In this video, Dr. Doug Ethell presents groundbreaking research on a new approach to tackling brain aging and Alzheimer’s disease. Discover how restoring cerebrospinal fluid (CSF) flow could be key to preventing and potentially reversing cognitive decline. Learn about the crucial role of the cribriform plate and a novel implantable device in this cutting-edge research.

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Lifelong exercise promotes brain health in older adults

Individuals who maintain a regimen of physical activity throughout their lives may prevent brain deterioration during middle and older adulthood. NIA researchers made the discovery by measuring cardiorespiratory fitness in 125 cognitively unimpaired adults, ranging in age from 22 to 94, and by examining their brains. Specifically, they assessed the white matter of the brain, which is composed of myelin, a fatty layer of insulation that surrounds neurons. The study suggests lifelong exercise could be a therapeutic strategy for promoting brain health and reducing the risk of developing neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease. The findings were published in Proceedings of the National Academy of Sciences.

Read the full NIA update:
https://www.nia.nih.gov/news/lifelong-exercise-promotes-brain-health-older-adults

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Three psychological profiles linked to cognitive and brain health in aging suggest personalized prevention strategies could mitigate dementia risk and enhance mental well-being. Comprehensive assessments are crucial.

On the other hand, a psychological profile with low levels of protective characteristics—such as a sense of purpose, extraversion or openness to new experiences—was associated with poorer cognition (especially in older people), more pronounced brain atrophy (already observable in middle-aged adults) and lower adherence to healthy lifestyles.

Finally, the third profile identified, characterized by high levels of negative or risky psychological traits, such as a high propensity for distress and negative thoughts, “may increase the risk of cognitive impairment and dementia through a psycho-affective pathway, including the expression of symptoms such as depression, anxiety, cognitive complaints, loneliness and sleep disorders,” says the researcher.

Open Access Paper:

Psychological profiles associated with mental, cognitive and brain health in middle-aged and older adults

Psychological characteristics are associated with varying dementia risk and protective factors. To determine whether these characteristics aggregate into psychological profiles and whether these profiles differentially relate to aging health, we conducted a cross-sectional investigation in two independent middle-aged (51.4 ± 7.0 years (mean ± s.d.); N = 750) and older adult (71.1 ± 5.9 years; N = 282) cohorts, supplemented by longitudinal analyses in the former. Using a person-centered approach, three profiles emerged in both cohorts: those with low protective characteristics (profile 1), high risk characteristics (profile 2) and well-balanced characteristics (profile 3). Profile 1 showed the worst objective cognition in older age and middle age (at follow-up), and most rapid cortical thinning. Profile 2 exhibited the worst mental health symptomology and lowest sleep quality in both older age and middle age. We identified profile-dependent divergent patterns of associations that may suggest two distinct paths for mental, cognitive and brain health, emphasizing the need for comprehensive psychological assessments in dementia prevention research to identify groups for more personalized behavior-change strategies.

https://www.nature.com/articles/s44220-024-00361-8

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Summary: A new study reveals that older adults experience the least attention difficulties when home temperatures remain between 68–75 ˚F (20–24 ˚C). Deviations beyond this range double the risk of attention lapses, highlighting how even current climate conditions may harm cognitive health. This risk is especially pronounced for low-income seniors who may lack the means to regulate indoor temperatures.

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This one deserves to be posted in full here:

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A predictive tool for determining the age at which individuals may develop mild cognitive impairment (MCI) or Alzheimer’s dementia (AD) has demonstrated the ability to predict MCI onset within 2.78 years and AD onset within 1.48 years.

Developed by Florey Institute of Neuroscience and Mental Health researchers, collaborating with the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarker, and Lifestyle (AIBL) study, the team has released validation results of the Florey Dementia Index (FDI).

FDI predicts the age at onset of MCI and AD with high accuracy, potentially enabling patients and clinicians to better plan care and prioritize early treatment before the presentation of classic symptoms.

