Alzheimer’s Disease

Update on Diagnosis and Treatment of Alzheimers Disease

There are some new developments in the diagnosis of Alzheimer’s disease. These developments mean more people may be eligible for the new treatments for Alzheimer’ disease. In this post I will write about the new blood tests for Alzheimer’s disease and also revisit the available treatments. This will be an update of my previous post New Treatment for Early Alzheimer’s Disease – What You Need to Know.

Blood tests for Alzheimer’s disease

The monoclonal antibody treatments for Alzheimer’s disease only work if patients have evidence of amyloid proteins in their brains. Prior to the new blood tests, the only way to tell if patients had the amyloid protein was either to measure it in spinal fluid (which means a spinal tap) or to see it on a PET scan (which is a very expensive type of scan). The FDA has approved a new blood test that has been shown to work as well as a spinal tap or PET scan. It measures a protein called ptau217. The test is called the ALZpath ultra-sensitive pTau217  test. Because it requires just a blood sample, that means a lot more people will get the test and if positive will be eligible for treatment with the new monoclonal antibody treatments. This is a somewhat mixed blessing as I will outline below.

Theories of the cause of Alzheimer’s disease

On November 3, 1906, a clinical psychiatrist and neuroanatomist, Alois Alzheimer, reported “A peculiar severe disease process of the cerebral cortex” to the 37th Meeting of South-West German Psychiatrists in Tubingen, Germany. He described a 50-year-old woman whom he had followed from her admission for paranoia, progressive sleep and memory disturbance, aggression, and confusion, until her death 5 years later. His report noted distinctive plaques and neurofibrillary tangles in the brain at autopsy. In 1909 he presented two more patients with a similar history and pathology in the brain after death. These were all relatively young patients, so the name Alzheimer’s disease originally was applied to patients who developed dementia in their 50’s and 60’s (it was also called “pre-senile dementia.”

In later years it was discovered that many people who developed dementia at any age, including advanced age had the same plaques and neurofibrillary tangles when their brains were examined after they died. It turned out that 90 % of people who had dementia had these plaques and neurofibrillary tangles in their brains found at autopsy..

The Toxic Protein Hypothesis

The composition of the plaques turned out to be a protein called amyloid protein and the neurofibrillary tangles were composed of another protein called tau. The theory was that accumulation of these proteins was toxic to brain cells and that this toxic effect caused dementia. Because dementia is associated with age, it was hypothesized that in predisposed individuals gradual accumulation of these proteins in brain cells over many years eventually results in dementia.

There is one problem with this hypothesis. Several studies have followed aging people over time and measured the presence or absence of dementia. People in all these studies have agreed to have their brains studied after they died. In all of these studies anywhere from 12% to 30% of people who never had dementia during their long lifetimes (many were in their 80’s or older when they died) had plaques and neurofibrillary tangles that met the criteria for Alzheimer’s disease. It appears that the accumulation of amyloid and tau proteins is associated with Alzheimer’s dementia, but not necessarily the main cause of it.

Treatments based on the toxic protein hypthesis

There are three monoclonal antibodies now approved by the FDA for the treatment of Alzheimer’s disease. They newest ones are lecanemab and donanemab. They both target the amyloid beta protein that accumulates in people with Alzheimer’s disease. They are both used in people with mild cognitive impairment and they do reduce the beta amyloid protein as shown by follow up spinal fluid testing and/or PET scanning. Unfortunately, they only have a modest effect on slowing progression from mild cognitive impairment to Alzheimer’s disease. The cognitive test used in the studies of both drugs is called the Clinical Dementia Rating–Sum of Boxes. The range of this test is 0-18. Only people with mild cognitive impairment were included in the trials. The treatment group in the lecanemab trial got lecanemab, which has to be given by iv infusion every two weeks for 18 months. The placebo group got a saline infusion every two weeks. In both the placebo group and the treatment group, the scores on the dementia test got worse by 18 months, but the dementia scores for the treatment group did not increase as much as the placebo group. The absolute difference in the scores was about 14%. This was a statistically significant difference in slowing the progression of mild cognitive impairment to Alzheimer’s disease, but it’s not a very big difference.

