Category Archives: Brain health

Glymphatic brain clearance system – draining the brain

The glymphatic system, which was identified in 2012, is the network that clears out waste products from the brain and central nervous system.

Essentially, this system is the way that fluid surrounding the brain and spinal column moves out of the brain, carrying waste products with it. The glymphatic system is found in the areas alongside the arteries that bring in blood and oxygen and the veins that take the blood back to the heart.

The interstitial and cerebrospinal fluid that makes up the glymphatic system moves by the pulsing of the arteries in the brain. [ref][ref][ref]

Pretty cool, huh.

The brain works hard all day, producing metabolites or by-products in many of its processes. The glymphatic system then moves the metabolites out of the brain – like a wastewater system cleaning everything up. The corollary for the rest of the body is the lymphatic system, which also moves fluids around.

Exactly how the glymphatic system works is a hot new research topic, so there are still a lot of unanswered questions here. I’ll cover the highlights of what is currently known and why it is important in healthy aging.

Let’s start with some background …

Why is the glymphatic system important?

Decreased glymphatic function is linked to neurodegenerative disorders in aging, such as dementia, Parkinson’s, and Alzheimer’s disease. No one wants neurodegeneration when aging…

Causes of glymphatic dysfunction include:[ref]

  • decreased cerebral spinal fluid
  • decreased flexibility in the arteries
  • changes in the glial cells that make up the glymphatic vessels

Animal studies show that glymphatic function decreases dramatically in the aged. In animals, there is an 80-90% reduction in glymphatic function in aged animals compared to young.[ref]

What is the glymphatic system cleaning out?

One big thing that the glymphatic system clears is soluble amyloid-beta.[ref] Other waste metabolite proteins include alpha-synuclein and tau proteins.[ref]

Much of the research focuses on the above proteins because they are linked to neurodegeneration in aging. But the glymphatic system clears out many metabolites. The brain is a big energy user and thus waste produce.

Where does it come from?

The fluid in the glymphatic system comes from cerebral spinal fluid and interstitial fluid. Certain areas of the brain produce cerebral spinal fluid, which is important in the glymphatic system as well as in the spinal column and nervous system. Interstitial fluid is the fluid between blood vessels and cells.

When looking at interstitial fluid in the brain, a protein type known as aquaporin is important. Aquaporins are the cell membrane transport proteins that control the flow of water through membranes due to osmosis. Think back to high school chemistry and moving water across a membrane to balance out salts.

AQP4: While there are several different aquaporins in the nervous system, spinal cord, and sensory organs, AQP4 (aquaporin 4) is the important one in the glymphatic system. AQP4 on astrocyte membranes controls a large part of glymphatic function. Astrocytes are a type of brain and spinal cord cell that support the function of the neurons. Astrocytes do a lot – including producing nutrients and cholesterol for neurons as well as interacting with the blood-brain barrier. The AQP4 membrane protein on astrocytes is controlling the flow of water into and out of the brain. [ref]

Where does it go?

Initial research pointed to a flow of brain metabolic waste into the veins of the brain.[ref] The blood then takes the waste out to be taken care of in other parts of the body such as the kidneys and liver.

Other research shows that the glymphatic system drains into the cervical lymph nodes. [ref]

Thus, good blood flow and lymph drainage are important here.

Sleep is essential for cleaning out the brain:

Did you know that we can go a lot longer without food than we can without sleep? All animals sleep, and for a long time, scientists weren’t exactly sure why.

In 2013, a landmark study on sleep was published in Science. The study explains how metabolites are cleared from the brain during sleep via the glymphatic system. It is an answer to the age-old question of “why do we sleep?” Laying down and sleeping is absolutely essential for brain function.

Recent research answers questions on whether it is just the lying down and resting or whether more processes are involve.

A 2020 study explains that there is a circadian rhythm to glymphatic function, and the mid-point of sleep is when the peak flux takes place. Your circadian clock is the molecular clock that drives the body’s 24-hour rhythm. For example, hormones like cortisol and melatonin rise and fall at certain times of the day. Similarly, circadian rhythm seems to drive glymphatic function. [ref]

Sleep posture and glymphatic transport:

Glymphatic transport is increased during sleep… and most of us sleep laying down. It would make sense, then, that body position matters in the glymphatic system.

fMRI studies give researchers a glimpse into the glymphatic transport system. Researchers were able to visualize how body posture matters for glymphatic transport. They found that: [ref]

  • Upright (standing, sitting) posture has the slowest clearance from the brain.
  • Laying on the back has better clearance than being upright.
  • The best glymphatic transport is while laying on the side.

My take away: Sleep on my side whenever possible

What can you do to improve glymphatic function?

Let’s take a look at several lifestyle factors that are important in glymphatic function…

Sleep QUALITY is imperative in glymphatic function

Researchers have known for a while that people with disturbed and fragmented sleep have higher than normal amyloid-beta levels. [ref] Sleep dysfunction and Alzheimer’s go hand in hand.