The Developers:

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Wow. Great article. I hope I get this right: The 14-3-3G protein complex is important in promoting autophagy. If Hexokinase-1 links to that 14-3-3 protein, it prevents that 14-3-3 protein from promoting autophagy, but if ezetimibe instead links at the proposed hexokinase-1 site, then the 14-3-3G protein can then promote autophagy. All this suggests that it might have nothing to do with cholesterol control, but rather, ezetimibe might compete for a molecular site on 14-3-3G protein, and when it links, it prevents hexokinase-1 from linking (that would then cause loss of autophagy). And ezetimibe is generic, cheap and well-tolerated. This will be fun to follow.

A Breath Away From a Cure: How Xenon Gas Could Transform Alzheimer’s Treatment

A breakthrough study highlights Xenon gas as a potential game-changer in treating Alzheimer’s disease, demonstrating its ability to mitigate brain damage and improve cognitive functions in mouse models. A forthcoming clinical trial aims to test its efficacy in humans.

Most current treatments for Alzheimer’s disease focus on addressing amyloid plaques and tau tangles in the brain. However, researchers from Mass General Brigham and Washington University School of Medicine in St. Louis have identified a groundbreaking alternative: Xenon gas.

Their study demonstrated that inhaling Xenon gas reduced neuroinflammation, minimized brain atrophy, and promoted protective neuronal states in mouse models of Alzheimer’s disease. These findings, published today (January 15) in Science Translational Medicine, have paved the way for a phase 1 clinical trial in healthy volunteers, set to begin in early 2025.

https://scitechdaily.com/a-breath-away-from-a-cure-how-xenon-gas-could-transform-alzheimers-treatment/

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Harvard researchers looked at 133,000 adults for four decades and evaluated how much processed and unprocessed red meat they ate on an average per day.

They found that eating one serving of processed red meat - roughly two slices of bacon or a single sausage - was linked to a 13 percent increased risk of dementia.

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For those who like betting, I created this prediction market on Manifold:

Hopefully AGI will accelerate research in the area :sweat_smile:

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These markets are also interesting:


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An interesting podcast

A discussion on Lithium (and Lithium + rapamycin) for Alzheimer’s and dementia prevention:

Brain Disorder Expert: Tackling Alzheimer’s & Other Brain Disorders with LITHIUM

Matt and psychiatrist Jon Berner chat about the potential of lithium, a generic drug typically used as a mood stabilizer in illnesses such as bipolar disorder, as an Alzheimer’s disease and/or life extension drug. They discuss the data supporting lithium’s potential effectiveness in preventing premature dementia, practical considerations and challenges around lithium dose optimization, and possible biological mechanisms that explain lithium’s effectiveness. They also delve into the various challenges of studying lithium’s effects on humans as well as useful further directions for lithium research.

Jon has been in solo psychiatric practice at Woodinville Psychiatric in Washington since 1997. He spent several years working at the Monroe Correctional Complex, a Washington State Department of Corrections prison. His specialties include brain disorders, particularly bipolar and psychotic illnesses, complex pain, addiction, and “undiagnosed” neuropsychiatric syndromes, and other general psychiatric disorders such as anxiety and depression. Jon has published multiple scientific papers about various topics in the realm of mood disorders and treatments for them. He holds an M.D and a PhD in neuroscience from the University of California, Los Angeles and a B.A. in psychology from Harvard University.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Lithium treatment extends human lifespan: findings from the biomedical database UK Biobank

According to this study, lithium supplementation correlates with an over threefold decrease in mortality among people suffering from affective disorders such as mania and bipolar depression, compared to those who use other anti-psychotic drugs. The study does not go into the likely molecular mechanisms by which lithium might extend human lifespan.

Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial

In a randomized, double-blind trial, 45 patients suffering from mild cognitive impairment received either lithium or a placebo over the span of a year. The trial found a correlation between lithium use and lower cerebrospinal fluid (CSF) concentrations of phosphorylated tau (p-tau), an Alzheimer’s disease biomarker. Researchers speculate that lithium may be more beneficial for individuals suffering from mild, as opposed to severe, cognitive impairment.

