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.


Lifehacks:

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

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