Choline supplements may help delay dementia in APOE4 gene carriers
MIT and National Institute of Diabetes and Digestive and Kidney Diseases, March 18, 2021
Researchers found that the APOE4 gene may increase the risk of developing Alzheimer's disease and other dementias by altering brain cells' lipid metabolism.
Choline supplements reversed these defects in cell studies, supporting further research in people carrying APOE4.
Choline supplements may help delay dementia in APOE4 gene carriers
MIT and National Institute of Diabetes and Digestive and Kidney Diseases, March 18, 2021
Researchers found that the APOE4 gene may increase the risk of developing Alzheimer's disease and other dementias by altering brain cells' lipid metabolism.
Choline supplements reversed these defects in cell studies, supporting further research in people carrying APOE4.
Certain genes can increase the risk of developing dementia, including Alzheimer's disease. One of the most significant genetic risk factors is a form of the apolipoprotein E gene called APOE4. About 25% of people carry one copy of APOE4, and 2 to 3% carry two copies. ApoE4 is the strongest risk factor gene for Alzheimer's disease, although inheriting ApoE4 does not mean a person will definitely develop the disease.
The APOE gene comes in several different forms, or alleles. APOE3 is the most common and not believed to affect Alzheimer's risk. APOE2 is relatively rare and may provide some protection against Alzheimer's disease.
The reason APOE4 increases Alzheimer's risk isn't not well understood. The APOE protein helps carry cholesterol and other types of fat in the bloodstream. Recent studies suggest that problems with brain cells' ability to process fats, or lipids, may play a key role in Alzheimer's and related diseases.
Lipid imbalances can impair many of a cell's essential processes. This includes creating cell membranes, moving molecules within the cell, and generating energy.
Dr. Li-Huei Tsai and the late Dr. Susan Lindquist of MIT investigated how APOE4 affects lipid metabolism in brain cells. The study was funded by NIH's National Institute on Aging (NIA), National Cancer Institute (NCI), and National Institute of Neurological Disorders and Stroke (NINDS). Dr. Priyanka Narayan of NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) was a co-first author. Findings were published in Science Translational Medicine on March 3, 2021.
The research team began by creating brain cells called astrocytes using stem cells. They used skin cells from people carrying APOE3 or APOE4 that were reprogrammed into a state where they could develop into any cell. Called induced pluripotent stem cells, these cells were then coaxed into becoming astrocytes, star-shaped cells that produce the most ApoE in the brain.
The researchers found changes in how APOE4 astrocytes were able to process lipids. The astrocytes accumulated droplets containing fats called triglycerides. These triglycerides had many more unsaturated fatty acid chains than normal. Lipid buildup in the APOE4 astrocytes was much greater than in APOE3 astrocytes. The researchers also found disruptions in lipid metabolism when they coaxed the cells into becoming other brain cells called microglia.
The team next tested whether yeast cells with the human version of APOE4 would have the same disruption in lipid metabolism. Lipid metabolism pathways are very similar between yeast and humans. Yeast with a copy of the APOE4 gene accumulated lipids much like the human cells did. Genetic screens in the yeast identified a molecular pathway that could be responsible for the defects. Boosting the activity of a pathway that normally produces phospholipidsan essential building block of the cell membranereversed some of the lipid accumulation.
Further research showed that supplementing the yeast cells' culture with choline restored normal lipid metabolism. Choline is needed to synthesize phospholipids. Similar benefits were seen after treating the human APOE4 astrocyte cells with choline. These findings provide preliminary support for testing choline supplements in people who carry APOE4.
"What we would really like to see is whether in the human population, in those APOE4 carriers, if they take choline supplements to a sufficient amount, whether that would delay or give them some protection against developing dementia or Alzheimer's disease," Tsai says.
However, it is important to keep in mind that results from isolated cells don't often translate into successful approaches when tested in people.
Acupuncture Tops Usual Care for Pain in Cancer Survivors
Two types of acupuncture proved superior, with one better than the other
Memorial Sloan Kettering Cancer Center March 18, 2021
Two types of acupuncture significantly reduced chronic musculoskeletal pain in cancer survivors as compared with usual care, a randomized trial showed.
Electroacupuncture reduced patient-reported pain by 1.9 points versus usual care, and auricular acupuncture reduced patients' mean pain score by 1.6 points as compared with usual care, which consisted of analgesics, physical therapy, and steroid injections.
Auricular acupuncture, developed by the U.S. military and widely used in VA health facilities, failed to achieve noninferiority to electroacupuncture and was associated with more adverse events (AEs), reported Jun J. Mao, MD, of Memorial Sloan Kettering Cancer Center in New York City, and co-authors in JAMA Oncology.
"The magnitude of effect of electroacupuncture was clinically important and durable," the authors wrote. "This finding is consistent with evidence from other large acupuncture trials for chronic pain in the general population. Electroacupuncture has been shown to influence endogenous opioid release, which provides a mechanistic basis for chronic pain management."
"The present trial includes a large and diverse group of cancer survivors and provides evidence that electroacupuncture provides additional benefits beyond usual care, including not only reduction in pain severity, but also improvements in physical function and quality of life and reductions in analgesic use."
The U.S. has a growing population of cancer survivors, who have a greater pain burden than the general population. Almost half of cancer survivors receive inadequate pain relief, adversely affecting quality of life, physical function, and cancer-related outcomes.
A large body of evidence supports the superiority of acupuncture over usual care for relief of chronic noncancer pain, and last year CMS approved coverage of acupuncture for chronic lower back pain. A recent meta-analysis showed that acupuncture reduced cancer-associated pain, but the strength of evidence was considered moderate because of trials' small sample sizes and heterogeneity of acupuncture techniques.
Mao and colleagues reported findings from the largest randomized trial to date of acupuncture for cancer-related pain. The multicenter PEACE study enrolled adults with a history of cancer but no current evidence of disease. Eligible patients had musculoskeletal pain for at least 3 months and at least 15 of the preceding 30 days and a worst pain intensity within the past week of ≥4 (moderate or greater) on the 0-10 scale of the Brief Pain Inventory (BPI).
Patients were randomized 2:2:1 to electroacupuncture, auricular acupuncture, or usual care. Licensed experienced acupuncturists provided both types of acupuncture. During electroacupuncture, needles were placed at four sites near the pain location and four additional sites elsewhere on the body to address comorbid symptoms. The angle and depth of insertion were individualized to each patient's body type and point location. Treatment consisted of 10 once-weekly 30-minute sessions.
The protocol for auricular acupuncture, often called "battlefield acupuncture," was standardized and began with insertion of one needle into the cingulate gyrus of one ear. The patient then walked for 1 minute. If pain remained ≥1 on the BPI, another needle was inserted into the other ear. The process was repeated for the remaining ear points: thalamus, omega 2, point zero, and shen men.
The primary endpoint was change in average BPI score from baseline to week 12, and data analysis included 360 patients. Of 145 patients randomized to electroacupuncture, 136 (93.8%) completed at least eight sessions, as did 117 of 143 (81.8%) patients assigned to auricular acupuncture.
Mean baseline BPI scores ranged from 5.0 to 5.6. The most common sites of pain across all three groups were lower back (27.8% to 36.6%), knee/leg (14.5% to 23.6%), and hip/thigh (11.0% to 12.5%). At week 12, mean BPI score had declined by 0.48 in the usual care group, 2.39 in the electroacupuncture group (P
