1 for 10 Million: Alzheimer’s disease modifiable risk factors

Delaying the onset of Alzheimer’s disease could prevent 10 million new cases by 2050.1

Some of our lab’s recent research focuses on plant natural products that seem to correct certain metabolic pathways that are often disrupted in Alzheimer’s disease pathology.  As a small liberal arts college our research program is modest in size and our focus is on the training of young scientists but we do participate in collaborative efforts to understand the metabolism of the disorder.  Sometimes we do some outreach….

I was recently invited to give a short talk for a local community group focusing on the current state of Alzheimer’s disease research.  Here’s the talk – more or less, I didn’t read it word for word – and some additional links at the end.  I did begin with an short introduction of myself and my interest in all of this, which included a clear disclaimer that I am not a medical doctor.  My message was simply this: while there is no effective treatment or cure there are modifiable risk factors and accumulating evidence that the disease can be at least delayed.  I summarized some of these modifiable risk factors as topics that could be discussed with one’s personal physician or healthcare team.  My goal is to encourage these discussions with healthcare providers.  As someone who has watched several loved ones develop this disease, and seen first hand the impact it has on families, I feel strongly that – in the absence of an effective treatment or cure – there is value in any type of health approach that could delay the symptoms of the disease.   

They are entirely my thoughts and do not necessarily reflect those of my employer or any other organization.  This information comes from many dozens of published studies and several organizations.

Alzheimer’s disease (AD) is the cause of 60–70% of dementia cases.  Symptoms include difficulty in remembering recent events, problems with language, disorientation, mood swings, loss of motivation, lack of self-care, and behavioral issues.  Early-onset Alzheimer’s disease is rare.  Late-onset AD, usually diagnosed after age 65, is much more common.  However, the silent effects of AD on the brain begin decades earlier.  Following diagnosis the typical life expectancy is three to nine years.  In the late stages, patients require heroic assistance from caregivers.

Today there are 30 million people living with Alzheimer’s disease, including 5 million Americans. Nearly eight times as many people have preclinical or “silent” AD.  By 2050, those numbers will increase to 160 million globally and 13 million in the United States alone.  Healthcare analysts have predicted that this will bankrupt the Medicare system.  Alzheimer’s is not only one of the most feared diseases it is among the most costly.

There is currently no effective treatment or cure for Alzheimer’s disease.

What occurs inside the brain of someone with AD is not fully understood.  The most widely accepted view of Alzheimer’s disease goes something like this: Neurons begin to shed sticky amyloid beta peptides which clump and aggregate to form the plaques seen in the brains of Alzheimer’s patients.  You may be surprised to learn that this is a normal immune response of brain cells to attack by bacteria, parasites, and viruses – indeed, the sticky amyloid beta proteins entomb these invaders (you can see them under a microscope, buried inside of plaques!).  In AD, however, the plaques build up and overwhelm the brain.  They tend to occur around blood vessels.  Here they damage the brain’s protective blood brain barrier….allowing more invaders into the brain.  Dying neurons release a second type of protein, called tau, which also accumulates.  This, along with the resulting inflammation, overwhelms the brain’s clean-up crew, cells called microglia.  As the cycle continues, the brain – especially the hippocampus, where memories are stored – shrinks.

Why does this occur?  We don’t know exactly but there are several known risk factors for AD.  About half of the risk is genetic.  Hundreds of genes contribute to the disease but the most widely known is the apoe4 risk gene.  We each have no copies, one copy, or two copies of this gene.  For men this raises the risk of developing the disease by age 85 from 11% to 23% to 51%.  For women the risk increases from 14%, 30%, to 60%.  But having the gene does not automatically mean that one will develop AD; genes are not destiny because the other half of the risk comes from “modifiable” risk factors – ones we can change!

Why isn’t there a cure?  It’s not for a lack of trying.  In the past decade, hundreds of clinical trials have been conducted, costing billions of dollars, without success.  There are currently 112 potential new drugs in the pipeline but, so far, there is no revolutionary cure in sight.  In light of this disappointing track record some are now questioning whether a single magic drug will ever be found.  They suggest that AD is a complex disease that will be managed, not cured – like cardiovascular disease, diabetes, or metabolic syndrome – with a combination of drugs and lifestyle changes.

Are such therapies possible?  Perhaps they are.  There is evidence that combinations of medicines, diets, exercise, and social activity can those “modifiable” risk factors enough to delay or slow the progression of AD, especially when started early.  Evidence comes from large population studies in Europe, Asia and the United States.  Some of you might have been on campus in April when Dr. Dale Bredesen, neurologist and researcher from UCLA, visited to talk about his multi-factorial protocol, which has shown some success.  Other groups are testing similar approaches.  More research is needed.

But consider this: In the absence of an effective treatment or cure any therapy that could delay or slow the disease would have great value.  If we had a therapy to delay onset by only 1 year there would be almost 10 million fewer people suffering from Alzheimer’s disease in 2050. 

What are these “modifiable” risk factors?

