Dawn of the Age of the Alzheimer's blood test

We've written periodically about the promise of blood tests to detect Alzheimer's disease, even in very early stages.  That promise is being fulfilled, but there are some rubs.

A few blood tests for beta amyloid have now been through clinical trials, and we even have at least one that detects tau protein of the type associated with Alzheimer's disease.  These tests are extremely helpful, because they will bypass the need for PET scans and MRIs that are currently used to identify biomarkers.  Recall that biomarker evidence is required for a reliable diagnosis of Alzheimer's disease.  As we said in Beating the Dementia Monster, my care team found a biomarker of atrophy of my brain in a series of MRIs, and they used this in my diagnosis.  

In the recent Alzheimer's Association International Congress (San Diego, July 31 -- August 4), the Alzheimer's Association Global Workgroup released their recommendations on the use of blood tests, noting that the tests aren't ready for prime time.  At least not as a standalone diagnostic tool.

So what's the problem?  Clinical trials have generally been carried out with homogeneous, largely white populations.  It's well known that Alzheimer's disease sometimes proceeds differently in different populations, creating uncertainty about how test results are to be interpreted.  Also, more needs to be known about how comorbidities and medications will influence test results.  So the Global Workgroup developed its recommended guidelines to account for these uncertainties.  It is expected that the guidelines will be adjusted on a regular basis as more is known about the tests.

For now, the guidelines would limit blood biomarker use to people with cognitive symptoms who are seen in specialist memory clinics and, ideally, receive follow-up with amyloid-PET or CSF to confirm they really do have amyloid plaques in the brain.  This is likely to be most common in clinical trials for new treatments.  They specifically recommend against using the tests in a primary care setting.  The guidelines also consider the relationship with comorbidities, especially kidney dysfunction. 

So far, I haven't seen anyone commenting on my concern.  What does this do to long-term care insurance?  When I signed up, I went through a pretty rigorous evaluation.  This was long before I had any suspicion I had Alzheimer's disease, but I could tell from the cognitive tests that they were interested in my memory and cognition.  Since blood tests appear to detect the disease in early stages, I'm thinking that, should insurance companies be permitted to use the tests to evaluate prospective policy holders, there are a lot of people who will have a very difficult time getting insured. 

Gut and Brain Redux

Perhaps there's a love-hate relationship between your gut and your brain.  On the one hand, it appears that microbes in your gut are controlling much of what goes on in your brain in mysterious ways.  That's called the gut-brain axis.  But at the same time, your "leaky gut" is killing your brain.  With respect to the latter, we've known for a long time that, as we age, the walls of the intestines are less able to contain the gut bacteria.  The bacteria leak out into the abdominal cavity and create inflammation throughout the body, including in the brain.  Much of our battle against Alzheimer's disease is to control inflammation, and gut bacteria becomes a major adversary.

How the gut bacteria makes its way to the brain is coming into sharper focus, and there's better information on how to put the brakes on that process.  (Spoiler alert:  It's a high fiber diet.)  My friend Teale sent me this article from Neuroscience News about new research findings on leaky gut and brain inflammation.  The researchers at the LSU Health New Orleans Neuroscience Center and the Departments of Cell Biology and Anatomy, Neurology, and Ophthalmology examined the culprit bacteria, Bacteroides fragilis.  This bacteria generates a neurotoxin known as BF-LPS.  At autopsy, it's found in the brain cells of Alzheimer's patients.  

How BF-LPS is able to cross the blood-brain barrier is not clear to me.  Perhaps it's a relatively small molecule, allowing it to cross both the intestinal membranes and the blood-brain barrier.  Recall that the blood-brain barrier allows smaller molecules to pass but screens out larger molecules and microbes.  But the intestinal membranes and the blood-brain barrier both weaken as we age.

When the BF-LPS reaches the brain, it not only causes inflammation, but it also inhibits the action of a protein called NF-L.  NF-L is important to the survival of neurons, and when its actions are inhibited like this, brain cells die, and the brain atrophies.  