New research on the glymphatic system shows why the quality of sleep is so important in brain function. Deep, slow-wave sleep is when the most glymphatic flux takes place. [ref] Thus, if deep sleep is impaired due to aging, getting up a lot in the night (prostate problems?), or other sleep issues, the glymphatic system is not going to work as well.

(Learn how glycine may help increase deep sleep.)

Are you wondering how much time you spend in slow-wave deep sleep? Sleep trackers such as the Oura ring, woop strap, or Apple watch can help you quantify it.

I don’t know that any sleep tracker is truly accurate. Instead of obsessing over the exact amount of time spent in slow wave sleep, I use my sleep tracker (an Oura ring) to determine how different interventions impact my sleep – tracking whether it trends up or down.

Breathwork and the glymphatic system:

Ultra-fast fMRI study shows that breathing – and not breathing – affects the glymphatic system. The researchers found that voluntary breath-holding increases pulses in certain regions of the brain. When you hold your breath, CO2 levels increase, which causes dilation in the blood vessel in the brain. This is a dynamic process. Initially during a breath-hold, the pulses in the brain decrease, but then there is a compensation reaction that causes an increase in blood flow and oxygen. The fMRI showed that the cardiovascular pulses in the brain (moving the glymphatic system) increased in certain brain regions with breath holds. [ref]

Breathing well is important for oxygenation in the brain — and for the glymphatic clearance.

Breath training, such as the Wim Hof method or yoga breathing, may be something to look into for brain health.

The flip side here is that decreased respiration in older individuals could be contributing to decreased glymphatic movement. Additionally, sleep apnea could be having a negative impact on glymphatic waste removal during sleep. Sleep apnea increases the relative risk of Alzheimer’s.

A recently published study (June 2021) directly shows the connection in Alzheimer’s patients between brain activity during sleep and the glymphatic system’s ability – or inability – to clear out amyloid-beta. [ref]

Alcohol, glymphatic flux, and AQP4

I mentioned above that AQP4 – aquaporin 4 – is important for glymphatic clearance. AQP4 is a transporter that moves water and solutes from astrocytes into the glymphatic system. [ref]

Low-level alcohol consumption may help? A mouse study showed that low levels of alcohol consumption increase glymphatic function. But higher levels of alcohol consumption decreased AQP4 and decreased glymphatic clearance. [ref] This may explain why moderate

Diabetes and brain health

Recent animal studies show that in type-2 diabetes models the glymphatic clearance is decreased by 3-fold. This is one explanation of the connection between diabetes and the progression of neurological diseases in aging. [ref]

More of a stretch…

Going out on a limb here, the following are a few more options that research points to:

Transcranial magnetic stimulation – in rats – increase brain drainage via increasing glymphatic flow. [ref]

Lymphatic massage: The research about the glymphatic system draining into the cervical lymph nodes sent me off on a rabbit trail of looking into lymphatic massage. It turns out that there is an animal study showing that boosting the lymphatic system (mouse massage therapy?) helped with elderly cognitive function. [ref]

Here’s a video on self-massage for the cervical lymphatic system:

Omega-3 fats show promise in research on concussions and brain injuries. Mouse research shows that omega-3 fatty acid supplementation increased glymphatic clearance after a brain injury.[ref] Perhaps this is part of the protective role of fish oil in Alzheimer’s disease.


The research on the glymphatic system points to a solid reason to prioritize sleep quality for brain health.

How you go about doing this individually will vary.

There are all kinds of websites and books on ‘sleep hygiene’. Essentially, it boils down to blocking blue light from screens for an hour or two before bed and going to bed at a reasonable hour so that you can get enough sleep. Everyone is unique in what it takes to turn off the brain and go to sleep (or stay asleep). If you can’t sleep when it is hot, get a fan or air conditioner. If noise bothers you, try a white noise machine or move to a quiet place.

The key here is that it is worth putting a little time and effort into prioritizing sleep quality – but don’t obsess about it to the point of being stressed. For me, a Ken Burns documentary, especially that one on the Civil War, will lull me into a very deep sleep. So I encourage you to find your own Ken Burns documentary… In other words, have a plan for how to get back to sleep if you are an early waker, or know what makes you sleep if you have trouble drifting off.

Clinical trial showing reversal of early Alzheimer’s

A pre-print study posted in May 2021 shows positive results in a clinical trial with the goal of reversing early Alzheimer’s disease.

This is big!

An attitude of acceptance that Alzheimer’s is a non-reversible fate prevails in medical practices, and a positive clinical trial showing marked improvement in many participants is wonderful to see.

The clinical trial used Dr. Dale Bredesen’s protocols for Alzheimer’s prevention, much of which he has outlined in his book, The End of Alzheimer’s.

Why am I writing about a pre-print? This study seems to be of very high quality and backed by a lot of other research. It comes together showing a personalized approach to Alzheimer’s prevention is the right approach. I’ll update this article whenever the preprint is published in a major scientific journal.