Side effects of monoclonal antibody treatment

Both approved monoclonal antibody treatments attack the amyloid beta protein and produce an inflammatory response in the brain. This resulted in brain edema and/or micro hemorrhages in 17% of the treatment group vs 9% of the placebo group. Also nearly a quarter of the treatment group had reactions to the infusion. Most of the people with brain hemorrhages or edema did not have symptoms but some had headache, visual disturbance and confusion.

Expense of monoclonal antibody treatment

Lecanemab, which goes by the trade name Leqimbi is priced by the manufacturer at $26,500 per year. The other approved monoclonal antibody, aducanumab is priced at $28,200 per year. The UK has not approved either of these drugs because they don’t feel the modest benefit justifies the cost. The UK also points out that we have no idea what the long term effects of either one of these drugs might be.

Other treatments for Alzheimer’s disease

The other major class of drugs that has been used for Alzheimer’s disease are the cholinesterase inhibitors. The theory behind using these drugs is that nerve cells that produce a neurotransmitter called acetyl choline are diminished in Alzheimer’s disease. The cholinesterase inhibitors have the effect of increasing levels of acetyl choline in the brain because they inhibit the enzymes that break it down. These drugs are donazepil (Aricept), rivastigmine (Excelon), memantine in combination with donazepil (Namzeric), galantamine (Razadyne) and tacrine (Cognex).

These medicines don’t work very well Fourteen out of 100 patients with mild to moderate Alzheimer’s disease have some improvement in thinking skills. Side effects, especially nausea and vomiting are common. None of these medicines has been shown to work any better than the others in the class.

Genetics

There is no specific Alzheimer gene. Almost 80 genetic sequences have been identified that either decrease or increase the risk of Alzheimer’s disease. If you have a first degree relative who has had or has Alzheimer’s disease, then your risk is increased somewhat. Each of these sequences has only a minimal effect by itself, so you would have to have a lot of them to substantially increase the risk of Alzheimer’s disease. It is estimated that genetics accounts for less than 5% of Alzheimer’s disease.

Integrated theory of cause of Alzheimer’s disease

In doing research for this post, I discovered a very interesting paper by Richard Armstrong that reviews current theories of the cause of Alzheimer’s disease and proposes a new integrated theory that accounts for everything we know about Alzheimer’s disease so far. Here is a link to that paper if you would like to read the whole thing: Review article: What causes alzheimer’s disease?. It is from a Polish neurological journal, but the article is in english.

On the basis of current evidence Dr Armstrong believes that the primary factor in Alzheimer’s disease is an age-dependent breakdown of anatomical systems and pathways within the brain and the consequent loss of synapses. The degree of this aging effect depends on the amount of lifetime stress (also called allostatic load). The brain is the ultimate recipient of stress through hormonal changes resulting from high blood pressure, diabetes, cardiovascular disease, and immunological problems. The result of all this is gradual disconnection of synapses, degeneration of nerve cells, and the expression of genes determining various reactive and breakdown products such as Aβ and tau. The brain has a protective mechanism that removes breakdown products, and this protective mechanism continues to function and prevents the accumulation of Aβ and tau. As a person enters old age and the effects of excessive body stress accumulate, then senile plaques and neurofibrillary tangles begin to form as the brain’s protective systems get overwhelmed. In this theory, accumulation of Aβ and tau are the result of loss of synapses and connections in the brain rather than the cause. By the time these proteins can be detected in the spinal fluid or blood, the process of brain degeneration is already well underway. It is no wonder that targeting these proteins with monoclonal antibodies only modestly slows but does not reverse the progression of mild cognitive deficit to full blown Alzheimer’s disease.