So what can we do about this?  Control Bacteroides fragilis, so that it can't generate BF-LPS.  The design of your gut is such that it expects a certain fraction of what you eat to be dietary fiber.  I'd describe the situation like this.  If you're not eating enough fiber, your gut bacteria becomes unbalanced, and Bacteroides fragilis will generate a lot more BF-LPS.  So make sure you have a high-fiber diet.

How much fiber?  The USDA recommends that women up to age 50 consume 25 grams a day and men 38 grams.  Women and men over age 50 should consume 21 and 30 grams daily, respectively.  A medium-sized apple contains about 4.4 grams of fiber.

Take 2 -- The highway to Alzheimer's disease: Ultraprocessed foods

I should have learned a long time ago never to use bullet points in blog posts.  They look fine on the blog itself, but in the emails, they mess up the fonts and sometimes remove the content completely!  Aaaak!  So I am re-posting yesterday's post with dashes instead of bullets, so everyone gets a clean version with all of the content.  But I also want to make one clarification regarding types of studies.

The clarification is this (and we've said this before): longitudinal studies that simply follow different populations can be misleading.  In the longitudinal study on ultra-processed foods, the authors were careful to point out that the study showed a correlation between diet and dementia, but this does not prove that bad diet caused dementia.  It probably did, but this kind of study doesn't prove it.  As we said in Beating the Dementia Monster, people who eat well  probably also have other healthy habits (e.g., they exercise more), and that may be the real reason they haven't developed dementia.  Or more to the point, people who are more likely to eat ultra-processed foods may also be less likely to get good exercise and adopt other brain-healthy lifestyle habits.  So good or bad diet may simply be coincidental.

When we discussed the FINGER Study, we noted that they had actually changed peoples habits and then measured the results.  It was a randomized study with controls.  That type of study is much more reliable than a longitudinal study.

In any event, here's what we posted yesterday, but without the disruptive bullet points:  

--------------------------

Lately there have been several articles in the media emphasizing the link between "ultra-processed foods" and the development of Alzheimer's disease. Or, more accurately, "food products," since they're not exactly real food.  What prompted the recent interest is a new study published in the July 27 issue of Neurology, the journal of the American Academy of Neurology, entitled "Association of Ultraprocessed Food Consumption With Risk of Dementia; A Prospective Cohort."  Chinese researchers using data on citizens of the UK found an association between ultra-processed foods and incidence of dementia.  They found that for every 10% increase in daily intake of ultra-processed foods, people had a 25% higher risk of dementia.

In other words, a small increase in the consumption of ultra-processed foods led to a big jump in the risk of dementia.

The authors were careful to point out that they found an association, not necessarily a causal relationship.

Recall that the government of China is the second biggest funder of Alzheimer's research behind the US government.  The Alzheimer's Association is third.

So what do we mean by "ultra-processed foods?" Ultra-processed foods are high in added sugar, fat, and salt, and low in protein and fiber. There's a system called NOVA (that's not an acronym) for categorizing food processing that breaks it down like this:

-- Unprocessed or minimally processed foods 
-- Processed culinary ingredients 
-- Processed foods 
-- Ultra processed food and drink products 

So what's special about ultra-processed foods?  Brazilian nutrition researcher Carlos Monteiro, at the Center for Epidemiological Research in Nutrition and Health at the University of São Paulo, Brazil, coined the term.  He said the term doesn't relate to the food, but rather to all of the processing.  What foods are in question?  You're not going to like this.  Here are some examples:

-- Carbonated soft drinks 
-- Sweet, fatty, or salty packaged snacks 
-- Candies (confectionery)
-- Mass-produced packaged breads and buns 
-- Cookies (biscuits) 
-- Pastries Cakes and cake mixes 
-- Margarine and other spreads 
-- Sweetened breakfast cereals 
-- Sweetened fruit yogurt and energy drinks 
-- Powdered and packaged instant soups, noodles, and desserts 
-- Pre-prepared meat, cheese, pasta, and pizza dishes 
-- Poultry and fish nuggets and sticks 
-- Sausages, hamburgers, hot dogs, and other reconstituted meat products  

You'll note that none of these foods are included in the MIND diet, the DASH diet, or the Mediterranean diet.

