An ancient human foraging instinct, fueled by fructose production in the brain, may hold clues to the development and possible treatment of Alzheimer’s disease (AD), according to researchers at the University of Colorado Anschutz Medical Campus.
“We make the case that Alzheimer’s disease is driven by diet,” said the study’s lead author Richard Johnson, MD, professor at the University of Colorado School of Medicine specializing in renal disease and hypertension. The study co-authors include Maria Nagel, MD, research professor of neurology at the CU School of Medicine.
Steve Parker, M.D.
PS: The Mediterranean diet is linked to lower risk of dementia.
The study at hand was very small, only 20 participants. So results may not be reproducible. The Canadian researchers’ main conclusion: “This is the longest duration MCT Alzheimer Disease study to date. Eighty percent had stabilization or improvement in cognition, and better response with 9‐month continual MCT oil.”
MCT stands for medium chain triglycerides, which apparently are derived from coconut and palm oil. The MCTs provide a source of energy for the brain – ketones – as a partial substitute for the brain’s usual energy source, glucose.
Study participants as expected were elderly and had mild to moderate Alzheimer Disease. Folks with diabetes were excluded from participation.
The article introduction has some interesting facts:
The brain is an obligate glucose metabolizer using 120 to 130 g/day of glucose. It uses 16% of the body’s total O2 consumption, despite representing only 2.0% to 2.3% of adult body weight. In conditions of low carbohydrate intake or fasting, the body uses ketones (acetoacetate and beta hydroxybutyrate [BHB]) as an alternative energy source to glucose. Ketones are normally generated in fasting states from beta‐oxidation of adipose stores to maintain cerebral function. In long‐term fasting, ketones can supply > 60% of the brain’s energy requirements, and are preferentially taken up by the brain over glucose. This occurs in cognitively normal younger and older adults, as well as in those with mild cognitive impairment (MCI) and AD.
Ketones can also be induced with a very low carbohydrate high fat (VLCHF) diet. Medium chain triglyceride (MCT) oil has the potential to produce a nutritional source of ketones for an alternative brain fuel to glucose, or by the consumption of MCT oil or esterases in freeze‐dried form. This is independent of the fasting state or carbohydrate intake. Long‐term compliance with fasting or VLCHF and LCHF diet regimes is challenging and requires strict medical supervision. Hence, the potential advantage of nutritional ketone sources (MCT) over these restrictive diets. Our recent study showed a clear dose‐dependent effect on ketone (BHB) generation with varying doses of MCT supplementation, and was found to be equivalent in young, elderly, and AD subjects.
In Alzheimer Disease (AD), the brain is unable to use glucose normally, causing hypofunction of 20% to 40% in key areas of the brain responsible for the symptoms in AD.
The MCT oil used was Bulletproof Brain Octane ® (NPN 80057199). Are other MCT oils just as good? Hell if I know. The goal dose was three tablespoons (15 ml) daily. My sense is that it was recommended as one tablespoon (15 ml) three times daily. The average consumption ended up as two tablespoons daily. Caregivers were in charge of dosing and they tended to forget or omit the lunchtime dose. Some study participants had limited dosing due to MCT side effects: abdominal pain, diarrhea, or vomiting.
This study shows that participants taking MCT supplementation for 11 months continuously did better cognitively than their peers who had their 11 months of MCT interrupted by 4 months of placebo (olive) oil. Given that most patients should experience a drop in their cognitive scores over the 15 months, the fact that those on longer continuous MCT did not, could be a sample size error for the outcomes other than Montreal Cognitive Assessment, but it could also be that the difference in scores (showing stability) is valid.
In other words, MCT oil didn’t improve cognition, but stabilized it. I.e., it prevented the usual expected decline over time.
Question Is cataract extraction associated with reduced risk of developing dementia?
Findings In this cohort study assessing 3038 adults 65 years of age or older with cataract enrolled in the Adult Changes in Thought study, participants who underwent cataract extraction had lower risk of developing dementia than those who did not have cataract surgery after controlling for numerous additional risks. In comparison, risk of dementia did not differ between participants who did or did not undergo glaucoma surgery, which does not restore vision.
Meaning This study suggests that cataract extraction is associated with lower risk [~30% less] of developing dementia among older adults.