A triple drug combination targeting components of the nutrient-sensing network maximizes longevity

This study suggests that the combination of trametinib, rapamycin, and lithium increases longevity in flies by nearly 50 percent. Combining the drugs (combinations: lithium + rapamycin, lithium + trametinib, rapamycin + trametinib) extended lifespan by an average of 30 percent, compared to an average lifespan extension effect of 11 percent for each drug in isolation.

Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS)

There exists considerable variability in the clinical response to lithium. This study identified a specific pattern of gene expression in individuals who responded to one month of lithium treatment, with the gene expression changes being related to mechanisms including autophagy regulation, neurite outgrowth, and mitochondrially-mediated apoptosis. The researchers identified differential regulation of 62 genes in people who responded compared to those who didn’t respond to lithium treatment.

Lithium treated mood disorders, paroxysmal rhinorrhea and mesial temporal lobe epilepsy

Jon authored this paper presenting evidence for the effectiveness of lithium in mood stabilization via two case studies of mood disorders. In the first, lithium helped control shoplifting and major discrete cycles in a woman suffering from bipolar II disorder. In the second, lithium contributed to mood stabilization in a prison inmate suffering from chronic depression, though the drug also brought about side effects such as diarrhea and sudden attacks of rhinorrhea.

Amyloid-Tau-Neurodegeneration (ATN) Profile

This is the blood biomarker for Alzheimer’s disease pathology that Matt and Jon discuss in the podcast episode.

Source: Brain Disorder Expert: Tackling Alzheimer's & Other Brain Disorders with LITHIUM — The Optispan Podcast

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Circulation problems in the brain’s seat of memory linked to mild cognitive impairment in older adults

Mild cognitive impairment is linked to blood vessel dysfunction in the brain’s temporal lobes — the seat of memory — according to a new USC-led study.

The findings, seen in people with and without signs of amyloid buildup in the brain, suggest that microvascular trouble may be an important, early biomarker for dementia as well as a potential target for therapy.

The research, involving scientists from multiple universities, appears in the journal Neurology.

“We’re studying the ability of these very small vessels to respond to stimuli and to dilate, and they’re showing dysfunction in people who have memory problems,” said senior author Daniel Nation, a professor of gerontology and medicine at the USC Leonard Davis School of Gerontology. “It could implicate blood vessel dysfunction in a very early stage of memory loss. It happened whether or not people had Alzheimer’s-related brain changes. They still had this blood vessel problem if they had memory issues.”

“Our findings underscore the need to focus on vascular health as a critical factor in memory decline,” said first author Arunima Kapoor, a graduate student at University of California, Irvine.

Nation said that some blood pressure drugs may potentially protect vascular function in a way that preserves memory, but more research is needed.

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Very interesting. There is some contradictory, mixed and paradoxical data when it comes to blood pressure. It’s pretty clear that high BP in midlife is a big negative for health in general and the brain in particular. Meanwhile the picture becomes blurry in the old. Generally, BP goes up with age. This is hotly debated, because there have been suggestions that moderately higher BP in old age is brain protective. The thought is that with age the vascular system experiences stenosis. With less blood able to go through narrower vessels, you need greater blood pressure to push through and bring vital nutrients in and take the waste out. Conversely, low blood pressure in the old is sometimes associated with poor brain health. At least that was the view for some time, wherein there would be efforts made to get BP under control in middle age, but the standards for what constitutes treatable HBP in the old was slightly relaxed - I don’t know what the latest thinking is on the subject, are BP drugs prescribed in the old in borderline HBP cases?

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Published in the journal Brain Research, the study highlights how physical activity not only protects healthy brain cells but also restores balance in the aging brain.

The research focused on the hippocampus, the brain region responsible for memory and learning, and measured the impact of aerobic exercise on key Alzheimer’s markers: amyloid plaques, tau tangles, and iron accumulation in myelin-producing cells known as oligodendrocytes. These markers are central to Alzheimer’s pathology.

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What’s The Link Between The Two?