Clinical trial to reverse Alzheimer’s

Let’s take a look at the clinical trial:

The study involved 25 patients (ages 50-76) with either Alzheimer’s disease or mild cognitive impairment. The Montreal Cognitive Assessment (MoCA) was used to quantify the degree of cognitive impairment.

The researchers evaluated the participants for “markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure (metals, organic toxicants, and biotoxins), genetic predisposition to cognitive decline, and other biochemical parameters associated with cognitive decline.“

Researchers then used this information to create a personalized protocol for each patient.

The study participants were then followed for 9-months, with cognition tests every three months.

Genetically, the participants covered a range of APOE types (E2/E3, E3/E3, E3/E4, and E4/E4). If you have 23andMe genetic data, you can check your APOE type here, if you want to know.

Before we get into the results, a couple of things stand out about the trial…

First, it is awesome to see a study using so many different parameters and personalized targeted interventions. But, it is important to note that the participants were younger than many Alzheimer’s patients. Additionally, the study participants were almost all college graduates, with almost half of the cohort having a graduate degree. Both of these factors make it more likely to have a positive outcome than a general population group. This was a proof-of-concept clinical trial, so I would assume that the researchers chose the participants carefully.

Treatment interventions:

The protocol for all participants included:

  • All participants were encouraged to exercise (aerobics and strength training) for 45 minutes a day for 6 days a week.
  • Sleep hygiene was encouraged, and sleep apnea was treated.
  • Everyone ate a diet that included a lot of organic high-fiber vegetables (raw and cooked) and pastured eggs and meat. The diet was ‘mildly ketogenic’ and avoided processed foods, gluten, and dairy.
  • The participants used biofeedback, heart-rate variability training (HeartMath), and brain training.

Individual protocols included:

  • Hormone replacement when needed.
  • Thyroid supplement for participants with less than optimal thyroid function.
  • Vitamin D, omega 3, B-vitamins, CoQ10, and minerals were supplemented for people who had suboptimal levels.
  • Gut healing protocols for people with leaky gut, inflammation, infection, or impaired digestion.
  • Anti-inflammatory herbs for people with systemic inflammation. Low-dose naltrexone was prescribed for some.
  • Anti-virals were prescribed for Herpes simplex and an herbal protocol given for active Epstein-Barr virus. For tick-borne infections, herbal antimicrobials and immune system support were given.
  • Detoxification protocols were used for people with heavy metals, biotoxins, and organic pollutants (e.g. phthalates, organophosphates). This was done with binding agents, sauna, herbs, and restricting mercury-containing fish.

Results of the intervention:

A caregiver questionnaire showed that 84% of patients improved (mild to marked improvements). This is a great result since caregivers are likely to have a keen eye for either improvements or declines.

What about the Montreal Cognitive Assessment? 76% of participants improved their scores, 12% declined in scoring, and 12% remained the same.

You may be thinking, “Why didn’t everyone improve?” Good question, but important here is that most people without intervention would have shown a decline in cognitive scores over 9 months. So 76% improving scores and 12% remaining the same is pretty impressive.

The results are not broken out by APOE genotype, though, which is something that I would be interested in seeing. I would be most interested in knowing if any of the E4/E4 carriers were able to improve. But in the discussion section of the study, the researchers report that “both groups—the ApoE4+ group and the ApoE4- group—showed statistically significant improvements in MoCA and NCI (Neurocognitive Index)


Research on Alzheimer’s disease shows that there are likely many different contributing factors to the pathology. A single intervention – drug, lifestyle change, etc – is unlikely to be effective. Instead, this proof-of-concept clinical trial points to the efficacy (and common sense) of using multiple interventions that target many different factors that contribute to the risk for Alzheimer’s disease.

Want more information? Check out Apollo Health. This healthcare group is implementing Dr. Bredesen’s protocol with testing, nutritional plans, supplements, cognitive training, medical practitioners, and health coaches.

The time to prevent Alzheimer’s is in the decades before symptoms begin.

Interested in how your genetic variants could play into the different risk factors for Alzheimer’s? Check out the following Genetic Lifehacks articles:



Lithium orotate: A natural mineral that affects mood, Alzheimer’s disease, and aging

I read a lot of studies on health and genetics, and I keep finding research on the mineral lithium popping up. Topics such as circadian rhythm dysfunction, Alzheimer’s disease, telomere length, type 2 diabetes, and obesity…all linking to lithium?

The rest of this article explains the research showing the importance of this mineral in our health and longevity.

There is a stigma, at least in my mind, around lithium, and I’ve hesitated at times to write about it. Funny, isn’t it, that no one has hesitation about talking about other minerals such as magnesium or potassium. I’ll let you read through the research overview and decide for yourself.

Recent scientific research on lithium and health

Minerals are needed by the body in the right amount, and it is important to look at the safety and health effects before supplementing with any mineral.

