Choline-enriched Diet May Help Reduce Alzheimer’s Risk Across Generations, Mouse Study Finds

A maternal diet supplemented with choline, an essential nutrient, reduced the number of amyloid plaque deposits and improved memory across two generations of a mouse model of Alzheimer’s disease, a study reports.

These findings support the long-lasting effects of dietary choline and suggest that a maternal choline-rich diet may help reduce Alzheimer’s across multiple generations.

The study, “Maternal choline supplementation ameliorates Alzheimer’s disease pathology by reducing brain homocysteine across multiple generation,” was published in the journal Molecular Psychiatry.

The incidence of Alzheimer’s disease is predicted to rise significantly in the next few decades — in the U.S. alone, it is estimated that, within about 30 years, 13.5 million people will develop the disease.

With no current effective medications for preventing, treating, or managing its progression, there is an urgent need for the development of new treatment options.

Environmental factors such as diet are associated with the risk of developing Alzheimer’s disease. For example, dietary interventions, such as the Mediterranean-Dietary Approaches to Stop Hypertension, or DASH, have been shown to lower the prevalence rate of Alzheimer’s with some success.

Homocysteine is an amino acid — the building blocks of proteins —  that can act as a potent neurotoxin and has been found to accumulate in many neurological disorders, including Alzheimer’s disease. Scientists believe that homocystein increases the uptake of calcium by neural cells, promoting accumulation of amyloid and tau proteins — a hallmark of Alzheimer’s disease.

In fact, homocysteine is thought to double the risk of developing Alzheimer’s disease and is found in elevated levels in these patients.

Choline is an essential vitamin-like nutrient found in certain foods and is used by cells to build key components (certain fats) of their cell membranes (lipid). It is also used by the body to produce acetylcholine, an important neurotransmitter essential for brain and nervous system functions including memory, muscle control, and mood. Choline also reduces the activation of microglia — the immune cells of the central nervous system — whose hyperactivation observed in Alzheimer’s disease causes brain inflammation and may trigger nerve cell death.

Choline is able to convert the harmful homocysteine into a safe amino acid called methionine. Supplementing the diet with this nutrient therefore represents a potential strategy to reverse the effects of homocysteine accumulation.

Based on this, researchers at the Biodesign Institute at Arizona State University and the Translational Genomics Research Institute in Phoenix hypothesized that a diet rich in choline could help prevent Alzheimer’s disease.

The beneficial effects of choline for early brain development is the reason why pregnant women are advised to maintain their choline levels at a certain concentration (550 mg per day) to ensure the fetus develops normally.

However, “studies have shown that about 90 percent of women don’t even meet that requirement. Choline deficits are associated with failure in developing fetuses to fully meet expected milestones like walking and babbling,” the study’s first author Ramon Velazquez, PhD, a postdoctoral research associate at the Biodesign Institute, said in a press release.

Previous studies have shown that increasing choline intake during gestation and lactation improves cognition in mouse models of Down syndrome. Whether the same occurs in Alzheimer’s disease and whether choline supplementation during gestation may have an impact on the animal’s offspring remains unknown.

Researchers used a mouse model of Alzheimer’s disease and exposed two generations of the animals to a choline-supplemented diet of 5 grams of choline/kilogram (a control diet usually has 1.1 grams of choline/kilogram).

They first exposed 2.5-month-old mice (progenitors) to the choline-supplemented diet. The animals were bred with each other, and their offspring (the first generation) was again fed with the choline-supplemented diet for 21 days (the period of gestation and lactation). After that, the animals were kept on the control, nonsupplemented diet for the remainder of their lives.

This first generation was then bred to give rise to a second generation that exclusively fed on the control nonsupplemented diet.

Results showed that the offspring of mice fed with the choline-supplemented diet had a significant reduction in homocysteine accumulation, as well as a lower level of amyloid plaque deposits, compared with the control group.

Moreover, mice showed a significant improvement in spatial memory, as shown by the animals’ performance in the Morris water maze test — a behavioral procedure used to assess learning and spatial memory, or the part of the memory responsible for the recording of information about one’s environment and spatial orientation.

Surprisingly, these observations still held true for the second generation of mice that were never exposed to choline. Moreover, microglia activation, a hallmark of Alzheimer’s progression, was also reduced in both generations.

“We found that early choline supplementation decreased homocysteine while increasing methionine, suggesting that high choline levels convert homocysteine to methionine,” Velazquez said. “This conversion happens thanks to an enzyme known as betaine-homocysteine methyltransferase (BMHT). We found that choline supplementation increased the production of BMHT in 2 generations of mice.”

Researchers performed a a genetic analysis of the mice’s hippocampus — a brain region linked to memory and spatial navigation — and found that choline supplementation altered this region’s gene expression, which is the process by which information in a gene is synthesized to create a working product, like a protein.

They found that genes related to brain immune response, epigenetic modifications — external modifications to DNA that turn genes on or off but do not change the actual DNA sequence — and regulation of molecules involved in nerve cell death, were differently expressed in choline-supplemented mice.

These epigenetic changes observed with choline supplementation are likely the mechanism behind the transgenerational effects of choline, as they are able to pass from cell to cell and persist throughout multiple generations.

These findings suggest that a maternal choline-supplemented diet can improve spatial memory and reduce the burden of Alzheimer’s across generations via epigenetic changes.

No one has ever shown transgenerational benefits of choline supplementation,” Velazquez said. “That’s what is novel about our work.”

If these early findings are translated to humans, choline-supplemented diets may help halt the increasing incidence of Alzheimer’s. Moreover, choline is an attractive and rather safe therapeutic target for Alzheimer’s — it takes about nine times the recommended daily dose of choline to produce harmful side effects.

The team now plans to test the effects of a choline-supplemented diet in adult mice and believe that a controlled clinical trial in humans will help determine the effectiveness of choline as a new approach against Alzheimer’s disease.