Of course, not all ultra-processed foods are created equal.  For example, plant-based hamburgers could be both of nutritional high quality but also be classified as ultra-processed.  But check the label -- no trans-fats or other problematic ingredients. 

We never used the term "ultra-processed foods" in Beating the Dementia Monster.  Actually I'd never heard the term before I saw this study.  Nevertheless they have no place in the Dementia Toolkit.  And they have no place in your diet if you're concerned about your brain health.

The highway to Alzheimer's disease: Ultraprocessed foods

Lately there have been several articles in the media emphasizing the link between "ultra-processed foods" and the development of Alzheimer's disease. Or, more accurately, "food products," since they're not exactly real food.  What prompted the recent interest is a new study published in the July 27 issue of Neurology, the journal of the American Academy of Neurology, entitled "Association of Ultraprocessed Food Consumption With Risk of Dementia; A Prospective Cohort."  Chinese researchers using data on citizens of the UK found an association between ultra-processed foods and incidence of dementia.  They found that for every 10% increase in daily intake of ultra-processed foods, people had a 25% higher risk of dementia.

In other words, a small increase in the consumption of ultra-processed foods led to a big jump in the risk of dementia.

The authors were careful to point out that they found an association, not necessarily a causal relationship.

Recall that the government of China is the second biggest funder of Alzheimer's research behind the US government.  The Alzheimer's Association is third.

So what do we mean by "ultra-processed foods?" Ultra-processed foods are high in added sugar, fat, and salt, and low in protein and fiber. There's a system called NOVA (that's not an acronym) for categorizing food processing that breaks it down like this:

• Unprocessed or minimally processed foods 
• Processed culinary ingredients 
• Processed foods 
• Ultra processed food and drink products 

So what's special about ultra-processed foods?  Brazilian nutrition researcher Carlos Monteiro, at the Center for Epidemiological Research in Nutrition and Health at the University of São Paulo, Brazil, coined the term.  He said the term doesn't relate to the food, but rather to all of the processing.  What foods are in question?  You're not going to like this.  Here are some examples:

• Carbonated soft drinks 
• Sweet, fatty, or salty packaged snacks 
• Candies (confectionery)
• Mass-produced packaged breads and buns 
• Cookies (biscuits) 
• Pastries Cakes and cake mixes 
• Margarine and other spreads 
• Sweetened breakfast cereals 
• Sweetened fruit yogurt and energy drinks 
• Powdered and packaged instant soups, noodles, and desserts 
• Pre-prepared meat, cheese, pasta, and pizza dishes 
• Poultry and fish nuggets and sticks 
• Sausages, hamburgers, hot dogs, and other reconstituted meat products  

You'll note that none of these foods are included in the MIND diet, the DASH diet, or the Mediterranean diet.

Of course, not all ultra-processed foods are created equal.  For example, plant-based hamburgers could be both of nutritional high quality but also be classified as ultra-processed.  But check the label -- no trans-fats or other problematic ingredients. 

We never used the term "ultra-processed foods" in Beating the Dementia Monster.  Actually I'd never heard the term before I saw this study.  Nevertheless they have no place in the Dementia Toolkit.  And they have no place in your diet if you're concerned about your brain health.

A Eureka Moment

Yesterday we discussed research at Tufts and Oxford universities that found evidence for a mechanism by which two types of herpes viruses may work together to cause Alzheimer's disease.  Most of our eggs have been in the amyloid research basket, but the amyloid scandal suggests we should be looking harder for causes in other places.  

I sometimes think of Alzheimer's disease as a wound spring waiting to be released.  And so the risk factors set up conditions where the spring can be released.  But what could actually cut it loose?  Pathogens is a good place to start, especially with the two herpes viruses studied in the research.