Lithium is a mineral that can be naturally found in food and drinking water. It is also available in low-dose supplemental form (lithium orotate).

Is Lithium Orotate the same as lithium (prescription)?

First, let’s look at the different types and amounts of lithium being referenced in the research studies. Quite a range exists – from natural levels found in water to high levels in prescription meds.

For a lot of people, lithium brings to mind the prescription medication for bipolar disorder. This is almost always in the form of lithium carbonate.

Prescription doses of lithium carbonate are around 900-1200 mg/day, although this can vary based on the individual. For lithium carbonate, there is about 18.8 mg of elemental lithium per 100mg of lithium carbonate. Thus, a 900mg dose would give about 170 mg elemental lithium.[ref]

Lithium orotate usually comes as a 120 mg supplement giving about 5mg of elemental lithium.

The amount of natural lithium that we get in foods and drinking water varies based on the mineral content of the soil, with estimates of .5 to 3 mg/day.

A provisional RDA  of 1 mg/day is recommended.[ref]

Breaking this down, for an average person, a standard lithium orotate (5mg elemental lithium) supplement would be around twice the normal daily consumption from food and water, while the prescription dosages are closer to 80 to 100 times normal daily intake.

Alzheimer’s Disease and Lithium:

A 2017 study investigated Alzheimer’s rates and natural lithium levels in the drinking water in Texas.[ref] In an article about the study (much quicker read than the full paper), the lead author of the study explains the findings.

Essentially, water samples from almost all of the counties in Texas were tested for their natural levels of the mineral lithium, which varies depending on the concentration in rock and soil.

Alzheimer’s rates have risen everywhere, but the researchers found that Texas counties with higher levels of lithium in the groundwater had less of an increase in Alzheimer’s rates compared with counties that had lower levels of lithium.

The study results are not a total surprise since previous studies linked lithium to a decreased risk of dementia, but it is a great confirmation at a large scale population level. Additionally, observational studies show patients taking prescription lithium are at a lower risk of dementia.

Research studies on lithium and Alzheimer’s disease:

  • A 2015 review in the Journal of Alzheimer’s Disease analyzed the data from three randomized placebo-controlled clinical trials of lithium for treating Alzheimer’s patients. The trials found that lithium “significantly decreased cognitive decline as compared to placebo“.[ref]
  • An October 2017 article in JAMA Psychiatry details a nationwide study in Denmark on the exposure to lithium in drinking water and the incidences of dementia. This was a large study, with 73,000+ dementia patients and 733,000+ people without dementia as the control. The study found a decreased rate of dementia in people with naturally higher levels of lithium in their water (measured since 1986).[ref][ref]
  • A March 2018 animal study looked into the mechanisms of how lithium chloride lowers the risk of Alzheimer’s. It found that lithium chloride caused an increase in soluble β-amyloid clearance from the brain. In mice genetically bred to be a model of human Alzheimer’s, lithium chloride restored the clearance of soluble β-amyloid to the levels of normal mice. One big thing to note from this study is that lithium chloride did not affect β-amyloid that had formed plaque already.[ref]
  • A study in 2015 looked at the effects of microdoses of lithium on a mouse model of Alzheimer’s disease. The study found small doses of lithium carbonate in the drinking water of mice carrying the genes for Alzheimer’s disease caused a “decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in the cortex when compared to non-treated transgenic mice.” This was a follow-up study to the human study in 2013 which showed that microdoses of lithium stopped the cognitive decline in Alzheimer’s patients.[ref][ref]

You may be wondering at this point why all doctors aren’t handing out low doses of lithium to everyone at risk for Alzheimer’s. I think the quick answer is that it isn’t the ‘standard of care’ with enough clinical trials backing it up. Lithium is a cheap, natural mineral with no money in it for funding clinical trials. There seems to be a couple of ‘novel’ low-dose formulations in the works by pharmaceutical companies, though.[ref][ref][ref]

Telomeres, aging, and lithium:

Telomeres are the sequences of DNA found at the ends of each chromosome. This sequence protects the ends of the chromosome from deterioration. The common example given is to think of telomeres like the plastic on the end of shoelaces that protects the shoelace from fraying. When cells undergo cellular reproduction (mitosis), a little bit of the telomere shortens. Thus, telomere length is considered to be a biomarker of cellular aging. Shorter telomere length has associations with several age-related chronic diseases including Alzheimer’s.

A recent transgenic mouse study found lithium carbonate treatment leads to longer telomere length in mice bred to have Alzheimer’s disease.[ref] Interestingly, the normal mice had no effect on telomere length from lithium. Couple this information with a meta-analysis showing that Alzheimer’s patients have shorter telomeres.[ref]

A human study looked at telomere length in patients with bipolar disorder. The study found that patients with bipolar disorder (not on lithium) and their relatives had shorter telomeres lengths than healthy, unrelated people. More interestingly, patients with bipolar disorder treated with lithium had longer telomere lengths than non-lithium-treated patients with bipolar disorder as well as relatives of bipolar patients.[ref]

Telomere length is a new field of investigation for researchers looking into so many different topics of aging, longevity, and disease. I don’t think the handful of studies on telomere lengthening from lithium can really lead to a conclusion on aging. But I look forward to seeing what future studies tell us on the topic.

