Medical Bulletin 26/ March/ 2024

Ketogenic diet could potentially delay the onset of memory loss, finds study

A new study published in the journal Nature Communications Biology utilized a mouse model to reveal that a ketogenic (keto) diet postponed the onset of Alzheimer’s disease (AD) and is credited with a sevenfold increase in the mice’s levels of the beta-hydroxybutyrate (BHB) molecule.

Alzheimer’s disease, a progressive neurodegenerative disorder, involves cognitive deficits and synaptic dysfunction. Beta-hydroxybutyrate (BHB) has shown promise in delaying mild cognitive dementia onset. This molecule, produced during fat metabolism in humans, aids energy transfer from the liver when glucose is low. Research has suggested that BHB has anti-inflammatory effects on brain cells inflamed by beta-amyloid plaques.

In the study, researchers involved genetically modified APP/PS1 mice who express a mouse/human amyloid precursor protein as well as a mutant human presenilin 1 gene. Both target central nervous system neurons. The mice were bred. Their female and male offspring lived in a 12-hour light and 12-hour dark environment, with up to four mice in a cage eating a standard mouse chow diet for six months. At that age, they were assigned to weight-balanced groups, with each mouse living in a separate enclosure for the remainder of the study, so researchers could control their consumption of food. Mice were given either a keto diet or a carbohydrate-rich standard diet — both diets provided the same number of calories.

The results showed that female mice had higher levels of BHB in their bodies than males, as well as brain enzymes known to support memory. At the same time, male mice who were switched to a late-midlife keto diet exhibited improved spatial memory.

The findings suggested that the ketogenic diet, Ketone supplements, and BHB formulation are most likely to have an impact on this earliest phase of human Alzheimer's disease, and could potentially extend/rescue this phase in humans, as KD/BHB appears to rescue in APP/PS1 mice.

“While the new study presents intriguing findings, more research is needed to understand the impacts and outcomes of a ketogenic diet on people living with, or at risk for, Alzheimer’s,” said Dr. Stefania Forner Ph.D., Alzheimer’s Association director of medical and scientific relations.

Reference: Jacopo Di Lucente, Giuseppe Persico, Zeyu Zhou, Lee-Way Jin, Jon J. Ramsey, Jennifer M. Rutkowsky, Claire M. Montgomery, Alexey Tomilov, Kyoungmi Kim, Marco Giorgio, Izumi Maezawa & Gino A. Cortopassi; Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer’s mouse model and stimulates synaptic plasticity pathway enzymes; Journal: Nature Communications Biology

People at higher genetic risk of obesity require increased workout intensity: Study

According to a study conducted at Vanderbilt University Medical Center (VUMC) and published in JAMA Network Open, individuals with a higher genetic risk of obesity need to work out harder than those of moderate or low genetic risk to avoid becoming obese.

Individuals with a higher genetic predisposition to obesity may find that they need to put in more effort during workouts to achieve similar results because genetic factors can influence their metabolism, fat storage, and energy expenditure, making it more challenging to maintain a healthy weight through exercise alone.

“Physical activity guidelines do not account for individual differences. Genetic background contributes to the amount of physical activity needed to mitigate obesity. The higher the genetic risk, the more steps needed per day.” said senior author Douglas Ruderfer, PhD, associate professor of Medicine, Division of Genetic Medicine, and director of the Center for Digital Genomic Medicine at VUMC.

The study included 3,124 middle-aged participants without obesity who owned a Fitbit device and walked an average of 8,326 steps per day for a median of more than 5 years. The data revealed that the incidence of obesity over the study period increased from 13% to 43% in the lowest and highest polygenic risk score groups. Individuals with a polygenic risk score in the 75th percentile were required to walk an average of 2,280 more steps per day (a total of 11,020 steps per day) than those in the 50th percentile to have a comparable risk of obesity. People with a baseline BMI of 22, 24, 26 and 28 who were in the 75th percentile of polygenic risk score were required to walk an additional 3,460, 4,430, 5,380 and 6,350 steps per day, respectively, to have a comparable risk of obesity to persons in the 25th percentile.

“I think it is intuitive that individuals who have a higher genetic risk of obesity might need to have more physical activity to reduce that risk, but what is new and important from this study is that we were able to put a number on the amount of activity needed to reduce the risk,” said lead author Evan Brittain, MD, associate professor of Medicine in the Division of Cardiovascular Medicine at VUMC and lead investigator in Digital Health for the All of Us Research Program Data and Research Center. “We would like to test whether knowledge of one’s genetic risk for obesity actually has an impact on their behaviour. I think these findings could be empowering for patients because the current physical activity guidelines take a one-size-fits-all approach, and what we learned is that depending on your genetic risk, the guidelines may underestimate the amount of activity needed to reduce your risk of obesity.”

Reference: Physical Activity and Incident Obesity Across the Spectrum of Obesity Genetic Risk; Journal: JAMA Network Open

Could Delirium be a strong factor for dementia?

A study published in the journal The BMJ found that delirium is a strong risk factor for dementia and death among older people and has a strong independent effect in this clinical population.

Delirium is a sudden change in a person’s usual mental state. Symptoms include agitation, confusion or being unable to stay focused when awake. Delirium is much more common in hospital patients and older people. Previous observational studies have suggested an association between delirium and subsequent dementia, but the relationship remains unclear.

For the study, researchers in Australia analysed data from 626,467 patients aged 65 years and older with no dementia diagnosis who were admitted to hospitals between January 2009 and December 2014. Of these patients, 55,211 had at least one recorded episode of delirium and were matched to another 55,211 patients without delirium by age, sex, frailty, reason for being in hospital, length of stay in hospital and length of stay in the intensive care unit. These 110,422 patients (average age 83) were then followed up for five years to see how many of them were diagnosed with dementia. Collectively, 58% of patients died and 17% had a newly reported dementia diagnosis over the follow-up period.

The results revealed that patients with delirium had a 39% higher risk of death and three times the risk of being diagnosed with dementia than patients without delirium. The relationship between delirium and dementia was stronger in men than women and each additional episode of delirium was associated with a 20% increased risk of developing dementia (a dose-response relationship).

The researchers discovered that among hospital patients with at least one episode of delirium, the risk of receiving a new dementia diagnosis was three times higher than for patients without delirium and each additional episode of delirium increased that risk by 20%.

“While our results are consistent with the hypothesis that delirium plays a causative part in dementia, they are not conclusive owing to the fundamental limitations of observational studies in determining causality. Nevertheless, the results of this study provide valuable insights because prospective randomised controlled trials are unlikely to be conducted,” concluded the researchers.

Reference: Emily H Gordon, senior lecturer, David D Ward, research fellow, Hao Xiong, research fellow, Shlomo Berkovsky, professor of medical artificial intelligence, Ruth E Hubbard, professor of geriatric medicine; Delirium and incident dementia in hospital patients in New South Wales, Australia: retrospective cohort study; Journal: The BMJ; DOI: 10.1136/bmj-2023-077634