A variety of factors connect visceral fat to an increased risk of dementia. “We’ve known for at least 15 years that visceral fat is linked with lower brain volumes in healthy middle-aged adults,” says Moon.3She adds that, more recently, studies suggest a higher level of visceral fat in older adults is associated with worse cognition and damage to white matter (what helps conduct messages between brain cells) and a thinning of gray matter, which is made up of neurons that help us think, learn and remember.24

Cho J, Seo S, Kim WR, Kim C, Noh Y. Association between visceral fat and brain cortical thickness in the elderly: A neuroimaging study. Front Aging Neurosci. 2021;13:694629. doi:10.3389/fnagi.2021.694629.

Visceral fat is also an indirect risk factor for dementia because of the other types of conditions it is associated with, like diabetes.5 Pincus notes, “An older, but important meta-analysis of 28 studies showed a 73% increased risk of all type dementia, 56% increase of Alzheimer’s Disease, and 127% increase of vascular dementia in patients with diabetes.”6

Elevated blood sugar and its related conditions, such as high cholesterol and blood pressure, can impact blood vessels and cause inflammation. Pincus adds, “Chronic elevated blood glucose damages blood vessels in the brain while insulin resistance affects brain glucose metabolism.” This is important because the brain thrives on glucose and needs it to function optimally. Moon adds that damage to blood vessels can reduce the flow of oxygen and nutrients to the brain.

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Rhonda Patrick of FoundMyFitness sends an email Newsletter to my inbox - The following cut/pasted from my email: Jan 16, 2025: The Case for Vitamin D in Dementia Prevention Well written and compelling reading (not sure about the accuracy of the science reporting).


Vitamin D isn’t just a vitamin—it’s a hormone that controls thousands of genes in the human body, many of which are in the brain.

The primary source of vitamin D is UVB radiation from the sun—which our skin uses to synthesize vitamin D3. Insufficient sun exposure, season changes in UVB, aging, and body weight can all affect our ability to produce vitamin D and its bioavailability. Because nearly 70% of the population has insufficient levels of vitamin D (blood levels <30 ng/mL) and a large percentage have deficient levels (<20 ng/mL), supplementing with vitamin D makes sense for most!

This might be especially true if you’re concerned about dementia risk (as we all should be).

In a study of over 12,000 dementia-free adults, those who used vitamin D had a 40% lower risk of dementia over a decade.

Remarkably, 84% of supplement users were dementia-free after five years, compared to just 68% of non-users. The benefits of vitamin D even extended to high-risk groups: In adults with mild cognitive impairment (MCI) and those who carried one or two copies of the APOE e4 allele—a major risk factor for neurodegenerative diseases—the risk of dementia was 33% lower compared to adults with MCI/APOE e4 carriers who didn’t use vitamin D.

While vitamin D reduced dementia risk across the board, some groups benefitted more.

Women, adults with normal cognition, APOE e4 non-carriers, and those without depression saw the greatest brain-protective effects from vitamin D supplementation.

Regardless of sex, genetic risk, or baseline cognition, the evidence is clear: Vitamin D is a powerful ally in reducing dementia risk. Though dosage details and optimal blood levels remain unknown, the link between vitamin D and brain health is too significant to ignore.

In today’s email, we’ll explore the importance of vitamin D for brain and body health and break down this study in more detail. I’ll also provide some practical takeaways about vitamin D supplementation.
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Why Vitamin D Benefits the Brain

Vitamin D is linked to several benefits for human health.

  • Supports neurodevelopment: High-dose vitamin D supplementation in early childhood reduces the risk of internalizing behaviors such as depression and anxiety, especially in children with low prenatal vitamin D exposure.
  • Enhances brain function synergistically with exercise: Vitamin D supplementation combined with exercise improves functional brain connectivity in regions associated with memory and cognition.
  • Improves muscle strength and mass: Higher vitamin D levels enhance muscle strength and mass while reducing fat mass, likely through metabolic and hormonal pathways.
  • Promotes tooth remineralization: Vitamin D supplementation increases calcium and phosphorus in teeth, reducing the risk of demineralization and cavities.
  • Supports healthy aging: Vitamin D maintains genomic stability, mitochondrial function, and reduces cellular senescence, mitigating the hallmarks of aging.
  • Facilitates calcium homeostasis and bone health: Vitamin D regulates calcium absorption and bone remodeling, reducing the risk of osteoporosis and fractures, especially in aging populations.