The anti-Inflammatory action of lithium:

Lithium exerts anti-inflammatory effects on the body — as well as pro-inflammatory effects under specific conditions. Since the 1970s, it’s been known that lithium inhibits prostaglandin synthesis and COX2 in some parts of the brain. While there is some debate on the topic, the majority of studies also point to lithium decreasing the production of TNF-α, a pro-inflammatory cytokine.[ref]

A recent cell study looked at the potential of lithium plus caffeine, theobromine, and catechin on the innate immune system and inflammation. The results showed that stacking lithium with caffeine, theobromine, and catechin was more effective as an anti-inflammatory than using them separately.[ref]

Another recent study looked at the anti-inflammatory effects of lithium on cells containing the SOD2 genetic variant rs4880.  The study found that those with the rs4880 alanine allele (G/G for 23andMe) had more of an anti-inflammatory response than those with the valine allele (A/A for 23andMe).[ref] This was a cell study though, so it is hard to know how well this translates to the whole body.

Obesity, Diabetes, Thyroid, and Natural Lithium:

What surprised me about the Nov. 2017 study that I referenced above was that Texas counties with higher levels of lithium in their water also had lower levels of obesity and diabetes.  I was surprised by this because one of the side effects of long-term, high-dose lithium carbonate usage is an increased risk of hypothyroidism and possible weight gain.

Part of the explanation for the high levels of lithium in water correlating to lower levels of obesity and diabetes may be due to the effects on circadian rhythm. Another possible connection between lithium, obesity, and T2D may be the effect on blood glucose levels. In mice, certain levels of lithium reduced non-fasting blood glucose levels.[ref]

Suicide levels decrease as natural lithium increases:

A number of studies have investigated the link between lithium in drinking water and its effect on overall mood — such as aggression (violent crime rate) and suicide.

A meta-analysis of 15 different studies shows that areas with higher lithium concentrations in their drinking water have lower suicide rates.[ref]

How is lithium affecting our body and brain?

For a long time, exactly how lithium worked for bipolar patients was not understood. (Quite a few psychiatric medications were used for decades without fully understanding the mechanisms by which they work – or don’t work – for people.)

Studies over the past decade or two have shed light on the neurobiological mechanisms of lithium and genetic studies have increased that knowledge.

One effect of chronic, low-dose lithium is an increase in BDNF, which is a protein that promotes the growth of nerve cells.[ref]

The American Chemical Society published a great overview of the neuroprotective effects of lithium.[ref] One of the effects of lithium is its inhibition of GSK-3β (glycogen synthase kinase-3 beta), which is involved in neuronal cell development and energy metabolism. Genetic mutations of GSK-3β increase the risk of bipolar disease.

Lithium ions compete with sodium and magnesium ions in the body for binding sites in certain circumstances. The thought on lithium’s inhibitory effect on GSK-3β might be due, in part, to binding to a site normally occupied by magnesium. For a comprehensive overview of the biochemical properties of lithium, including its effect on the activation energy of water within a cell and its effect on mitochondrial function,  read “Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology.

One action of GSK-3β is its inhibition of glycogen synthase, which is an enzyme involved in the reaction that takes excess glucose and turns it into glycogen for storage. Thus inhibiting GSK-3β increases glycogen synthesis and increases insulin sensitivity.[ref][ref]

GSK-3β and Circadian Rhythm:

Our body’s core circadian clock runs by a couple of core genes expressed during the day and a couple of core circadian genes that rise at night. It is this daily rise and fall of gene expression that drives our internal daily cycles of waking and sleeping, temperature, and energy metabolism. GSK-3β is involved in the phosphorylation of both the day and night core circadian genes.

Genetic variants that change our circadian rhythm have links with an increased risk for bipolar disorder. People with bipolar disorder who respond well to lithium therapy have changes in their circadian gene expression when they take lithium.[ref][ref][ref][ref]

The link between Alzheimer’s disease and circadian disruption is strong.[ref]

Prevention of lead toxicity:

A recent article hypothesized that some of the benefits reported for higher lithium levels in the drinking water (lower suicide rate, lower homicide, and crime rates) could be due to lithium mitigating the effects of lead toxicity. “Animal studies demonstrated that lithium pre-treatment mitigates lead toxicity.”[ref]

Toxicity of lithium:

Many consider lithium to be an essential trace element. Its complete elimination from the body causes a decline in fertility, higher mortality rates, and behavioral abnormalities.[ref]

But, like all substances, there is a toxic upper limit.