If Doctor Armstrong’s theory is correct, then we should see a markedly increased risk of developing Alzheimer’s Disease with aging in people with certain chronic conditions. Here are some numbers:

Metabolic Syndrome

Metabolic syndrome is defined by having at least three of the following five conditions:

  1. Excess abdominal fat (Waist circumference greater than 40 inches for men or 35 inches for women)
  2. High blood pressure (Systolic greater than 140 or diastolic greater than 90)
  3. High blood sugar (fasting blood sugar greater than 100 mg/dl)
  4. high blood triglycerides (fasting triglycerides greater than 150 mg/dl)
  5. Low HDL cholesterol (less than 40 mg/dl)

People with metabolic syndrome have 11.5 times the risk of developing Alzheimer’s disease as they age as people without metabolic syndrome. About one in every three adults in the US has metabolic syndrome.

Type 2 diabetes

A recent review of the literature found that type 2 diabetes increases the risk of eventually developing Alzheimer’s disease by 56%.

Coronary artery disease

People with coronary artery disease, especially at a relatively young age have a 26% increased risk of eventually developing Alzheimer’s disease.

Sedentary Lifestyle

In a study from the UK the more hours a person spent sedentary, the higher the risk of all cause dementia. Since Alzheimer’s disease accounts for the vast majority of dementia, we can assume that the more hours per day you spend on the couch, the greater the risk of eventually developing Alzheimer’s disease.

Social Networks

Many longitudinal studies show that maintenance of supportive social networks (family, friends) decreases the risk of development of Alzheimer’s disease. Conversely loneliness increases the risk of developing Alzheimer’s disease

Heavy alcohol consumption

Light to moderate alcohol consumption (2 drinks a day for men and 1 drink a day for women actually decreases the risk of developing Alzheimer’s disease. Heavy alcohol consumption (4 drinks a day or greater for men and 3 drinks a day or greater for women) increases the risk of developing Alzheimer’s disease by 300%!

Bottom Line

The new blood tests help diagnose people with mild cognitive impairment who are at high risk of progressing to Alzheimer’s disease. This is only helpful if there are good treatments to prevent progression to Alzheimer’s disease. Unfortunately, the best current treatments modestly slow the progression from mild cognitive impairment to Alzheimer’s disease but do not reverse or prevent the progression. These monoclonal antibody treatments have significant side effects that include microhemorrhages and brain edema. At present there is no medical treatment to reverse or prevent Alzheimer’s disease.

Dr. Armstrong has proposed a theory that the non-hereditary form of Alzheimer’s disease results from loss of synaptic connections in the brain from chronic lifetime body stress and that the amyloid protein accumulations are the result rather than the cause of loss of synaptic connections in the brain. This theory is supported by the fact that people with lifestyle related chronic diseases (metabolic syndrome, diabetes, heart disease, sedentary lifestyle, lack of meaningful mental activity, loneliness, heavy alcohol intake) have a markedly increased risk of developing Alzheimer’s disease as they age.

The best treatment for Alzheimer’s disease is prevention. Risk of developing Alzheimer’s disease with age is decreased by maintaining normal body weight, eating mostly unprocessed foods, exercising regularly, staying mentally active, maintaining supportive social networks, and avoiding heavy alcohol intake.

Dementia: How to Reduce Your Risk

In my previous post, I described two population studies that showed that some people who had the structural brain changes of Alzheimer’s disease showed no evidence of dementia during their lives. How did their brains become so resilient? That is the subject of this post.

Sleep

There is a drainage system in the brain that removes beta amyloid proteins that can accumulate to cause Alzheimer’s disease. This drainage system only operates in stage 4 sleep. The problem is, of course, that elderly people who are at the highest risk of Alzheimer’s disease tend to have less deep stage 4 sleep. Nonetheless, getting adequate sleep significantly decreases the risk of Alzheimer’s disease. Sleep deprivation even in midlife is associated with an increased risk of developing Alzheimer’s disease later on in life. Adequate sleep for the vast majority of people means 7-9 hours of sleep a night. There are many other health benefits of adequate sleep (and conversely many health risks with chronic sleep deprivation). If you would like to learn more about sleep there is an excellent book by Matthew Walker called Why We Sleep. He also has a podcast if you prefer to listen rather than read. His podcast is called the Matt Walker Podcast.

