Medicines for 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.

New Treatment for Early Alzheimer’s Disease – What You Need to Know

There is a new treatment for early Alzheimer’s disease that has been approved by the FDA. The trade name is Lequimbi and the generic name is Lecanemab. It is a monoclonal antibody (all of this class of medicines end in “mab) that targets the protein called amyloid-beta that accumulates in the brain of many patients with dementia due to Alzheimer’s disease. The press has been full of articles about this treatment, but it is important to understand the evidence for how well it works and in what kind of patients. I will go through that evidence in this post.

Who does Lecanemab work for?

The study that led to the FDA approval was done in people with early Alzheimer’s disease or what is called mild cognitive impairment. People with mild cognitive impairment often progress to dementia from Alzheimer’s disease. All of the people in the study had confirmed amyloid-beta deposition in the brain documented by PET scan or spinal fluid from a spinal tap. Not everyone one who has dementia has amyloid. There are many other kinds of dementia including vascular dementia, Lewy body dementia, frontotemporal dementia, mixed dementia (more than one type), dementia from Parkinson’s disease, dementia from Huntington’s disease, dementia related to alcoholism, and dementia from posterior cortical atrophy. Lecanemab only works for people who have documented excessive amyloid, not for any other type of dementia. In order to be able to take the drug, amyloid has to be documented either by a PET scan or a spinal tap. It has only been used in early Alzheimer’s disease. It does not work in people who already have more severe dementia from Alzheimer’ disease.

How well does Lecanemab work?

The study that established the effectiveness of Lecanemab was a placebo controlled double blind randomized trial. That is the gold standard for a clinical trial, so the results should be very reliable.

To measure the degree of cognitive impairment, the investigators used a test called the Clinical Dementia Rating–Sum of Boxes (CDR-SB).

The CDR-SB is measured by semistructured interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The range of scores is from 0 (no cognitive impairment) to 18 (severe impairment).

Patients were randomized to be in the treatment group or the control group. There were about equal numbers in both groups. The average baseline CDR-SB score for both treatment and control groups was about 3.2. out of 18 possible, so both groups had very mild impairment at baseline.

Results of the clinical trial of Lecanemab

The trial took place over 18 months. Lecanemab has to be administered through intravenous infusion every two weeks. The control group also got intravenous infusions, but only got a placebo and not the Lecanemab. Both treatment and control groups got slightly worse over the 18 months with increasing CDR-SB scores.

At the end of the 18 months, the CDR-SB score in the control group was 4.86, an increase of 1.66. The CDR-SB score in the Lecanemab group was 4.41, an increase of 1.21. That means that people who got Lecanemab progressed in their cognitive impairment somewhat more slowly than the people who got placebo. Although the difference was modest, it was highly statistically significant. The absolute risk decrease was 9%. The formula to calculate the absolute risk reduction (ARD) is 1-(4.41/4.86)=.09. The number needed to treat to benefit one person (NNT) is 1/.09 = 11. That number means that one out of 11 people with mild cognitive impairment from amyloid deposition will benefit from taking Lecanemab.

Adverse effects

Unfortunately the major adverse effects of Lecanemab are brain swelling and bleeding in the brain. In the clinical trial 12.6% of the treatment group had brain swelling or bleeding compared to almost zero in the control group. The Lecanemab group also had 26% more infusion reactions than the control group. We can calculate the number needed to harm (NNH) for one person to get brain swelling or bleeding. That formula is 1/0.126=7.9. That means that one out of every 8 patients who get Lecanemab will have brain swelling or bleeding. When the number needed to harm is less than the number needed to treat, that is not a good thing! Fortunately most of the people who had these abnormalities on scans did not have any symptoms. Nonetheless, potentially serious adverse effects from Lecanemab are common enough to be concerning.

Because of the risk of bleeding in the brain, anyone who is on any blood thinner including aspirin is not eligible for Lecanemab, nor is anyone else who may be pre-disposed to bleeding.

Cost

A one year supply of Lecanemab costs $26,500. Your Medicare part D, which pays for medicines, or your Medicare Advantage plan may or may not cover the cost of this drug. That cost does not include the cost of the PET scan or the spinal tap that needs to be done before anyone is eligible to to take Lecanemab.

Bottom Line

Lecanemab is the first drug that shows clear benefit in slowing the progression of Alzheimers’s disease related to amyloid-beta deposition in the brain. At this point the effects of Lecanemab on the progression of early Alzheimer’s disease are modest at best, at the cost of significant side effects. This research is promising, but at this point I think that the modest benefits may be outweighed by the very significant and sometimes dangerous side effects.