Patients taking lithium carbonate or lithium chloride for mood stabilization show a variety of side effects, depending on dosing. (e.g. around 170 mg elemental lithium). Most patients taking prescription lithium carbonate need blood tests done at regular intervals to determine their serum lithium levels. Plasma lithium levels above 1.2 mM cause nausea, diarrhea, and tremors.[ref]

Other side effects noted by patients taking prescription levels of lithium chloride include increased thirst and urination, weight gain, and mental dullness. It was theorized that bipolar patients taking lithium may drink more calories due to increased thirst, thus causing weight gain.[ref] Other side-effects of higher doses of lithium include increased risk of kidney problems and hypothyroidism.

Lithium orotate, as a supplement, comes in much, much lower doses than the lithium in prescription lithium carbonate. There is one case report, though, of nausea and mild tremor from a teenager taking 18 tablets of a supplement that contained 100mg of lithium orotate.

If you have questions on any mineral supplement, talk with your doctor or health care provider for medical advice. 

Side effects of Lithium Orotate:

There aren’t any recent research studies or case reports (other than the one above) on lithium orotate side effects, so this section is n=1 personal experiences and internet hearsay.

A couple of people that I’ve talked with have reported that lithium may make them tired or a little sleepy during the day. An article from a holistic doctor who suggests lithium orotate to most of his patients notes that very few have any side effects. He does suggest taking lithium orotate before bed instead of during the day. This makes sense in light of the circadian rhythm effects via GSK-3B inhibition.

A study from 1986 on using lithium orotate for alcoholism listed minor side effects to the treatment (included more than just lithium orotate -e.g. low carb diet and other supplements) as loss of appetite, mild apathy, and muscle weakness.[ref]


If you have medical questions, talk with your doctor – especially if you are on any medications or if pregnant or nursing – before supplementing with lithium orotate. 

Supplement Doses: Lithium orotate is available as a natural supplement in many health food stores and online (Amazon). You can get it in doses from 5 mg to 20 mg.

Anti-inflammatory: The study on stacking lithium with caffeine, theobromine, and catechin for an increased anti-inflammatory effect was interesting. If you are considering this combo, a good source of theobromine is cacao nibs. Catechins and caffeine are found in green tea.

Where to buy:

Lithium orotate is relatively inexpensive as a supplement. It is available on Amazon as well as in a few health food stores.

Alzheimer’s prevention through targeting the liver

Preventing Alzheimer’s is at the top of the list for many people when considering longevity and healthspan. Genetics, as well as environmental factors, play into the susceptibility to this disease of aging. While most focus is on the brain, recent research shows points to another key player in Alzheimer’s prevention: the liver!

Bile acids, Alzheimer’s, the liver, and brain health:

Alzheimer’s disease is due to neurodegeneration in the brain. A buildup of amyloid-beta plaque and tau tangles are characteristics of the Alzheimer’s brain, but not everyone with amyloid-beta plaque ends up with dementia symptoms.

The biggest genetic risk factor for Alzheimer’s is the APOE E4 allele, which is a lipoprotein involved in cholesterol transport. But even without the APOE E4 risk factor, Alzheimer’s prevention should be at the top of the list for almost everyone. To put this into perspective, in the UK in 2018, Alzheimer’s was the number one cause of death in women (2nd biggest cause of death for men).[ref]

While many decades of clinical trials, animal studies, and theories surround the amyloid-beta hypothesis of Alzheimer’s disease, not much progress has been made on this front.

Newer research is branching out and looking at Alzheimer’s disease from different perspectives — as a mitochondrial disorder, like type-3 diabetes or glucose dysregulation in the brain, as a response to viral pathogens, due to the gut microbiome, or a lack of serine.

But the genetic link from the APOE E4 allele solidly remains. And this ties into cholesterol transport, metabolism, and the gut microbiome. (Cholesterol is essential to the brain and about 25% of the total cholesterol in the body is in the brain.[ref])

Now some researchers are pointing towards the liver as the organ that we need to look at for Alzheimer’s prevention.[ref]

Before we dive into the research on the liver and bile acids in Alzheimer’s prevention, let’s do a very quick overview of amyloid-beta…

Quick background overview: Amyloid-beta in the brain and periphery

Amyloid-beta, a peptide formed from the amyloid precursor protein (APP), breaks apart to form the amyloid-beta peptide. This naturally occurring peptide exists in plaques in the brains of people with Alzheimer’s.

Amyloid-beta normally circulates in the plasma, cerebrospinal fluid, and the brain interstitial fluid, and clears out of the brain during sleep via the lymphatic system. (Yep – sleep is important in Alzheimer’s prevention)

One theory suggests Alzheimer’s possibly misfolds the amyloid-beta that doesn’t clear out like it should instead of forming the plaques that eventually cause neurons to die.