Purpose in Life

A sense of purpose in your life substantially reduces your risk of developing Alzheimer’s disease. If your job gives you a sense of purpose, then continue to work as long as your health (or your employer) permits. If you are already retired, then find something to do that gives you a sense of purpose. It could be volunteer work or a part time job, or a hobby that you find meaningful. Anything you do that helps other people is more likely to give you a sense of purpose.

Good Nutrition

The subject of nutrition keeps coming up whenever we discuss any health topic. Eating a nutritious diet including high fiber, minimally processed foods decreases your risk of developing dementia. Here is a link to my previous post on good nutrition: Good Nutrition: A Review of the Evidence

Exercise

Regular exercise reduces the risk of developing Alzheimer’s disease. Although any regular exercise including walking reduces risk, the kind of exercise does matter somewhat. Walking out of doors especially on trails in parks stimulates your brain because you have to pay attention to where to put your feet. Even if you live in a city, you likely have access to parks with walking trails. Even walking several blocks in the city outside stimulates your brain more than walking on a treadmill at home or in a gym.

Drink less alcohol

Heavy alcohol use substantially increases the risk of developing dementia, but light to moderate alcohol use may actually be protective. 14 or less units of alcohol per week does not increase your risk of dementia and may somewhat reduce your risk. A unit of alcohol is 10 ml (about 1/3 of an oz) of pure alcohol. Here is a link to a calculator that calculates how many units are in multiple kinds of alcoholic beverages: Alcohol Change Unit Calculator.

Don’t Smoke

Smoking increases your risk of developing Alzheimer’s disease by 60%. If you do smoke, quit. If you don’t smoke, don’t start.

Learn New Skills

When you learn new things, your brain forms new connections and the more new connections are formed, the more resilient is your brain. This resilience helps protect your brain function and substantially decreases your risk of developing dementia. It is important to do a variety of things that stimulate your brain. Just doing crossword puzzles or other games that purport to stimulate your brain have not been shown to decrease the risk of dementia. Start keeping a journal, write a blog, learn a new skill that requires eye-hand coordination. Take art lessons, or woodworking lessons, or lessons in any other new skill that strikes your fancy. Engaging in creative activities helps form a variety of new brain connections, and those are what protect you from dementia.

Social Contacts

Frequent face to face contact with friends and family substantially reduces your risk of developing dementia. We are social animals and our brains were designed to interact with others. Loneliness may increase the risk of developing dementia by as much as 40%. Conversely, a good social support system can reduce the risk of developing dementia by as much as 60%. Contact with others mainly through electronic social media may reduce the risk of dementia somewhat, but interactive face to face contact with others seems to be necessary for reducing dementia risk substantially.

Bottom Line

There is nothing you can do that reduces your risk of developing dementia to zero. You can, however reduce your risk quite a bit. Get 7-9 hours of sleep a night. Avoid highly processed foods. Exercise regularly, especially outside if possible. Drink 14 units or less of alcohol per week. Don’t smoke. Maintain a sense of purpose in your life. Continually learn new skills. Maintain an active social network.

If you do all of these things, you stand a good chance of remaining alert and having a productive life well into your eighties and nineties.

Dementia: The Scourge of Old Age

This is the fourth in a series of posts about chronic disease.

Age is the biggest risk factor for dementia. You can’t keep from getting older, but there are things that decrease the risk of dementia at any age. In this post I will discuss the types of dementia, the symptoms associated with each and what is known about the epidemiology of each type. In the next post I will talk about ways to reduce your risk of dementia.