Importance Visual function is important for older adults. Interventions to preserve vision, such as cataract extraction, may modify dementia risk.
Details in the abstract:
Objective To determine whether cataract extraction is associated with reduced risk of dementia among older adults.
Design, Setting, and Participants This prospective, longitudinal cohort study analyzed data from the Adult Changes in Thought study, an ongoing, population-based cohort of randomly selected, cognitively normal members of Kaiser Permanente Washington. Study participants were 65 years of age or older and dementia free at enrollment and were followed up biennially until incident dementia (all-cause, Alzheimer disease, or Alzheimer disease and related dementia). Only participants who had a diagnosis of cataract or glaucoma before enrollment or during follow-up were included in the analyses (ie, a total of 3038 participants). Data used in the analyses were collected from 1994 through September 30, 2018, and all data were analyzed from April 6, 2019, to September 15, 2021.
Exposures The primary exposure of interest was cataract extraction. Data on diagnosis of cataract or glaucoma and exposure to surgery were extracted from electronic medical records. Extensive lists of dementia-related risk factors and health-related variables were obtained from study visit data and electronic medical records.
Main Outcomes and Measures The primary outcome was dementia as defined by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. Multivariate Cox proportional hazards regression analyses were conducted with the primary outcome. To address potential healthy patient bias, weighted marginal structural models incorporating the probability of surgery were used and the association of dementia with glaucoma surgery, which does not restore vision, was evaluated.
Results In total, 3038 participants were included (mean [SD] age at first cataract diagnosis, 74.4 (6.2) years; 1800 women (59%) and 1238 men (41%); and 2752 (91%) self-reported White race). Based on 23 554 person-years of follow-up, cataract extraction was associated with significantly reduced risk (hazard ratio, 0.71; 95% CI, 0.62-0.83; P < .001) of dementia compared with participants without surgery after controlling for years of education, self-reported White race, and smoking history and stratifying by apolipoprotein E genotype, sex, and age group at cataract diagnosis. Similar results were obtained in marginal structural models after adjusting for an extensive list of potential confounders. Glaucoma surgery did not have a significant association with dementia risk (hazard ratio, 1.08; 95% CI, 0.75-1.56; P = .68). Similar results were found with the development of Alzheimer disease dementia.
Conclusions and Relevance This cohort study found that cataract extraction was significantly associated with lower risk of dementia development. If validated in future studies, cataract surgery may have clinical relevance in older adults at risk of developing dementia.
What else reduces risk of dementia? The Mediterranean Diet!
Viagra (one brand name for generic sildenafil) is used to treat erectile dysfunction and pulmonary hypertension. I bet that usage for ED is far more common than for pulmonary hypertension.
From an article published in Dec 2021 by National Institutes of Health:
…the team analyzed insurance claims data from more than 7 million Americans. They found that the people (mostly men) who took sildenafil were 69% less likely to develop AD [Alzheimer’s Disease] over 6 years than those who did not take the drug. This association between sildenafil and AD held after adjusting for sex, age, and other diseases and conditions.
To understand how sildenafil might affect AD, the researchers grew neurons from stem cells derived from AD patients. Exposing the cells to sildenafil led to increased growth of neurites, which connect neurons to each other, and decreased tau phosphorylation, an early biomarker of AD.
Taken together, these results show an association between sildenafil use and reduced AD risk. But the researchers emphasize that they haven’t shown that sildenafil prevents or reverses AD.
These things usually don’t pan out, but one can hope. How often were these guys taking viagra? Once a month? Twice a week? To treat erectile dysfunction, sildenafil is typically taken as needed one hour before sexual activity. A typical dose for pulmonary hypertension is 20 mg by mouth three times a day, every day. Would this drug affect dementia in women? As they say, further studies are needed.
Here’s the abstract of an article in Advances in Nutrition. This is the first I’ve heard of “gray literature.”