While I’ve often pictured amyloid-beta similar to the gunky plaque building up before you get your teeth cleaned (but in the brain), in actuality, a natural production and clearance occur of the amyloid-beta peptides and it goes on all the time from the brain. Amyloid-beta moves from the interstitial fluid around the brain and transports across the blood-brain barrier and into the bloodstream.[ref]

The question then arises as to how to keep brain levels of amyloid-beta in check, and how the flow of amyloid-beta across the blood-brain barrier affects the balance of amyloid-beta in the brain.

Research in animals shows that reducing amyloid-beta in the bloodstream may reduce brain amyloid-beta.[ref] Studies also show that cholesterol is linked with Alzheimer’s, and statins slightly reduce the risk of Alzheimer’s. Cholesterol doesn’t cross the blood-brain barrier, but some cholesterol metabolites do.[ref]

This brings us around to the liver and bile acids…

Bile acids:

A recent study took a deep dive into the changes in postmortem brain samples of Alzheimer’s patients and cognitively healthy controls of a similar age. The study determined bile acids are altered in the brains of Alzheimer’s patients.[ref] This adds to several previous studies that also found altered bile acid metabolites in Alzheimer’s brains.[ref][ref]

Certain bile acid metabolites are neuroprotective and other bile acids are neurotoxic in the brain.[ref] On the neuroprotective side is TUDCA, which we will come back to in the Lifehacks section.

High neurotoxic bile acid metabolites are could be playing a role in the cognitive decline in Alzheimer’s.[ref] Or it could be the alteration in the ratio of the different metabolites.

Stay with me hereThis all ties together in Alzheimer’s disease with cholesterol metabolism, the liver, cell signaling, and the gut microbiome.

Digging deeper into bile acids:

Quick background science: Bile acid production takes place in the liver and then transports to the gallbladder for storage as bile until needed. Bile gets released in response to eating foods containing fat and then emulsifies that fat for absorption by the intestines. Bile acids are a component of bile, which I think of as acting kind of like a detergent to break up fat from foods.

Bile acids are derived from cholesterol, and bile acid production is linked with cholesterol homeostasis. So one role of bile acids is to keep cholesterol levels in balance. Bile acids also act as cellular messengers, and secondary bile acid production occurs from the gut microbiome.

There are two primary bile acids, cholic acid (CA) and Chenodeoxycholic acid (CDCA). These two primary bile acids are conjugated with either glycine or taurine, making them into bile acid salts that are better at breaking up fats.[ref]

Once the bile acids break down fats and complete their job, the intestines reabsorb them. The bile acids then recycle back to the liver to be reused. About 10% reach the colon and break down into secondary bile acids by the gut bacteria.

CA (cholic acid), converts into the secondary bile acid, deoxycholic acid (DCA) by bacteria in the colon. CDCA, the other primary bile acid, converts into lithocholic acid (LCA) and ursodeoxycholic (UDCA). They can then get reabsorbed in the colon and taken back to the liver to be reused.[ref]

So that is what happens with most of the bile acids produced in the liver…into the intestines (usually by way of the gallbladder), doing their job with fats, and then eventually recirculated and reused.

But…some bile acids ‘spill over’ into circulation and act as signaling molecules for regulating energy. Additionally, bile acid receptors exist in the brain and link to Alzheimer’s disease.[ref]

To get a little more complicated, cholesterol doesn’t cross the blood-brain barrier but instead, the brain synthesizes it. That cholesterol can break down in the brain cells into primary bile acids using a little bit of a different pathway than liver cells use (called the alternative pathway).[ref] But, bile acid metabolites, such as TUDCA and UDCA, can cross the blood-brain barrier.

In brain samples from Alzheimer’s patients, several studies now show a reduction in CA (primary bile acid, cholic acid) and an increase in the secondary bile acids produced by bacteria.[ref][ref] Remember – some of those secondary bile acids are neurotoxic.

In addition to the primary bile acid to secondary bile acid ratio being altered in Alzheimer’s, that ratio also links to increased cognitive decline. So the ratio gets worse as cognitive performance goes downhill.[ref]

What causes a decrease in the primary bile acids and an increase in gut microbe-derived secondary bile acids?  I’m not sure that the research gives us an answer there yet. The gut microbiome changes in aging[ref]…and the biggest risk factor for Alzheimer’s is age. So that may be part of the answer to the changes in bile acid metabolites. Additionally, there are links between liver dysfunction and Alzheimer’s…Perhaps both?

One more role of bile acids: Connective tissue growth factors

In the area of the brain with the amyloid-beta plaque and neurofibril tangles, researchers find higher levels of connective tissue growth factors. These growth factors possibly play a role in amyloid-beta plaque production. A secondary bile acid, TUDCA, downregulates the connective tissue growth factors.[ref]

More about the liver in Alzheimer’s prevention:

This link with the liver and Alzheimer’s isn’t just about bile acids, though.