Higher levels of vitamin D have also been associated with lower odds of dementia and mild cognitive impairment (MCI), better cognitive function, a reduction in Alzheimer’s disease risk, and larger total brain, gray matter, and hippocampal volumes.

How might vitamin D protect against dementia and Alzheimer’s?

Vitamin D helps clear amyloid beta aggregates which are considered to be one of the hallmarks of Alzheimer’s disease. It also appears to target another hallmark of Alzheimer’s disease—tau protein hyperphosphorylation. These effects have been attributed to less reactive oxygen species production, greater immune system clearance of amyloid beta proteins, and an increase in glial cell line-derived neurotrophic factor or GDNF—a brain protein that helps neurons survive and regenerate.

A 12-month randomized controlled trial found that vitamin D supplementation improved cognitive function, intelligence quotient scores, telomere length, and lowered oxidative stress markers in older adults with mild cognitive impairment (compared to placebo), suggesting that not only does vitamin D supplementation improve biomarkers of aging, but also functional outcomes.

Even though the study we’ll discuss today didn’t investigate these mechanisms, its results are still a testament to the importance of vitamin D for neurological health, especially later in life.
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Supplementing with Vitamin D Reduces Dementia Risk

The study included 12,388 adults who were divided into two groups: Those who reported using vitamin D supplements in any form (calcium-vitamin D, ergocalciferol/vitamin D2, or cholecalciferol/vitamin D3) and those who didn’t.

During the 10-year follow-up period, supplementing with vitamin D was associated with a 40% lower incidence of dementia: Over 2,000 participants who reported never using vitamin D supplements developed dementia compared to just 679 of those who used vitamin D.

Supplementing with vitamin D was also associated with a greater 5-year dementia-free survival—84% of adults in the vitamin D group were free of dementia during this time period while only 68% of the non users were dementia-free.

This was also true regardless of whether or not the participants had baseline MCI or normal cognitive function—vitamin D provided a benefit in both cases. While dementia prevalence was higher in adults with MCI, it was around 15% lower in this group for adults who supplemented with vitamin D compared to those who didn’t.
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Some populations benefit more

Although vitamin D supplementation reduced dementia risk among all groups, there were several interesting findings regarding the benefits of vitamin D for certain populations:

  • Women derived a greater benefit from vitamin D: They experienced less dementia compared to men who supplemented. Furthermore, while vitamin D-using men had a 26% lower dementia incidence than non-using men, vitamin D-using women had a 49% lower incidence compared to non-using women.
  • Adults with normal baseline cognitive function had a 56% lower dementia incidence if they supplemented with vitamin D; however, adults with MCI had only a 33% lower incidence if they supplemented.
  • Among APOE e4 carriers, supplementing with vitamin D reduced the incidence of dementia by 33%, and among non-carriers, vitamin D reduced the incidence of dementia by 47%. Furthermore, among APOE e4 non-carriers, vitamin D use was associated with a 47% reduction in dementia incidence, while among carriers, vitamin D only mitigated dementia incidence by 33%.

Supplementing with vitamin D wasn’t enough to outweigh the effects of carrying one or two copies of the APOE e4 allele—these participants still had a 16% greater risk of dementia than non-carriers, even non-carriers who didn’t use vitamin D. The same was true for another risk factor—having MCI—which elevated dementia incidence by nearly 400% compared to having normal cognition, even in the presence of vitamin D supplementation.

Slowing the Decline for Those with Cognitive Impairment

Participants with MCI who didn’t supplement with vitamin D had more than a 600% increase in dementia risk compared to adults with normal cognitive function, even those who didn’t use vitamin D. But having MCI and supplementing with vitamin D offered some risk reduction—these participants’ dementia risk was 390% higher than adults with normal cognitive function—still high, but not as bad as having MCI and not using vitamin D!

It didn’t matter the form of vitamin D used—all of them were associated with a lower dementia risk. Specifically, using calcium-vitamin D was associated with a 44% lower dementia risk, using cholecalciferol (vitamin D3) was associated with a 37% lower risk, and ergocalciferol (vitamin D2) was associated with a 50% lower risk. Using combined forms of vitamin D was associated with a 50% lower risk.

