It’s a well-known fact that Alzheimer’s disease is closely linked to metabolic health, to the point that some experts have begun to refer to it as Type III Diabetes. But what many people don’t know is that poor metabolic health is a strong risk factor for dementia long before it progresses to diabetes, even for people without a family history.

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Decoding metabolic syndrome

Before you get diagnosed with diabetes, your body goes through a number of changes. Cells in your body become desensitized to insulin, which usually tells them to absorb sugar from your bloodstream. This results in chronically elevated blood sugar and in turn starts causing problems for your heart, liver, brain, and other organs. This pre-diabetic phase is called metabolic syndrome, and it affects ~25% of adults worldwide, including 40% adults aged 60+ in the U.S. Most of them do not know that metabolic syndrome is a health risk. 

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Metabolic syndrome is diagnosed when an individual has three or more of the following: 

• High triglycerides (≥150 mg/dL)
• Elevated blood pressure (≥130 mmHg systolic or ≥85 mmHg diastolic) OR use of antihypertensive medication
• High fasting glucose (≥100 mg/dL OR use of glucose lowering medications)
• Low HDL cholesterol (<40 mg/dL in men; <50 mg/dL in women OR use of lipid-modifying medication)
• Abdominal obesity (waist circumference ≥102 cm for men and ≥88 cm for women)

It’s worth noting that hemoglobin A1c (HbA1c), a common marker for diabetes, does not feature on this list. Although a doctor won’t use A1c to diagnose metabolic syndrome, it’s still an important marker to keep track of your metabolic health.

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Connecting metabolic syndrome to brain health

A large retrospective study¹ analyzed data from 175,000 participants over a period of 15 years. Participants were aged 60+ and represented a variety of sociodemographic, lifestyle, and genetic backgrounds. With regards to the metabolic syndrome diagnosis criteria listed above, the study found that:

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• Having three conditions increases dementia risk 12% 
• Having four to five conditions is associated with an even stronger risk 
• The link between metabolic syndrome and dementia is particularly strong in individuals who do not carry the APOE ε4 allele (typically, these are individuals with a lower risk of dementia)

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Taking action

The first step is to know where you stand. It’s important to establish a baseline by measuring metabolic markers in your blood and potentially using a continuous glucose monitor (CGM) to see how your blood sugar reacts to your daily habits. This will help you make an informed decision on how to approach your metabolic health. 

Metabolic health is strongly tied to your lifestyle - particularly your diet, physical activity, and sleep. There’s also several different drugs, like statins or ACE inhibitors, available to help manage symptoms. However, this post isn’t meant to serve as a meal plan or exercise sheet. Instead, we’ve put together a list of hacks that we think can make a difference even if you haven’t fully optimized your health.

• Drink a tablespoon of vinegar ~20 minutes before a meal. This helps avoid spikes in your blood sugar.
• Go for a walk after meals, especially if those meals are heavy on carbs (e.g., pasta, potatoes, bread). This helps your muscles absorb glucose more efficiently. 
• Perform at least 10m of vigorous exercise per day. Raising your heart rate (e.g., through a short HIIT session) helps boost your insulin sensitivity, which keeps blood sugar low.some text
  • Exercise is most effective at reducing blood sugar spikes when done within an hour before or after a meal
• Eat your carbs last. Start your meal by eating vegetables (which are high in fiber), then eating proteins and fats, and finally moving to carbs. This helps slow the absorption of sugar into your bloodstream, and in turn reduce sugar spikes.

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Small steps add up

Although the hacks mentioned above aren’t meant to replace a healthy lifestyle, they can help you make an immediate improvement in your metabolic health and kickstart your dementia prevention efforts. Remember - working on your metabolic health isn’t just about preventing diabetes, it’s about safeguarding your cognitive health.

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Actions to consider

• Measure your metabolic markers. Some of these you may get on your annual physical (e.g., HbA1c, HDL-C, LDL-C, glucose, triglycerides, insulin). Others are less common (e.g., Lp(a), ApoB). Most importantly, don’t settle for just ok. These markers are worth optimizing. All the tests mentioned above are part of the 50+ biomarkers tested during your BetterBrain Essentials blood draw.
• Consider using a CGM to get a more accurate view of how your body processes sugar. Using a CGM, you can observe the effects of what you eat and your lifestyle on your blood sugar in real time, which can help inform the daily choices you make. We love the Dexcom G7, which may be challenging to buy over-the-counter but can be bought for cheaper through Signos.‍
• Learn more about homocysteine on the Peter Attia Drive podcast #252. This episode covers a wide variety of topics related to brain health, and links many different risks and possible interventions to metabolic health.

