With new therapies that promise to slow Alzheimer's disease, researchers race to reform how patients are diagnosed

With new therapies that promise to slow Alzheimer's disease, researchers race to reform how patients are diagnosed


Remember these words. Rose, Chair. Hand. Blue. Spoon. Draw a clock. Name as many different animals in one minute. What is the date? Remember the first five words that begin with the letter F.

Since the 1980s these memory tests, which are often performed with paper and pencil, and scored by trained clinicians who can read the results, were the mainstay in diagnosing Alzheimer's. Alzheimer's is a brain disease that erodes the memory and thinking of a patient, leaving them unable to do basic tasks. According to the Alzheimer's Association, this condition affects approximately 6.7 million Americans aged 65 and older.

These symptom-based testing are good for determining if a person’s memory or thinking isn’t normal. However, they aren’t great at helping doctors determine the cause of these impairments. This can be anything from vitamin and hormonal deficiencies, to small strokes to infections to disorders such as Parkinson’s and Lewy Body disease.

One of the reasons for the failures in early amyloid clearing drug for Alzheimer's is symptom-based tests. In reviews of data from clinical trials of two drugs, bapneuzumab or solanezumab, it was found that up to one third of the patients enrolled did not have the disease for which they were being treated. This is the buildup of sticky beta amyloid pieces and tau proteins within the brain.

The doctors' dependence on symptoms-based testing may soon change. According to new draft guidelines on the diagnosis of Alzheimer’s disease that were unveiled at an international meeting of doctors and researchers on Sunday, memory tests will be replaced by biomarkers, which are proteins and other signals detected in blood and spinal fluid as well as on brain scans. These biomarkers can provide telltale signs about the disease in the brain.

These tests are available to doctors, but not to patients. With new, expensive, and potentially dangerous drugs on the market that promise a slowing of disease progression, the need for better diagnosis is now more urgent.

Diagnosis is key

The Alzheimer's Disease Research Center at University of California at San Francisco's Dr. Gil Rabinovici said, "Getting the diagnosis correct is absolutely crucial to be able provide these new treatments to the right patient."

Dr. Rabinovici was the lead author of a large, multi-year study published in JAMA in 2019. The results showed how important these biomarkers are.

Researchers gave PET scans, which use radioactive tracers that light up beta amyloid deposits in the brain, to over 11,000 patients with early memory and cognitive changes.

The study found that PET brain imaging changed the diagnosis of 35% of patients. It ruled out Alzheimer's in 25% of cases where it was initially suspected and determined Alzheimer's as the cause of deficits in 10% of those who had been initially attributed to another cause.

Rabinovici stated that the memory clinics were specialized.

The scans have changed the way doctors manage patients 60% of time. They are typically prompting them either to prescribe memory-enhancing drugs like donepezil or Aricept or memantine, or to discontinue their use.

According to Dr. Charlotte Teunissen of the Amsterdam University Medical Center, biomarker-based diagnoses can improve patient quality of life in addition to drug treatment.

This allows people to remain at home and receive normal care longer. Teunissen, a coauthor of the guidelines, said that it would lead to a reduction in healthcare costs and burden.

Rabinovici praised the move towards a biological basis of diagnosis.

This is a long-awaited advancement for our field. We are elevating the care by starting to apply biomarkers in real life. It's a great step forward, said Rabinovici who wasn't involved in developing the new guidelines.

The FDA has approved the amyloid PET scanners Rabinovici uses in his study for over 10 years. However, Medicare only covers the cost for those patients who are enrolled in clinical research studies.

Now, with the first FDA approved medication--Leqembi--on the market, which requires evidence of beta amyloid build-up in the brain, Medicare is reportedly set to expand coverage for the amyloid PET scans that are required to see those deposits.

New blood tests for Alzheimer's

Researchers were right to test all suspected Alzheimer's patients with expensive brain scans and invasive spinal taps. But, Dr. Clifford Jack of the Mayo Clinic, Rochester, Minnesota who studies brain imaging in the diagnosis of memory disorders, said that this was not the best way to address a public health issue.

Jack is also co-authoring the new guidelines that are being developed for the Alzheimer's Association, and the National Institute on Aging. The guidelines were presented on Sunday in Amsterdam at the Alzheimer's Association International Conference, 2023.

These guidelines build on the 2018 guidelines for diagnosing Alzheimer's disease in patients taking part in clinical trials. These are the first changes to the diagnosis type used in clinical care since 2011

The guidelines will be posted for 30 days on the website of the Alzheimer's Association for public comments. Jack explained that after the 30-day public comment period the authors of the study will revise the guidelines and re-submit them to the Alzheimer's Association for approval. This could happen by the end the year.

