Experimenting with Time: Can Intermittent Fasting Help Manage Alzheimer’s Disease?

Animal research suggests time-restricted eating could slow progression, relieve symptoms of neurodegenerative conditions

Image of a older woman washing a carrot in the sink. — According to recently published research, intermittent fasting may be able to slow the progression and reduce symptoms of Alzheimer’s disease. Image credit: Centers for Disease Control and Prevention on Unsplash

by Lucy Gilak
January 30, 2024

The Food and Drug Administration has approved only two medications to slow the progression of Alzheimer’s disease, a debilitating neurodegenerative condition affecting more than 6 million people in the United States. Each comes with the risk of serious adverse effects and costs tens of thousands of dollars annually — with no promise insurance will cover the total price. Other drugs aim to treat the complex array of symptoms that can accompany the disease.

New research from scientists at the University of California, San Diego School of Medicine, published in Cell Metabolism, shows that time-restricted eating — or daily intermittent fasting — might be a viable complementary strategy to help slow the disease’s progression and reduce associated cognitive symptoms.

A look at other influences
of fasting on health

Beyond helping align the circadian rhythm, intermittent fasting pressures the body to adapt in other ways that can benefit health:

Promoting fat loss:

While fasting is often used as a way to cut calories, it also induces a metabolic shift from burning glucose (sugar from food) as a primary energy source to burning stored body fat, which can lead to weight loss.
Improving and protecting mitochondrial function:

In a fasted state, the liver creates and releases more of the molecule βOHB, which helps mitochondria produce energy within cells of various types. Protecting mitochondrial function can also minimize oxidative stress, which is associated with neurodegenerative and other diseases.
Reducing insulin resistance:

During fasting, the pancreas produces and releases less of the hormone insulin, which is responsible for regulating glucose uptake. In the absence of insulin, an enzyme called AMPK is activated, which makes cells more sensitive to insulin and enables them to better regulate blood sugar levels. Insulin resistance may also decrease with a loss of body fat.
Altering gene expression:

Some studies have shown that intermittent fasting can impact the expression of certain genes, from those related to metabolism to others related to neuroinflammation, by targeting proteins called transcription factors that determine which genes are copied into RNA.

Alzheimer’s disease is the most common type of dementia, marked by continuing cognitive decline. Although Alzheimer’s is most often associated with memory loss, the disease process impacts many facets of a person’s life by impairing brain regions related to thought, memory, and language. Sleep-related symptoms are common in Alzheimer’s disease. More than 80% of Alzheimer’s patients experience disruptions to their circadian rhythms, which manifest as irregular sleep patterns, trouble sleeping, and heightened confusion late in the day.

Research suggests impaired sleep might contribute to the brain changes that mark neurodegeneration, making the circadian clock — which regulates cyclical body processes in response to environmental cues on a 24-hour schedule — an attractive therapeutic target for Alzheimer’s researchers at UCSD. Paula Desplats, Ph.D., associate professor in the departments of neuroscience and pathology at UCSD and senior author of the paper, began looking for methods to fix that clock.

Eating schedules are closely related to maintaining the circadian clock and can act as zeitgebers — environmental factors that keep the clock in sync. Adhering to an eating schedule could help “resync” the clock in individuals with misaligned circadian cycles.

In a 2018 study published in eNeuro, mouse models of Huntington’s disease, another neurodegenerative disorder associated with sleep disturbances, saw improved symptoms after time-restricted eating. If it worked with Huntington’s, Desplats thought, it could also work with Alzheimer’s.

Desplats and her colleagues began their study with two sets of mice: “transgenic” mice genetically altered to model Alzheimer’s disease — a condition that does not occur naturally in mice — and “non-transgenic,” or unaltered, mice. The transgenic mice were then randomly assigned to one of two groups: continuous access to food (the control group) and access for only six hours during their “active phase.”

After three months, the mice with time-restricted feeding showed improved sleep and activity patterns. Both male and female mice fell asleep faster and exhibited decreased hyperactivity when awake. Female mice also reached a normalized total amount of sleep — about 10 hours per day — compared with the mice with continuous food access, which slept just over eight hours. Desplats could offer no explanation for the sex difference in sleeping behavior, but her team earmarked this phenomenon as a potential area for future research.

Perhaps most striking are the pathological results of the study, which address the biological changes that cause disease-specific symptoms. Alzheimer’s has two pathological hallmarks: amyloid plaques and neurofibrillary tangles of tau protein. The plaques are build-ups of beta-amyloid protein between neurons — cells that send messages throughout the body — that disrupt their function, while the tangles are build-ups of tau protein inside neurons that interfere with both their function and communication with other neurons.

UCSD researchers used a method called immunostaining, which involves incubating brain samples with a substance that only adheres to a desired molecule to visualize amyloid plaques in the mice’s brains. The total plaque area was smaller, and the number of plaques was lower in mice with time-restricted feeding. Further examination using two different dyes at two different time points — blue after seven weeks via injection into the live mouse and red after three months via immunostaining of the mouse’s brain tissue — revealed the plaque was both accumulating more slowly in these mice and being cleared more quickly and efficiently. Desplats described the resulting image as so captivating that one of her coauthors has an image of the brightly illuminated blotches of aggregated plaques as his screensaver.

Juan Troncoso, M.D., a pathology professor and director of the Brain Resource Center at Johns Hopkins University, wasn’t surprised by the results. “The clearance of [amyloid beta plaques] occurs predominantly while you’re asleep,” said Troncoso, who wasn’t involved in the study. An irregular sleep pattern can impact the clearance of those plaques, and re-regulating that pattern can, in turn, support faster clearance.

Finally, researchers tested the memory of the mice using a novel object recognition test and a radial arm maze. In the former, time-restricted-feeding mice spent more time exploring a novel object placed in their cage than a familiar one, with the difference between novel object and familiar object exploration time being larger than that of mice with continuous food access. This suggests mice with time-restricted feeding had a better ability to differentiate a new object from an old one. In the radial arm maze, time-restricted feeding mice more quickly and accurately returned to locations previously associated with a food reward, suggesting improved memory.

Next, Desplats and her colleagues hope to test time-restricted feeding with people experiencing Alzheimer’s-related cognitive decline. The results are promising in mice, but there’s no guarantee they’ll translate to improved outcomes in humans.

“Although we’re genetically related to other mammals, we’re quite different,” Troncoso said. “When you change from one species to another, there are going to be differences.” He pointed to the extent of environmental control and genetic variation as just two factors to consider when applying animal research to people.

Implementing intermittent fasting in Alzheimer’s patients — who likely won’t be able to keep themselves to an eating schedule without strict supervision — could be challenging, Desplats admitted. Patients with advanced disease and severe sleep-related symptoms, for example, may not even know the time of day. If they don’t understand why they can’t eat, she says, “they will be very agitated.”

According to Troncoso, intermittent fasting would be more feasible for younger individuals before cognitive impairment presents. “If you delay the onset of disease, that would be very beneficial,” he said. Even if this strategy proves impractical, further research might illuminate the precise way fasting affects Alzheimer’s, Troncoso added, thus paving the way for developing a drug targeting the same pathway.

Still, Desplats is optimistic the UCSD team will find a way to make this intervention feasible for Alzheimer’s patients. Such studies would show researchers whether intermittent fasting might slow disease progression and reduce symptoms the way it does in mice.

If humans respond as mice did, this represents a relatively safe strategy — one without the adverse effects that can accompany other interventions — to reduce the burden of this devastating disease.