Statistics

In the US, 5% of 70-79 year olds have dementia. For 80-89 year olds, 17% have dementia and for people 90 or over, 31% have dementia. The prevalence of dementia is not distributed evenly across the population. The lower the educational level, the higher the risk of dementia over age 70. The prevalence is also increased for African Americans and for hispanics. Death rates for dementia have marked regional differences. Southern states have the highest death rates. Tennessee has the highest death rate at 90.1 per 100,000 and New York has the lowest at 43 per 100,000. Women are slightly more at risk than men and people who are married are at lower risk than people who are unmarried.

Normal brain aging

As people get older it is normal for brain function to slow down some. Here are some signs of normal brain aging that are not dementia, early or otherwise: forgetting names and then remembering them later; going into a room and forgetting what you came for; forgetting where you put your keys; slower recall of dates and events.

What is dementia?

Dementia is not just slowing down or forgetting. Dementia is a loss of brain function that significantly interferes with daily life. It can range from mild cognitive impairment to complete inability to care for oneself. People with dementia don’t just forget recent events, they forget how to do things they have always done, like cooking from a recipe or balancing a checkbook. They can wander and get lost in a familiar neighborhood. Recent memory is so impaired that they will often ask the same question over and over again. They may have trouble expressing themselves verbally and/or in writing. Certain types of dementia have some distinct symptoms, which I will talk about later in this post. Here is a link to a CDC web page that describes 10 warning signs of early dementia: 10 Warning Signs of Alzheimers. People tend to equate dementia with Alzheimer’s disease, and that is certainly the most common type (about 75%) but there are other causes for dementia as well.

Alzheimer’s Disease

In 1906 Alois Alzheimer, a psychiatrist and neuroanatomist, described a severe disease of the cerebral cortex in a 50 year old woman at a psychiatry meeting in Germany. She had severe memory loss, speech disturbance, sleep disturbance, paranoia and confusion. He followed her in the hospital until she died 5 years later. An autopsy was done and the microscopic slides of the brain showed distinctive plaques and neurofibrillary tangles. He presented the clinical history and autopsy report at the meeting.

This pattern of progressive dementia associated with the brain findings of plaques and neurofibrillary tangles became known as Alzheimer’s disease. It was initially also known as pre-senile dementia, because the first patients described were relatively young. It was only later that it was discovered that the dementia commonly associated with old age had the same microscopic brain findings of plaques and neurofibrillary tangles, so the Alzheimer’s disease label came to describe dementia at any age associated with the characteristic microscopic brain abnormalities. Research has subsequently shown that the plaques are made up of a protein called beta amyloid and the tangles are made up of another protein called tau.

There is no lab test or brain scan that will confirm a diagnosis of Alzheimer’s disease. A firm diagnosis can only be made by examining the brain after the patient dies. A diagnosis of probable Alzheimer’s disease can be made with about 90% certainty based on slow onset and gradual progression of dementia.

Alzheimer’s disease is not curable. There are some medicines that have been approved for Alzheimer’s, but they don’t work very well. Most studies of these medicines show cognitive improvement of about two points on a one hundred point measurement scale. Although statistically significant, clinical significance is doubtful.

Lewy Body Dementia

Lewy body dementia is the second most common cause of dementia after Alzheimer’s disease. It affects about 1.4 million Americans. Brain autopsies show clumps of protein called Lewy bodies. They are made of a normal brain protein called alpha-synuclein. A mutation of the protein causes it to be misfolded and accumulate in nerve cells in the brain. People with Lewy body dementia have very vivid hallucinations and movement disorders similar to Parkinson’s disease. They also have fluctuating levels of consciousness, sometimes being very confused and sometimes having moments of clarity. There is no cure and it leads to death in 4-6 years. This is the type of dementia that the actor Robin Williams had.