Final Thoughts

These findings give strong support to the idea that everyone should probably be supplementing with at least some vitamin D to support optimal brain health.

This is especially true if you are exposed to risk factors for dementia like having one or more copies of the APOE e4 allele, mild cognitive impairment (or a family history of it), and others that weren’t investigated in this study like high blood pressure or metabolic dysfunction.

However, it is also important to note several caveats that warrant consideration. First, this was not a randomized controlled trial but an observational study, which introduces the potential for healthy user bias—adults who take supplements like vitamin D may also engage in other health-promoting behaviors that reduce dementia risk, independently of the supplement itself. Additionally, the study did not measure blood levels of vitamin D, so we lack insight into whether the observed effects were tied to correcting a deficiency or achieving a specific target range. Lastly, we don’t know the dose of vitamin D that was associated with health improvements—just whether participants used or didn’t use vitamin D supplements.

For these reasons, we can’t definitively say that vitamin D is certain to prevent dementia. But that doesn’t negate its critical importance for health. On that note, are some important and practical takeaways regarding vitamin D and your health.

  • Natural sunlight vs. supplementation: While sunlight exposure helps the body naturally regulate vitamin D synthesis, there is a natural built-in mechanism to prevent the body from producing too much vitamin D when in sunlight. This prevents toxicity.
  • Safe supplementation: Levels above 60 ng/mL of vitamin D are likely safe for most people. Levels up to 80 ng/mL have been shown to be associated with lower all-cause mortality, suggesting a beneficial range. Going above 80 ng/mL should be done with caution.
  • Avoiding toxicity: While vitamin D toxicity can occur with very high levels (especially through supplementation), a high dose taken daily for a long time is typically required to reach toxic levels. Commonly, it’s harder to reach toxic levels with moderate supplementation, and it’s unlikely unless extreme doses are taken consistently.
  • Consider your individual needs: Some people, particularly those with genetic factors (e.g., certain SNPs), may require higher doses to maintain optimal vitamin D levels. For example, some individuals may need 5,000 to 7,000 IU per day to reach levels of 30–40 ng/mL.
  • Standard doses probably aren’t sufficient: Large-scale studies often use standard low doses (e.g., 2,000 IU), but the results are inconclusive, particularly when participants’ starting levels aren’t considered. A better approach would be to adjust the dose to individual needs, aiming for higher target levels (e.g., 60 ng/mL or higher).
  • Monitoring blood levels: If you’re supplementing with vitamin D, monitor your blood levels regularly to ensure you’re maintaining an optimal range. If you’re aiming to achieve the highest levels safely, aim for levels between 60–80 ng/mL as these have shown potential benefits without the risks associated with high toxicity. However, always adjust based on personal needs and health factors, and consult a healthcare provider for personalized recommendations.
  • Avoid deficiency: Vitamin D levels below 30 ng/mL are considered insufficient, and levels above 40 ng/mL are generally beneficial for overall health. Vitamin D deficiency occurs at a blood level below 20 ng/mL.
    Interested in learning more about vitamin D and Rhonda’s current supplement routine? Check out these member-only Q&A episodes with detailed show notes that we’ve hand-picked to accompany this newsletter.
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No? Vitamin D supplementation: no cognitive benefits in older adults with mild to moderate deficiency

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The focus of Rhonda’s newsletter is the following study: Ghahremani M, Smith EE, Chen H-Y, Creese B, Goodarzi Z, Ismail Z. Vitamin D supplementation and incident dementia: Effects of sex, APOE, and baseline cognitive status. Alzheimer’s Dement . 2023; 15:e12404. https://doi.org/10.1002/dad2.12404

At a glance, the above study is an observational study of 10 years. In contrast to the study you give which is randomized control study for a period of 24 months. As a non-scientist I can’t speak with any expertise as to the significance of either study, but I will say Rhonda’s editorial team has made clear that they think the conclusions from the study are significant to act on

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It’s very typical in medicine where deficiency of nutrient (vitamin in this case) is bad, but there is no further benefit from supplementation beyond meeting the minimal requirements

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