findings from animal studies done in David Holtzman’s lab at WashU, presented by Jee Hoon Roh, link the waning Aβ fluctuation to Aβ buildup. In young APPswe/PS1dE9 mice, both the hippocampus and striatum showed normal ISF Aβ circadian fluctuations. At six months of age, plaques formed in the hippocampus, and circadian variations weakened there. In the striatum, where there were still no plaques at this age, daily fluctuation of ISF Aβ stayed normal. Striatal plaques appeared at nine months, at which time circadian cycles weakened there, too. What’s more, the mice also began to show a disrupted sleep cycle around that age. On the other hand, when the researchers actively immunized mice early on against Aβ, much less plaque accrued and the animals maintained both normal circadian Aβ fluctuation and sleep/wake cycle at nine months. “The accumulation of Aβ in the brain appears to have caused the disruption of the Aβ circadian fluctuation and disturbed sleep/wake cycle, since active immunization to Aβ blocks both abnormalities,” Roh told Alzforum.

Roh presented further evidence from humans that the drop in oscillation results from Aβ deposition rather than aging, as Huang’s study might suggest. He looked at CSF Aβ fluctuation in four middle-aged amyloid-positive and four amyloid-negative presenilin mutation carriers (average age 42.4), as well as four age-matched controls. The CSF Aβ42 levels of healthy controls fluctuated most strongly, followed by levels in amyloid-negative carriers. But amyloid-positive carriers’ CSF Aβ42 oscillation was crimped by half compared to that of negative carriers. Hence, even in middle age, circadian fluctuation of mutation carriers falls with amyloid buildup, Roh reported. If similar abnormalities show up in cognitively normal people and people developing AD pathology, then a dampened Aβ fluctuation may indicate early brain dysfunction, and be useful as an outcome measure in therapeutic interventions, Roh told Alzforum.

Other findings presented at the conference suggest that sleep problems may lead to dementia (see ARF related AAIC story), but those reports use more indirect measures and provide no mechanism for how the connection might come about. Does Roh’s finding hint that the relationship is reversed, i.e., that Aβ42 buildup causes the sleep problems in the first place? Not necessarily, said Roh. “Our data suggest that the sleep-wake cycle and Aβ pathology may have a reciprocal relationship,” he told Alzforum. “The findings reported here suggest that aggregation of Aβ results in abnormalities of the sleep-wake cycle, at least at the beginning.” Previous data from the lab imply that sleep deprivation drives Aβ accumulation as well (see ARF related news story on Kang et al., 2009).

“There are many different pieces here that will hopefully one day come together for a good picture,” said Grodstein. For example, more studies on clock genes, among other experiments, might help unravel the link between Aβ levels and circadian rhythms, she said. “This is a new field, but an incredibly exciting one.”—Gwyneth Dickey Zakaib.

This is Part 2 of a two-part series. See also Part 1.