Alzheimer disease (AD) is a global health concern with the majority of pharmacotherapy choices consisting of symptomatic treatment. Recently, ketogenic therapies have been tested in randomized controlled trials (RCTs), focusing on delaying disease progression and ameliorating cognitive function. The present systematic review aimed to aggregate the results of trials examining the effects of ketogenic therapy on patients with AD/mild cognitive impairment (MCI). A systematic search was conducted on PubMed, CENTRAL, clinicaltrials.gov, and gray literature for RCTs [randomized controlled trials] performed on adults, published in English until 1 April, 2019, assessing the effects of ketogenic therapy on MCI and/or AD compared against placebo, usual diet, or meals lacking ketogenic agents. Two researchers independently extracted data and assessed risk of bias with the Cochrane tool. A total of 10 RCTs were identified, fulfilling the inclusion criteria. Interventions were heterogeneous, acute or long term (45-180 d), including adherence to a ketogenic diet, intake of ready-to-consume drinks, medium-chain triglyceride (MCT) powder for drinks preparation, yoghurt enriched with MCTs , MCT capsules, and ketogenic formulas/meals. The use of ketoneurotherapeutics proved effective in improving general cognition using the Alzheimer’s Disease Assessment Scale-Cognitive, in interventions of either duration. In addition, long-term ketogenic therapy improved episodic and secondary memory. Psychological health, executive ability, and attention were not improved. Increases in blood ketone concentrations were unanimous and correlated to the neurocognitive battery based on various tests. Cerebral ketone uptake and utilization were improved, as indicated by the global brain cerebral metabolic rate for ketones and [11C] acetoacetate. Ketone concentrations and cognitive performance differed between APOE ε4(+) and APOE ε4(-) participants, indicating a delayed response among the former and an improved response among the latter. Although research on the subject is still in the early stages and highly heterogeneous in terms of study design, interventions, and outcome measures, ketogenic therapy appears promising in improving both acute and long-term cognition among patients with AD/MCI. This systematic review was registered at http://www.crd.york.ac.uk/prospero as CRD42019128311.
I have nothing against Prilosec in particular. It can be very helpful.
There are reasons our stomachs produce acid. One is that the acid helps kill pathogens in our food before they make us sick. Another is to start the digestion of proteins we eat. You can imagine that drastically reducing stomach acid production has some potential adverse effects.
We have two major classes of drugs that reduce acid production by the stomach. The first was H2 blockers, the granddaddy being Tagamet (cimetidine). Tagamet was the first H2 blocker on the market in the U.S., probably 25–30 years ago. Several H2 blockers are are available without a prescription. The second and later class of acid-reducing drugs are the PPIs: proton pump inhibitors. These are more potent than H2 blockers. Because of H2 blockers and PPIs, and the discovery that H. pylori causes many ulcers, we have many fewer patients requiring surgery for upper GI ulcers. Surgery like Billroth’s and vagotomy & pyloroplasty. Once the ulcer heals, most folks don’t need to take a PPI for the rest of their lives.
A German population study a few years ago linked PPI usage with higher risk of dementia.
A total of 73,679 participants 75 years of age or older and free of dementia at baseline were analyzed. The patients receiving regular PPI medication (n = 2950; mean [SD] age, 83.8 [5.4] years; 77.9% female) had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication (n = 70,729; mean [SD] age, 83.0 [5.6] years; 73.6% female) (hazard ratio, 1.44 [95% CI, 1.36-1.52]; P < .001).
The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail.
I don’t know about Germany, but there’s evidence that the incidence of dementia has been decreasing lately in the U.S. I’m guessing that the use of PPIs has been increasing over the last couple decades. So this doesn’t fit with the PPI-dementia theory.
These data suggest that closer adherence to MedD (the Mediterranean diet) was associated with better performance in verbal memory in patients with type 2 diabetes with known diabetes duration ≥5 years, but not in patients with recently diagnosed type 2 diabetes or in patients with type 1 diabetes or metabolically healthy individuals.
The MedD has been already reported to exert beneficial effects on cardiovascular disease and additionally on cognitive performance mainly in healthy elderly individuals or individuals with increased cardiovascular risk. The present results show an association between MedD and verbal memory in individuals with diabetes. Although the underlying mechanisms are currently unknown, one may speculate that the high content of antioxidants in MedD may contribute to better cognitive performance by reducing the production of reactive oxygen species and attenuating inflammatory processes, both of which have been linked to cognitive decline. Furthermore, positive effects might be mediated by n-3 fatty acids (FA). Higher dietary n-3 FA intake or circulating blood n-3 FA levels have been associated with better global or single cognitive function which was mainly explained by their anti-inflammatory, antioxidative and antithrombotic properties. However, the influence of n-3 FA is controversial according to the literature, as not all studies observed beneficial effects, possibly due to different study designs, methods and varying quality of studies.