Jack explained, "And two, you can do something about it."

The guidelines will now direct doctors to use blood testing to detect signs and symptoms of Alzheimer's disease in the brain. These blood tests, which were developed in conjunction with powerful amyloid- and tau-clearing treatments, are nearly as accurate as gold-standard tests to measure Alzheimer's protein levels in spinal fluid.

Jack stated that they are basically the same.

Some of these blood tests can be ordered by doctors through specialized labs. However, none have yet been approved by the FDA. Dr. Constantine Lyketsos of Johns Hopkins' Memory and Alzheimer's Treatment Center expects to see some pass this hurdle in the next year.

Rabinovici described the discovery as a "huge advance". Five years ago, I would have considered it science fiction to be able to measure brain proteins in blood.

Jack explained that blood tests would do a number of important things. They will reduce the cost and make diagnosis more accessible for patients who cannot easily access memory centers or specialists.

Jack added that the tests will allow doctors to stage the disease better, as markers for Alzheimer's show up in blood scans before any evidence of the disease is seen on the brain scans. This will help them determine the patient's progression.

Diagnose Alzheimer's disease before you see symptoms?

The new guidelines propose six stages of classification, whereby people are first diagnosed on the basis biomarkers, and then on the basis symptoms.

If the proposed new guidelines are implemented, an individual could be diagnosed with Alzheimer's Disease based on abnormal blood tests alone, without any memory loss. This would be Alzheimer's stage one.

Jack knows this idea won't be popular with his entire team.

Jack stated that this is a major controversy in the field.

Currently, to begin taking the new monoclonal amyloid-clearing antibodies, patients must have evidence of beta amyloid accumulation in their brains. This can be done through spinal fluid tests and brain scans. The symptoms of memory loss and impaired thinking must be early enough to be treated.

Clinical trials are currently being conducted to determine if these drugs can significantly delay or stop the development of memory problems in those who have amyloid deposits in their brains but do not have symptoms. Results of these trials will not be known for a few more years.

"So, in our new criteria when we ask, "Can Alzheimer's be diagnosed in a person who is asymptomatic?" Jack replied, "The answer is a resounding yes from us." "Symptoms are a consequence of disease." Jack said. They are not the definition.

Jack gives the example of type II diabetes. Most people diagnosed with diabetes through screening tests of fasting blood sugars have no symptoms.

Does that mean they do not have diabetes? They're not blind yet or haven't had kidney failure. Yes, they are. Jack said, "They have the disease."

Treatment decisions

Autopsies show that people with normal memory and thinking die with beta amyloid in the brain.

Jack believes that everyone who has beta amyloid in their brains eventually will suffer from impaired cognition. This is as long as they do not die first of another disease, such as a heartattack, a cancer, or a broken hip, followed by pneumonia.

Jack stated that 'in older people you can diagnose any disease in people with no symptoms, but some will die from other causes'.

He said that Alzheimer's patients deserve good diagnoses and care.

Lyketsos at Johns Hopkins said that for some people, the effort to determine if they are eligible to receive the new drugs is not worth it. The estimated benefits can be hard to measure or see for both patients and caregivers. Lyketsos said he has about 12 of these conversations with his patients each week, prompted by their curiosity about the new medications.

He may order simple tests right away, when patients show early difficulties in memory and thinking on the paper-and-pencil tests. This is to rule out vitamin deficiencies or low thyroid hormone.

If he suspects Alzheimer's disease, he suggests a brain scan or spinal tap to better understand what is causing the symptoms.

If the tests indicate that beta amyloid is causing their symptoms, he then looks at genetics. People with APOE4 are more susceptible to brain swelling and can take monoclonal antibody to remove amyloid.

The doctors must also determine if the patient needs other medications, such as blood thinners to treat atrial fibrillation. These drugs could complicate amyloid-clearing drugs.

While people may show biomarkers of Alzheimer's, this may not be the sole cause of their dementia. Jack explained that a brain MRI would be required to rule out any other issues, such as bleeding in the small vessels of the brain, or other memory-stealing disorders.

Jack explained that the patient would be given a choice. We could perform all of this screening assessment. If everything looks good, then you can start treatment. You may not be interested in screening and we will skip it. He said, 'That's the way it will have to be for patients at this time.

Rabinovici stated that patients are more interested in getting diagnosed and doing so earlier than before.

He said that doctors and patients had for years a somewhat nihilistic attitude towards Alzheimer's diagnosis because they believed that there was not much we could do to help. He believes that any information which can guide and plan the care of patients is valuable.

Rabinovici stated, "Now that we have treatments... I believe that this will really catalyze and elevate the care."