A low-density lipoprotein receptor (LRP1), found in the liver and the brain, also may be important in Alzheimer’s prevention:

  • To cross the blood-brain barrier, LRP1 (low-density lipoprotein receptor-related peptide 1) must transport amyloid-beta.
  • Additionally, LRP1 bound to amyloid-beta circulates in the bloodstream and prevents it from crossing back into the brain.
  • In the liver, LRP1 clears out systemic amyloid-beta.[ref]

Additional studies on LRP1 show that its effect on Alzheimer’s may be due not only to clearing out peripheral amyloid-beta but also due to APOE.[ref]

Thus, the APOE E4 genetic connection comes into play here also. APOE, an apolipoprotein, involves the transport and metabolism of cholesterol. In the liver, LRP1 and the LDL receptor work together in clearing out APOE particles.

LRP1 is important in regulating liver fat in a high cholesterol diet. Animal studies show that decreased LRP1 causes increased liver disease.[ref]

Thus, the liver and LRP1 come together in several ways to impact Alzheimer’s prevention: clearing out amyloid-beta in the peripheral circulation, acting on APOE E4, and regulating cholesterol (and thus impacting bile acids). Beyond the liver, LRP1 is also important in the blood-brain barrier.[ref]

This story of LRP1 isn’t clear, though, as just increasing LRP1 everywhere to get rid of amyloid-beta plaque. A lot of research on the LRP1 receptor in brain tissue shows conflicting results.[ref] To me, it seems that the research focused at the cellular level on brain cells with LRP1 may be missing the benefit of LRP1 helping to remove amyloid-beta in the peripheral circulation.


What can you do to alter bile acid metabolism in the brain? Or to clear out more amyloid-beta via the liver?

Gut health is important because gut microbiome changes have links to healthy aging. So one aspect is to feed your gut microbes healthy, whole food.  To be frank, that is more of a baseline that everyone should be doing at a minimum, rather than what I would qualify as a ‘lifehack’.  Research on probiotics may someday point to specific ways of altering the gut microbiome to prevent Alzheimer’s, but we aren’t there yet.

Supplements: The usual “talk with your doctor” advice applies here before starting any supplements, especially if you are in poor health or on prescription medications. 

Supplemental bile acids:

TUDCA is a bile acid metabolite that is readily available as a supplement. It is often marketed for gallstones or liver health (if you need to know which section of the health food store to look in).

In a mouse model of hereditary Alzheimer’s disease, six months of TUDCA supplementation prevented the Alzheimer’s pathology that should have happened in these mice.[ref]

Other studies show that TUDCA prevents cognitive impairment in animal models of Alzheimer’s disease.[ref]

Another mouse study using transgenic mice as an Alzheimer’s model found that TUDCA could reverse the amyloid-beta deposits in the brain. One thing noted was that TUDCA stopped the GSK3β hyperactivity, which is part of the formation of tau tangles. Most encouraging was the TUDCA partially rescued synaptic loss.[ref]

Of note here, TUDCA can cross the blood-brain barrier.[ref]

Mouse studies don’t always translate to humans in Alzheimer’s research, but the mechanism of action here is promising.

Another bile acid, UDCA, is a similar molecule to TUDCA but not conjugated with taurine (the T in TUDCA). UDCA is available as a prescription medication in many countries including the US. Cell studies using neuronal tissue from Alzheimer’s patients show that UDCA increases mitochondrial function.[ref]

Is TUDCA relatively safe to take? There are numerous human clinical trials on TUDCA, just none relating to Alzheimer’s disease. Instead, the trials have focused on the treatment of liver diseases, gallstones, and ALS with good safety profiles.[ref][ref][ref][ref]

Supplements: TUDCA is readily available at health stores and online. Here is one that I’ve used, but read through the reviews and choose one that you are comfortable with.

Targeting LRP1:

Withanolides, from ashwagandha, upregulates LRP1 in the liver and increases amyloid-beta clearance. In an animal model of Alzheimer’s disease, this decreased amyloid-beta in the brain and also reversed behavioral deficits.[ref][ref][ref][ref]

Supplements: Ashwagandha is also readily available as a supplement. Look for one that includes the percentage of withanolides, the active ingredient that impacts LRP1. Here is one example with a higher withanolide concentration, but shop around if you are interested in other formulations or simpler Ashwagandha powders to add to smoothies.

Cannabinoid receptor agonists have also shown to upregulate the expression of LRP1 in the blood-brain barrier and enhance the clearance of amyloid-beta across the BBB in animal studies.[ref]

Avoiding Fatty Liver Disease:

Non-alcoholic fatty liver disease (NAFLD) occurs by an increased fat accumulation in the liver. Estimates show that almost half of adults in the US have fatty liver. With the link between liver function and Alzheimer’s, it would make sense that NAFLD would be associated with AD. Indeed, research shows that NAFLD has an association with decreased cognitive performance (for everyone) and with Alzheimer’s disease.[ref][ref][ref]

For more information on NAFLD and lifehacks for reversing it, please read: Fatty Liver: Genetic variants that increase the risk of NAFLD