In the 1960s, researchers on Easter Island were investigating local indigenous peoples’ claims that the soil has healing properties. After testing various soil samples, the researchers isolated a small molecule they believed was responsible for the effects. They named it rapamycin⁵, after the traditional name for the island, Rapa Nui. Since its discovery, rapamycin has been used in various settings, from an antifungal agent to more recently a beacon of hope in anti-aging medicine. Additionally, it is showing promise in extending lifespan and preventing neurodegenerative diseases such as Alzheimer’s.

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From anti-rejection med to longevity enhancer

The transition from an antifungal to a potential longevity drug has been intriguing. Rapamycin, approved in 1999 for its immunosuppressant qualities, is still commonly used in kidney transplants to prevent organ rejection. However, a 2014 study¹ on older adults revealed a paradox: at much smaller doses, rapamycin boosted the immune response to flu vaccinations, despite their age-related weakened immune function. This unexpected enhancement suggests that rapamycin might have broader applications for disease prevention in older adults, potentially making it a valuable tool in combating age-related declines in the human immune system.

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How rapa works

To understand how rapamycin works, it’s important to understand the molecule that it targets: a cellular receptor named mTOR. mTOR is present in nearly all cells in the human body and is responsible for mediating pathways that regulate cell growth, metabolism, and survival.  Inhibiting mTOR completely is catastrophic - it prevents cells from making energy, eventually leading to their death. However, partial inhibition means that mTOR has a harder time forming a cluster with other proteins, which makes the cell act as if it's not getting enough food. This starts a process where the cell breaks down unneeded or damaged parts, like proteins that aren't folded correctly, which can otherwise impair the cell’s ability to function. This leads to improved cellular survival and resilience and is particularly relevant to brain health since one of the main features of Alzheimer’s is the accumulation of misfolded amyloid beta protein plaques in neurons. 

The partial inhibition of mTOR therefore shows potential for slowing down the progression of Alzheimer’s disease and improving the survival rate of neurons. Animal studies^2,3 suggest that rapamycin may help mitigate or improve many of the pathologies associated with Alzheimer's disease and potentially restore cognitive function.  

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Growing evidence yet limited human trials

While animal studies have robustly demonstrated lifespan and healthspan extensions—with remarkable outcomes like a 20-30% increase in the lifespan of mice⁴—human data remains scarce. The gap in human trials can be largely attributed to the fact that rapamycin use for longevity is considered “off-label”. This means that the Federal Drug Administration (FDA) has not yet approved rapamycin for this use, which diminishes incentives for comprehensive research funding. However, the evidence from animal studies  across a variety of species strongly suggests a significant potential for rapamycin in anti-aging treatments. 

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Rapamycin’s mainstream use

As mentioned earlier, the FDA has only approved rapamycin for use as an immunosuppressant. It’s important to recognize that rapamycin use for longevity is still considered experimental and will not be reimbursed by insurance. Because the FDA hasn’t established guidelines around its use, there is no single accepted protocol for rapamycin dosage. Given the drug’s complex effects, the risk of experiencing side effects is real. Nonetheless,many individuals already use rapamycin “off-label” under the supervision of a physician for its longevity benefits. This is a perfectly legitimate use of the molecule, even though there is a lot we have yet to learn.

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A promising option for the future

Rapamycin offers a compelling glimpse into the future of longevity and neuroprotection. Although its journey from a soil sample to a potential anti-aging miracle has been gradual, the promise it holds could change the landscape of preventive health. As research continues, both the medical community and potential users must weigh the benefits against the uncertainties of translating animal model successes to human health outcomes.

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Learn more

Listen to the Peter Attia Drive episode on rapamycin to learn more about the molecule, its history, how it works, and the most recent evidence on its effects.