Head injury.  Each year in the United States, there are 1.7 million traumatic brain injuries or TBIs, primarily in older Americans and those playing sports.  TBI is of particular concern for military service members.  It is a common battlefield injury, considered to be a “signature injury” of recent conflicts.  There is fairly strong evidence that a TBI increases the risk of developing AD.  For example, in a study with more than 350,000 veterans, even mild TBI without loss of consciousness, more than doubled the risk of dementia.  So, protect your head, lower your risk.

Air quality.  Air pollution, specifically ultrafine particulate PM2.5 pollution, is an established risk factor for heart disease, stroke, and respiratory disease and is an emerging risk factor for neurodegenerative diseases. There have been at least 18 studies testing the possible connection between air pollution and AD, with most confirming a link.  One large study in Ontario, Canada, reported that living close to major roads was associated with a higher incidence of dementia.  Another, published this month, examined health records for >130,000 individuals living near London, from 2004 to the present, and found that those living in areas most polluted by NO2 and PM2.5 had a 40 per cent heightened risk of being diagnosed with AD.  As you know, air quality is a significant problem in our area.  Six regions of the commonwealth rank among the “25 worst” in the US for PM 2.5 pollution. In these regions high PM2.5 levels have been correlated to rates of hospital admissions for Alzheimer’s, Parkinson’s, and general dementia. By the way, this particular study ranked our hometown as the 3rd, 3rd, and 2nd worst area for these PM-induced diseases, respectively, in the northeastern US.  If this concerns you consider supporting the Clean Air Board of Central PA.  cleanairboard.wordpress.com

Diet.  The standard American Diet is SAD…S….A….D.  There is general agreement and good scientific evidence that healthier diets – such as the Mediterranean and Nordic diets – lower inflammation, insulin resistance, and help to low the risk of numerous diseases, including AD.  Most general lifestyle approaches to lowering AD risk discourage the consumption of excess sugar and “bad” fats, while encouraging the consumption of colorful veggies, berries, and “good” fats.  In my lab we study the molecules in several so-called “superfoods”; some inhibit the clumping of the A-beta peptides.  There’s really no downside to smart, healthy eating.

Exercise.  Exercise is good for the brain as well as the body.  It can reduce, even reverse, hippocampal atrophy in the brain….even for those at genetic risk for the disease.  It also increases brain derived neurotrophic factor which promotes the health and growth of neurons.  Exercise improves insulin sensitivity, can lower inflammation, and improved the health of mitochondria.

Sleep.  Get enough.  Even one night of sleep deprivation increases plaque formation.  And A-beta aggregation, in turn, disrupts the sleep-wake cycle.  The glymphatic system, which drains wastes from the brain, works twice as fast during sleep.

Avoid or manage infections.  Chronic infections, including those from tick bites, and uncontrolled inflammation raise the risk of cognitive decline.  There is new and convincing evidence that some herpes viruses, especially herpes simplex virus types 1 and 2, are risk factors for Alzheimer’s disease.  These extremely common viruses lay dormant in neurons and are reactivated intermittently by events such as immunosuppression, infection, and inflammation. There over 150 published studies that strongly support a role for active HSV1 infections in the development of AD.  Several showed that the suppression of outbreaks via common and inexpensive antiviral medications alleviate the risk.  This is especially useful news for those carrying the apoe4 risk gene: the gene makes individuals more susceptible to hsv outbreaks and less able to repair the damage.  For someone suffering frequent hsv-1/2 outbreaks, the use of anti-viral medications are usually recommended; if they reduce the risk for later cognitive decline, all the better.

Together, these steps seem to reduce the overall risk of developing AD.  In fact, some of these approaches seem to work better in those with a family history of AD.   

Here is some more advice from patients and caregivers.

Start early.  Get educated.  Find a good “health team”.  Develop good relationships with doctors who will listen and learn.  Consider participating in a clinical trial.

If you opt to do genetic testing be aware that (1) you may learn good and bad things about your genetics and by extension those of your parents and your children, (2) that having a genetic test in your medical record may make you less likely to get long-term care insurance, and (3) that there is support available (one good online support community is available at apoe4.info).  A recent survey done by Dr. Doris Zallen at Virginia Tech found that “Adverse psychological reactions were reported by a substantial fraction of” those learning they carry risk factors for AD but that “nearly all.…said that they had benefited in the long term from lifestyle changes….that they subsequently made.

So if there is one thing I’d like you to remember today it is this: While there is not yet a cure, there are modifiable risk factors.  Even small reductions in risk, which might delay or slow AD, have great value.  By delaying onset by only 1 year there would be 10 million fewer people suffering from Alzheimer’s disease in 2050. 

For more information:

An example of recent media coverage of the topic: http://discovermagazine.com/2018/dec/alzheimers-under-attack

The state of the drug pipeline in 2018:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021548/

One example of a study finding value in addressing modifiable risk factors:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60461-5/fulltext

You can watch Dr. Dale Bredesen’s April 2018 Clarke Forum talk here:
http://clarke.dickinson.edu/dale-bredesen/