You're hurrying out of the grocery story to drive home and start cooking dinner. As the doors close behind you, you step into the parking lot and head… where? Where, among the rows of gleaming vehicles, did you park your car? The memory seems to have disappeared.
One important form of memory, episodic memory, is the recollection of these kinds of moments in life. Episodic memories are an important part of how we create long-term memories. They could be of something that happened long ago, such as your first day of elementary school, or as recent and everyday as the parking spot you maneuvered into before going into the grocery store.
As we age, our episodic memory gets weaker. Sensory details of life's moments become harder to recall, though scientists don't yet know why. This is true for almost all of us, but for some people, including those who are developing Alzheimer's disease, the scale of memory loss can be devastating.
New research by UC Berkeley neuroscientist Omer Sharon and colleagues, directed by former Berkeley sleep researcher Matthew Walker, may help explain why. The researchers identified a link between changes in brain wave patterns during non-REM sleep, poorer episodic memory formation and buildup of the protein tau, a known marker for development of Alzheimer's disease, in the brain's frontal cortex.
"This is the first time we've shown this relationship between tau and how it messes with memory consolidation by attenuating traveling slow waves that originate in the frontal cortex," said Sharon, a postdoctoral researcher at UC Berkeley's Center for Human Sleep Science. The findings were published in the journal Nature Neuroscience on Sept. 11.
Many of us are familiar with the rapid eye movement phases of sleep, when slumbering people's eyes flicker back and forth under their lids and most dreaming occurs. But non-REM sleep - a deeper form of sleep with little, if any, dreaming - is crucial for brain health.
During non-REM sleep, neurons shut down in slow, synchronized waves that move across the brain, beginning in the frontal cortex.
This coordinated shutdown has been observed only during deep sleep, and may be one reason why we sleep.
Omer Sharon, UC Berkeley Postdoctoral Researcher
"Each slow wave reflects an enormous population of neurons switching off and back on together," Sharon said. "Our study shows that for memory, it's critical that these events cascade in sequence across large parts of the brain. This coordinated shutdown has been observed only during deep sleep, and may be one reason why we sleep."
As we age, tau proteins build up in many people's brains. For them, these waves become irregular and less synchronized and travel shorter distances. This slow-wave breakdown is in turn linked to dwindling memory consolidation, cognitive decline and the development of Alzheimer's disease.
To study this correlation, the researchers used electroencephalograms (EEGs) to measure brain waves during sleep. They compared results from cognitively healthy participants in their early 20s to those from their mid-60s to mid-70s. In the younger adults, clusters of slow brain waves traveled roughly the length of a handspan across the scalp during non-REM sleep. In the older adults, the waves traveled shorter distances and were more solitary.
Using positron emission tomography (PET) scans conducted with Dr. William Jagust, a professor emeritus in public health and neuroscience at Berkeley, the researchers traced radioactive markers injected into the bloodstream to measure brain function. The scans confirmed that the buildup of tau in the frontal cortex of older participants correlated with those long wave breakdowns.
Courtesy of Omer Sharon/UC Berkeley Department of Psychology
This interference with slow brain waves shows up even before patients develop Alzheimer's disease. "These people did not have Alzheimer's," Sharon said. "They had tau in their brains, but with subclinical impacts. Their memory decline was within the normal range for their age." Indeed, Alzheimer's symptoms appear along a spectrum at first, Sharon said, with the amount of tau in a person's brain correlating to cognitive performance.
The researchers also measured corresponding changes in memory consolidation by giving participants word associations at night, then testing how well they remembered them the next day. People with more solitary, shorter-reaching slow waves - what the researchers called "lonely waves" - remembered less material.
After several years, a subset of participants was retested. Those whose frontal tau had increased over the years had worsened slow-wave coordination and lessened overnight memory retention. While this does not prove that frontal cortex tau buildup causes memory loss, it indicates that there is a connection between the protein and episodic memory loss that is related in some way to brain wave changes.
PET scans are expensive and require specialized equipment, making them hard to arrange, so the researchers worked with neurologist Yo-El Ju at Washington University in St. Louis to measure tau levels in the spinal fluid of a different group of elderly people. Although this test didn't reveal tau buildup specifically in the frontal cortex, a similar pattern emerged: The spinal fluid from participants whose brains had more solitary slow waves during sleep contained higher ratios of tau to another Alzheimer's disease linked protein, amyloid.
Sharon found it convincing to see these different methods arrive at converging results. "It's collected in a totally different place and in a different cohort, so I think that adds to the strength of the evidence," he said.
Altogether, the multiple measures led the researchers to connect tau buildup, a known form of Alzheimer's pathology, with a specific kind of brain function. "This longitudinal correlation suggests that Alzheimer's disease pathology is associated with a disruption of this main sleep feature," Sharon said.
And though it remains unclear to researchers why memory loss is correlated with aging, the findings suggest that the connection is more complex than previously thought. "It's not just about age," Sharon said. "It's how much pathology you have in frontal areas where global waves originate." It's also about sleep quality - a hard-to-define concept for which slow waves seem to be proxies.
"We can see tau and lonely waves rising together over time," Sharon said. "What we cannot yet say is which leads - and that question will shape how we design interventions."
Other co-authors of the study include Xi Chen, James Westphal, Chelsea Brown and Vyoma D. Shah at UC Berkeley, and Jason Dude at Washington University in St. Louis.
This research was supported by grants from the National Institute on Aging at the National Institutes of Health. Sharon was supported by a Glenn Foundation for Medical Research Postdoctoral Fellowship and a Weil Neurohub Fellowship.