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As the quest for effective Alzheimer’s prevention continues, recent studies^1,2 underscore the profound impact of dietary choices on our brain health. One nutrient class consistently at the forefront of neuroprotective research is Omega-3 fatty acids, particularly Docosahexaenoic Acid (DHA) and Eicosapentaenoic acid (EPA). In this post, we explore how integrating DHA and EPA into your diet can play a crucial role in reducing the risk of Alzheimer's disease.

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Fatty acids explained¹

DHA and EPA are a major omega-3 fatty acid predominantly found in fish oils. They are called essential fatty acids, meaning that the human body cannot produce them on its own, so they must come from dietary sources. Make sure not to confuse omega-3s (like DHA and EPA) with omega-6s. These are a different class of fatty acids typically found in vegetable oils and nuts. They are much more common in most diets, and can promote inflammation when consumed in excess. 

DHA and EPA are particularly important because the molecules are building blocks for neurons. This means that maintaining healthy levels of DHA and EPA supports neuronal membrane integrity, promotes healthy synaptic activity, and mitigates inflammation within the brain. Long-term, these fatty acids have been shown to help preserve cognitive abilities and delay the onset of dementia¹.

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Clinical insights on Alzheimer’s prevention

A growing body of research points to a direct correlation between DHA and EPA intake and a reduction in the risk for Alzheimer's. Animal studies provide compelling evidence, showing that diets rich in DHA can significantly reduce the formation of amyloid plaques, which are closely linked to Alzheimer’s pathology¹.

Furthermore, in human epidemiological research (research that investigates the distributions and determinants of health-related events in populations), increased consumption of DHA through dietary sources like fish has been associated with lower incidence rates of Alzheimer’s, suggesting its significant protective effect. One study³ found that people with the highest levels of DHA had a 49% lower risk of developing Alzheimer's disease compared to those with the lowest levels. This means that those in the top 20% were about half as likely to get Alzheimer's as those in the bottom 20%. Additionally, increasing DHA levels from the lowest group to the highest group was predicted to give an extra 4.7 years of life free from Alzheimer's disease. 

Other studies have concluded similar results, showing a 47%⁵ reduction in risk, though there is debate about when this effect may occur. The consensus is that DHA supplementation is most effective when started early, before symptoms get classified as dementia⁶. 

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Increasing your omega-3 intake

There are two main ways to make sure you’re getting enough DHA and EPA - either making conscious dietary choices⁴ or taking supplements. From the diet side, fatty fish are an excellent source of omega-3s. Typical guidance recommends eating fish like salmon, mackerel, herring, or halibut at least 3 times per week. It’s worth noting that chia seeds and flax seeds are also excellent sources of omega-3s. Predatory fish like tuna are also good sources of EPA and DHA, but be careful not to consume them too often since they also contain high levels of mercury.

Fish oil supplements can be another great way to increase your intake of omega-3s - if you carry the APOE4 gene, supplementation is particularly important since you may have more trouble absorbing dietary omega-3s. However, it’s important to recognize that not all supplements were created equal. Specifically, not all brands will have the same purity of fatty acids, and not all will contain sufficient levels of DHA and EPA. Here are some things to look out for to make sure you are getting high quality fish oil:

• High amounts of DHA and EPA per serving (at least 500mg combined per serving)
• Minimal additives in the ingredients other than the oil and capsule contents
• Packaged in dark containers to protect the oil from light

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A Step Towards Cognitive Longevity

Embracing a diet that includes adequate amounts of DHA and EPA can significantly contribute to brain health and potentially decrease the risk of Alzheimer’s. Start by evaluating your current dietary habits and consider how you might improve your omega-3 intake, ensuring your brain remains vibrant and healthy well into later life.

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Where to get started

• Measure your blood omega-3 index to learn your current EPA and DHA levels. This is one of the 50+ biomarkers tested during your BetterBrain Essentials blood draw.
• Eat at least 3 servings of fatty fish (e.g., salmon, mackerel) per week, but make sure not to overdo your intake of predatory fish like tuna.
• Consider using fish oil supplements to increase your EPA and DHA intake. We recommend Carlson’s fish oil, which is available at a discount with a BetterBrain membership.