A diet low in carbohydrates could stave off, or even reverse, the effects of aging on the brain, Stony Brook-led research finds.
A study using neuroimaging led by Stony Brook University professor and lead author Lilianne R. Mujica-Parodi, PhD, and published in PNAS, reveals that neurobiological changes associated with aging can be seen at a much younger age than would be expected, in the late 40s. But the study also suggests that this process may be prevented or reversed based on dietary changes that involve minimizing the consumption of simple carbohydrates.
Even in younger adults, under age 50, dietary ketosis (whether achieved after one week of dietary change or 30 minutes after drinking ketones) increased overall brain activity and stabilized functional networks.
Yes, some cases of dementia are preventable. If you have a genetic predisposition to develop dementia, the deck is stacked against you. But it’s not hopeless. A healthy lifestyle will help you, too.
The research at hand was done in the UK and involved over 500,000 older adults of European ancestry, free of dementia and cognitive impairment at baseline.
So what are the healthy lifestyle characteristics linked to lower risk of dementia, whether you have genetic risk or not?
Judicious alcohol consumption
Lifestyle details from the research report:
A healthy lifestyle score was constructed based on 4 well-established dementia risk factors (smoking status, physical activity, diet, and alcohol consumption) assessed at baseline using a touchscreen questionnaire. Participants scored 1 point for each of 4 healthy behaviors defined on the basis of national recommendations (full details in eTable 1 in Supplement 1). Smoking status was categorized as current or no current smoking. Regular physical activity was defined as meeting the American Heart Association recommendations of at least 150 minutes of moderate activity per week or 75 minutes of vigorous activity per week (or an equivalent combination) or engaging in moderate physical activity at least 5 days a week or vigorous activity once a week. Healthy diet was based on consumption of at least 4 of 7 commonly eaten food groups following recommendations on dietary priorities for cardiometabolic health, which are linked to better late-life cognition and reduced dementia risk. Previous studies of alcohol consumption and dementia risk support a U-shaped relationship, with moderate consumption associated with lower risk. Therefore, moderate consumption was defined as 0 to 14 g/d for women and 0 to 28 g/d for men, with the maximum limit reflecting US dietary guidelines.
What do they consider a healthy dementia-preventing diet? At least four of the following food groups and consumption levels:
Fruits: 3 or more servings a day
Veggies: 3 or more servings a day
Fish: 2 or more servings a week
Processed meats: no more than 1 serving a week
Unprocessed red meats: no more than 1.5 servings a week
Whole grains: 3 or more servings a day
Refined grains: no more than 1.5 servings a day
Regarding alcohol, the guideline is no more than one drink a day for women, and no more than two a day for men. Do a web search for standard drink sizes if needed. “One drink” is 14 grams of pure alcohol.
Steve Parker, M.D.
PS: You do know that the Mediterranean diet is linked to lower risk of dementia, don’t you?
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Sous vide chicken and sautéed sugar snap peas. This meal is part of a ketogenic diet.
From The Journal of Nutrition:
Recently, ketogenic diets have received substantial attention from the general public and nutrition research community. These very-low-carbohydrate diets, with fat comprising >70% of calories, have been dismissed as fads. However, they have a long history in clinical medicine and human evolution. Ketogenic diets appear to be more effective than low-fat diets for treatment of obesity and diabetes. In addition to the reductions in blood glucose and insulin achievable through carbohydrate restriction, chronic ketosis might confer unique metabolic benefits of relevance to cancer, neurodegenerative conditions, and other diseases associated with insulin resistance. Based on available evidence, a well-formulated ketogenic diet does not appear to have major safety concerns for the general public and can be considered a first-line approach for obesity and diabetes. High-quality clinical trials of ketogenic diets will be needed to assess important questions about their long-term effects and full potential in clinical medicine.