Vascular Dementia

Vascular dementia is caused by blockage of small arteries in the brain. The same risk factors for heart disease and stroke are also risk factors for vascular dementia. It is thought that vascular dementia occurs because of a series of tiny strokes in the brain. Sometimes vascular dementia proceeds in a stepwise fashion, but it can also progress gradually, just like Alzheimer’s disease. In that case it is clinically indistinguishable from Alzheimer’s disease and it is also not uncommon for people with vascular dementia to have Alzheimer’s disease as well. About 5-10% of people with dementia have vascular dementia alone. Just as with Alzheimer’s disease, there is no specific lab test or brain scan that reliably makes a diagnosis of vascular dementia. Once again, a firm diagnosis can only be made at autopsy. There is no treatment other than prevention.

Pick Disease

Pick disease is also called frontotemporal dementia or frontotemporal degeneration. It is less common than Alzheimer’s disease, Lewy body dementia and vascular dementia, but it tends to occur at much younger ages, often in the 40’s or 50’s. It is sufficiently rare that the epidemiology is not well understood. The brain cells of people with Pick disease have round bodies called pick bodies. They are made of tau fibrils, the same protein that is in the neurofibrillary tangles in the brains of people with Alzheimer’s disease. The symptoms of Pick disease are primarily loss of control of behavior as well as language difficulties. It is often initially misdiagnosed as a psychiatric disorder. There are three variants. One involves mostly behavioral abnormalities like mood changes, personality changes, inappropriate behavior, social withdrawal, and repetitive behaviors. The second variant is called primary progressive aphasia. People with this variant have progressive loss of the ability to speak, write and understand language. The third variant involves difficulty with movement and balance. The cause is unknown and there is no treatment. People with Pick disease eventually die from it, but can survive as long as ten years. This is a terrible disease. It is fortunate that it is relatively rare.

Treatable Causes of Dementia

Although the vast majority of people with dementia have one of the four diseases described above that are progressive and incurable, there are a few causes of dementia that are reversible. That is why we do blood tests, CT scans and MRI’s on people newly diagnosed with dementia, because every now and then we find one of the treatable causes. Treatable causes of dementia are: hypothyroidism (low thyroid hormone); vitamin B12 or folate deficiency; infections of the brain (syphilis, Lyme disease and others); brain tumors; subdural hematomas (blood clots under the membrane that covers the brain); normal pressure hydrocephalus (blockage of the flow of spinal fluid out of the brain). Depression in older people can look like dementia and should always be ruled out.

I will give you an idea about how uncommon treatable dementia is in clinical practice. In forty years of primary care practice, despite dutifully doing the recommended evaluation on every patient with a new diagnosis of dementia I found normal pressure hydrocephalus once and none of the others. That is not to say that I did not see and treat those other conditions, but none of them ever presented as undiagnosed dementia.

Brain changes of Alzheimer’s Disease Without Dementia

There have been two population studies that started with older people who had no evidence of dementia and followed them for years with followup tests for dementia. In both of them a small percentage of people who had plaques and neurofibrillary tangles typical of Alzheimer’s disease had no evidence of dementia on the tests during life.

The Nun Study

The participants in this study were Catholic sisters, who were members of the School Sisters of Notre Dame congregation living in the United States. All sisters born before 1917 were asked to participate in the study. There were 678 sisters who agreed to participate and they were all enrolled in the study between 1991 and 1993. Permission to do autopsies after their deaths was obtained from 95% of the sisters. A small group had typical plaques and neurofibrillary tangles in their brains at autopsy, but had no evidence for dementia while they were alive. Here is a link to one of the papers from that study: The Nun Study.

Adult Changes in Thought Study

This study recruited 4690 subjects from the Seattle area. Again, participants had no evidence of dementia at the beginning of the study. Tests for dementia were done periodically for all the living participants. Permission to do autopsies after their deaths was obtained from 25% of this group. Like the Nun Study, a small group of these people had typical Alzheimer’s disease changes in their brains, but no evidence of dementia while they were alive. Here is a link to the description of that study: Adult Changes in Thought Study.

Cognitive Reserve

Both of the studies described above suggest that some people have or can develop some sort of cognitive reserve that preserves brain function even in the presence of structural changes in the brain. I will talk about evidence for how that may happen in the next post.