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The Landscape of Alzheimer's Biomarkers

When it comes to assessing the risk of cardiovascular disease, we have straightforward biomarkers such as ApoB (LDL) and blood pressure which can predict risk fairly accurately. However, the realm of neurodegenerative diseases like Alzheimer's is a lot more messy. For years, researchers and clinicians have depended PET scans or cerebral spinal fluid (CSF) for analyzing biomarkers like amyloid and tau proteins. But these procedures are expensive ($5-10K in the case of PET) or invasive (CSF requires a lumbar puncture), making them impractical for widespread use.

Enter blood amyloid tests, a relatively new but promising diagnostic aimed at solving this problem.

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What Are Blood Amyloid Tests and How Do They Work?

As the name suggests, these tests measure the concentration of various amyloid beta proteins in the blood (and sometimes tau as well) as a proxy for amyloid deposition in the brain. While the scientific community continues to debate whether amyloid pathology is a root cause of Alzheimer's disease or merely a symptom of other underlying brain pathologies, there is a clear association between the extent of amyloid presence in the brain and the manifestation of the disease.

One of the original commercially available tests was PrecivityAD by C₂N. This test needs to be ordered by a physician and was designed to predict the likelihood of Alzheimer's Disease (AD) pathology by analyzing a few key factors:

• The ratio of two variants of amyloid beta proteins, specifically amyloid beta 42 and amyloid beta 40
• The ApoE variant of the patient
• The age of the individual

By amalgamating these variables, the test attempts to gauge the probability of a positive PET scan. While it's too early to draw any definitive conclusions, there are two primary reasons why looking at this data could be valuable:

1. Comprehensive Risk Assessment: The test results can be used in combination with other factors like family history, genetics, metabolic health, vascular health and cognitive testing to assess the overall risk.
2. Monitoring Interventions: The score could be used as a dynamic indicator to monitor the effectiveness of steps taken to mitigate Alzheimer's risk. If the score decreases, it suggests that the ratio of amyloid beta 42 to amyloid beta 40 has changed favorably and thus risk has been reduced.

Since then, C₂N launched a second generation version of the tests, PrecivityAD2¹, which accounts for serum tau concentration for additional accuracy. In August of 2023, Quest launched a direct-to-consumer version of the test that does not require physician ordering. While the test is not quite as accurate as C₂N in predicting a positive PET, it comes at a materially lower cost - $400 as of the date of this writing.

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Applicability: Who Should Consider blood amyloid tests?

According to medical experts, the test should be reserved for those at high risk of developing Alzheimer's, as its sensitivity and specificity are still not entirely understood. The key term here is "pre-test probability." The higher the pre-test probability, the more reliable the test becomes in predicting a positive or negative outcome.

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Final Thoughts

The emergence of amyloid (and tau) blood tests is an exciting development in the field of Alzheimer's research and prevention. Although not a complete solution, they do provide an additional layer of information that can potentially enhance our ability to serve people at risk of developing disease. As our grasp of amyloid biomarkers improves, these tests could become integral parts of a broader, more nuanced approach to diagnosis and risk assessment.

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Update April 19, 2024

Roche, in collaboration with Eli Lilly, has launched the Elecsys pTau-217² blood test, which has recently received breakthrough device designation from the FDA. This means it was recognized as an effective tool for diagnosis, and is a critical milestone in how we identify Alzheimer's Disease. This test targets the tau protein pTau-217 and has the unique ability to distinguish AD from other neurodegenerative diseases. This is particularly important given that clinical AD diagnoses often lack sensitivity and specificity. It’s all the more since over half of patients with cognitive impairment remain undiagnosed or incorrectly diagnosed. This advancement promises to enhance early diagnostic accuracy and significantly improve intervention strategies for AD, particularly as global dementia figures are projected to rise sharply by 2050. pTau-217 is now available as an add-on service with BetterBrain.

For centuries, saunas have been lauded for their supposed health benefits, from improved cardiovascular function to detoxification. The recent trends around longevity seem to have revitalized the use of saunas, now considered a popular "health hack". But could spending time in these heated chambers also benefit your brain? Recent research suggests that sauna use might indeed play a role in mitigating the risk of Alzheimer's disease. In this article, we'll explore the scientific evidence behind this claim and consider how sauna use may impact your brain health.