Yesterday, we also said that I continue to wonder why I developed Alzheimer's disease, when I don't have any of the conventionally identified risk factors.  (Except that I lived a very sedentary lifestyle, and my diet wasn't very good.)  But the question now occurs to me -- could it have been herpes?

As we discussed in Beating the Dementia Monster, the disease begins about 15 years before the first symptoms appear.  And according to the recent research on herpes, episodes of shingles can cut the disease loose, triggering the generation of the characteristic amyloid plaques and tau tangles.  Herpes simplex is resident in the brains of many people, and it is activated during episodes of shingles caused by herpes zoster.  Herpes zoster may be acquired by a childhood chickenpox infection, but the virus then waits in the brain to later cause shingles.  

Maybe that's what happened to me.  I had chickenpox when I was five and then had shingles three time beginning when I was in my early 30s.  But when was my last episode of shingles?  If my disease started then, does it fit the 15 year timeline we described?

So this morning I started shuffling through my old medical records and found when I last had shingles.  It was 2003, 12 years before my first symptoms of Alzheimer's disease.  I'm thinking that's pretty darn close to the 15 years they talk about, and maybe that's the answer to my riddle.  So, eureka.

If not amyloid, let's take another look at the herpes virus

One of the tragedies of the ongoing amyloid scandal is that pursuing the possibly flawed amyloid hypothesis for Alzheimer's disease may have distracted us from other pathways to effective treatments.  One of those pathways might be through the herpes virus and its suspected role in the development of the disease.  

Back in June 2018 and January 2020 we wrote about evidence that the herpes virus may be among several pathogens that spark the development of Alzheimer's disease.  Some studies found more herpes viruses in the brains of people dying of Alzheimer's disease, but this was not confirmed in other studies.  Nevertheless, there has been a longstanding association between herpes infections and the development of the disease, although how this occurs has not been clear.  But maybe there has been a breakthrough.

A recent study at Tufts University and the University of Oxford  developed an hypothesis about how this happens, and it involves two different versions of the herpes virus, herpes simplex (HSV-1) and varicella zoster (VCV).  HSV-1 is known to cause cold sores around the mouth, while VCV first causes chicken pox and later shingles.  Perhaps you're familiar with these.

As we noted in our earlier posts, after an infection, HSV-1 can take up residence in brain cells and remain innocuously dormant there for a long time.  Until VCV shows up. 

Both viruses attack nerve cells and cause inflammation.  If, like me, you've had shingles, you know that it produces a rash-like appearance of tiny red dots on your skin.  Those red dots are the inflamed ends of nerves reaching from the brain to the surface of the skin.  That's why shingles is so painful.  It also indicates that there is inflammation in the brain, and brain inflammation is an important factor in the development and progress of Alzheimer's disease.

What the researchers found was that an infection with VCV may somehow "activate" the HSV-1, causing it to promote inflammation and the development of the amyloid plaques and tau tangles that define Alzheimer's disease.  

But there may be ways of activating HSV-1 other than by VCV.  In Beating the Dementia Monster, we discussed an association between the development of Alzheimer's disease and factors like head trauma, alcohol consumption, and obesity.  The authors of the study suggested that these could promote the disease by activating the HSV-1 virus on their own, since HSV-1 is already resident in the brains of most of us.

So, how about stopping the VCV from activating HSV-1?  The authors of the study say you should get your shingles shot!  There is already an association established between people who get the shingles shot and a reduced risk of Alzheimer's disease, something I didn't know before reading this study.

I have wondered before why I developed Alzheimer's disease, when I don't have any of the commonly associated risk factors, such as the APOE4 gene.  Maybe this is the answer.  I had a serious case of shingles when I was in my early 30s, but I experienced two more episodes in the following decades.  To the best of my recollection, the most recent episode was about 15 years before my diagnosis in 2015.  As we discussed in Beating the Dementia Monster, the disease is thought to begin about 15 years before the appearance of the first symptoms.  So maybe that's the answer I've been looking for to my question, "Why me?"  

(I'm not whining when I say, "Why me?"  The years since my diagnosis have been some of the richest years of my life.)