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The Connection Between Saunas and Alzheimer's Disease

The Finnish Study

A study from Finland has brought attention to the potential benefits of saunas for brain health. According to the 2,315 person study¹, men who used a sauna 4-7 times a week showed a 65% reduced risk of Alzheimer's disease compared to those who used it once a week. Although the study mainly focused on men and thus requires further exploration for generalization, the findings are promising - 65% is a staggering number. If true, this would imply we could cut Alzheimer's prevalence from 6 million to 2 million in the US if only everyone used the sauna daily!

The Underlying Mechanisms

Scientists have proposed several mechanisms through which saunas may benefit the brain. One suggestion is that saunas can significantly improve sleep quality and time in deep sleep, which improves the brain's ability to clear toxic proteins. Moreover, heat stress activates heat shock proteins that can repair damaged proteins, which may play a role in neurodegenerative diseases like Alzheimer's. Lastly, saunas may improve various markers of vascular function, such as blood pressure and blood circulation, known risk factors for Alzheimer's.

Caveats and Considerations

First, the impact was more muted for those who used the sauna only 2-3 times a week (~22% risk reduction). Additionally, while the Finnish study shows a correlation, and certainly attempted to control for relevant variables, it is always very challenging to prove causation in retrospective studies.

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Conclusion

The notion that saunas could "incinerate" your Alzheimer's risk is captivating, they should not be viewed as a standalone solution. While promising studies hint at a beneficial correlation, saunas are not a guaranteed prevention method for Alzheimer's. However, given their other health benefits and the intriguing data suggesting a potential role in brain health, saunas could be a worthwhile addition to your wellness routine. Plus, who doesn't enjoy an intense sauna session followed by a cold plunge or shower?

When it comes to Alzheimer's disease, gender plays an undeniable role. A staggering two-thirds of those diagnosed with Alzheimer's in the United States are women. This disparity has puzzled researchers for years. Initially, many attributed it to the longer lifespan of women compared to men. However, as our understanding of the disease deepens, we've learned that longevity alone doesn't fully explain the 2X difference in prevalence.

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The Longevity Theory Falls Short

For a long time, the prevailing explanation for why more women than men were diagnosed with Alzheimer's was simple: women live longer, and Alzheimer's is a disease that primarily affects older adults. However, this explanation has increasingly come under scrutiny. As it turns out, the difference in lifespan between men and women isn't sufficient to account for the wide gap in Alzheimer's cases. The narrative is much more nuanced and involves a complex interplay of biological and social factors.

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The Menopause Transition Hypothesis

Menopause is a significant biological milestone in a woman's life, marked by the end of menstrual cycles and fertile years. One of the most significant changes that accompany menopause is a decline in estrogen levels. Estrogen is not just a reproductive hormone; it also has protective effects on the brain. The sharp decrease in estrogen during the menopause transition has been hypothesized to elevate the risk of Alzheimer's among women. In fact, cognitive decline associated with reduced estrogen levels has been reported, especially during the peri-menopausal and post-menopausal phases.

A beacon of hope: Hormone Replacement Therapy (HRT)

Given the hypothesized link between menopause and Alzheimer's risk, Hormone Replacement Therapy (HRT) has been studied as a potential preventive measure. Some evidence indicates that HRT could mitigate the risk of Alzheimer's among post-menopausal women. One prospective study¹in particular demonstrated a 41% reduction in the risk of Alzheimer's in women who did HRT vs those who did not. Of course, any decision to start HRT should be made through a physician who can account for all contraindications.

The Often Overlooked Role of Caregiving

The gender disparity in Alzheimer's doesn't end with disease prevalence; it also manifests in caregiving. Women make up a significant majority of Alzheimer's caregivers, often bearing the emotional and physical burden of caring for afflicted family members. This role can lead to heightened stress levels, which in turn could potentially impact a woman’s own cognitive health.

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Conclusion

The question of why Alzheimer's disproportionately affects women is far from straightforward. While the longevity theory has been partially debunked, the menopause transition and its hormonal changes offer a compelling avenue for understanding the gender disparity in Alzheimer's prevalence. Even social factors like caregiving roles cannot be discounted. Understanding these contributing factors can pave the way for gender-specific preventive strategies, which are beginning to be implemented in clinical practice.

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