Telltale Sign
ADVANCES IN DIAGNOSING ALZHEIMER’S DISEASE
A wave of recent scientific discoveries is changing our understanding of Alzheimer’s disease (AD) and other dementias and pointing the way toward earlier, more precise diagnosis and treatment.
Up to 30% of people who have been labelled as having Alzheimer’s disease are misdiagnosed.
This startling statistic is according to the “World Alzheimer Report 2021” from Alzheimer’s Disease International. But what does it mean?
That estimate is based on research that compares health records of individuals who were diagnosed with AD while living and the results of post-mortem brain autopsies. In one study, for example, Canadian researchers examined more than 1,000 people in the (U.S.) National Alzheimer’s Coordinating Center database, whom teams of specialists had followed for many years before death.
The research, which was published in Alzheimer’s & Dementia in July 2016, found “the error rate is approximately 22%,” said Dr. David Munoz, a neuropathologist at St Michael’s Hospital in Toronto, and one of the study co-authors. “That was divided into almost equal categories of 11% false positive and 11% false negative.”
In other words, in half of these cases, the individuals’ brain tissue lacked the deposits of two abnormal proteins — amyloid and tau – that are hallmarks of AD. Instead, their brains showed evidence of other types of dementia.
The others had been diagnosed with other forms of dementia, but samples of their brains did contain the amyloid plaques and tau tangles considered characteristic of AD.
It’s also worth noting that if the brain of a person diagnosed with AD showed evidence of both it and another form of dementia – vascular dementia, for instance – “that was considered a correct diagnosis,” Dr. Munoz explained, since this type of “mixed pathologies” is common.
This discrepancy is largely due to the way that AD has traditionally been diagnosed.
“The diagnosis was what we call clinical,” said Dr. Howard Chertkow, a cognitive neurologist, Chair in Cognitive Neurology and Innovation, and Director of the Kimel Family Centre for Brain Health and Wellness at Baycrest in Toronto.
This usually involved a history, physical exam, and tests to evaluate thinking, learning, and memory, “supported by blood tests to look for reversible cases, like low thyroid, and supported by brain imaging, so you didn’t miss a brain tumour,” Dr. Chertkow explained.
“The diagnosis of Alzheimer’s was made when there was a progressive dementia, with no other clear explanation, like a problem in the blood, or an infection.”
Dr. Michael Borrie, a geriatrician and Medical Director of the Aging Brain and Memory Clinic at St. Joseph’s Health Care London: Parkwood Institute, and an investigator with the Lawson Health Research Institute’s Cognitive Clinical Trials Group, compares the process to trying to detect specific problems in a used car by driving it and listening for certain noises.
A CLEARER PICTURE
OVER THE LAST DECADE, HOWEVER, SCIENTISTS HAVE DEVISED METHODS OF DETECTING THE PRESENCE OF AMYLOID AND TAU ABNORMALITIES IN LIVING PEOPLE.
“Probably the most important two developments have been (testing of) cerebral spinal fluid, and the possibility of detecting amyloid with a PET scan,” of the brain, said Dr. Munoz.
Testing of a sample of the cerebral spinal fluid (CSF, which is obtained via spinal tap) can detect changes in the levels of so-called biomarkers for AD — specific forms of amyloid and tau.
According to a 2022 report by the Canadian Agency for Drugs and Technologies in Health (CADTH) on emerging technologies for early diagnosis of AD, “in the CSF, amyloid-beta1-42 decreases throughout the course of the disease, and T-tau and P-tau181 increase.” (T refers to “total” and P to “phosphorylated.”)
CSF testing can help rule out AD in people with results in the normal range. It can be useful in some other circumstances, such as identifying AD in people with atypical presentations or symptoms.
PET imaging can be done to look for accumulation of either amyloid or tau in the brain. Before the scan, an individual is injected with a dye that will bond to the protein in question.
Areas where the protein has accumulated in the brain will “light up” on the image. “We know now that if the (amyloid) PET scan is negative, the patient cannot have Alzheimer’s,” said Dr. Munoz.
However, if the scan is positive, it does not mean the patient does have the disease, he added. That’s because “someone could have a significant buildup of the amyloid protein, but not have dementia,” said Dr. Sarah Main, research scientist for the Alzheimer Society of Canada and a research associate at the Brain and Body Lab at the University of Waterloo.
BASED ON THE RESULTS OF AUTOPSY STUDIES, IT’S ESTIMATED THAT MORE THAN 25% OF COGNITIVELY NORMAL OLDER PEOPLE HAVE SUCH AMYLOID DEPOSITS – THEIR BRAINS ARE SOMEHOW ABLE TO CONTINUE FUNCTIONING WELL DESPITE DAMAGE WROUGHT BY THE PROTEIN.
Consequently, PET scanning is not suitable for people who don’t have dementia symptoms. Expert guidelines from the 5th Canadian Consensus Conference on the Diagnosis and Treatment of Dementia do not recommend routine screening in asymptomatic individuals – even those with risk factors – with either PET or cognitive testing.
As well, the consensus report discourages, “the use of amyloid and tau imaging without memory decline, outside of the research setting.”
Currently, in Canada, CSF testing and amyloid PET scans are mostly limited to use in research, and specialized memory clinics. (CSF testing is only done by one Canadian lab and is not covered by all provincial health plans; and the majority of Canada’s 57 PET-CT scanners, which are concentrated in urban centres, are primarily used for oncology. “In some places in Canada, it’s impossible to get a scan,” noted Dr. Chertkow.)
IS IT AD?
These tests are just two of the numerous advances that are revealing a much more nuanced picture of AD and other dementias. But they are invasive or hard to get.
“If you ask do all the people with what we’ve been calling Alzheimer’s disease in the clinic over the past 30 years have amyloid in the brain, we can now answer that question much more precisely,” Dr. Chertkow said, thanks to research involving PET scanning.
There was a big study called IDEAS in the U.S., which found that about one-third of patients labelled as having Alzheimer’s did not have any amyloid.
These early findings from the Original IDEAS (Imaging Dementia-Evidence for Amyloid Scanning) study were published in Alzheimer’s & Dementiain July 2017.
With this, and other technological developments, “we’re beginning to understand there’s a bunch of other conditions that produce the signs and symptoms of Alzheimer’s disease, but chemically they’re different when we look at the brain,” Dr. Chertkow explained.
These entities include, “LATE, which stands for limbic-predominant age-related TDP-43 encephalopathy, PART, or primary age-related tauopathy, and hippocampal sclerosis,” he said.
WITH GREATER CHEMICAL PRECISION, WE’RE REALIZING WE WERE LUMPING TOGETHER PEOPLE WHO HAD DIFFERENT PROTEINS IN THEIR BRAIN CAUSING THEIR COGNITIVE IMPAIRMENT.
Until very recently, however, this knowledge, “wouldn’t have made a difference to your treatment,” Chertkow noted. (Arguably, however, early diagnosis could nonetheless offer valuable time to find support, and plan for future care.)
GOING BEYOND SYMPTOMS
The landscape is changing, however, with the arrival of the first “disease-modifying” drugs for AD. Unlike older AD drugs, which can only manage symptoms, the newer generation drugs use specific antibodies that can remove amyloid from the brain.
By January 2023, the U.S. FDA had approved two anti-amyloid drugs specifically for patients with mild or early dementia; however, they’re not yet available in Canada.
But there has been an update on this front. Biogen, the co-developer of both of these drugs, announced in late January 2024 that they were halting the development and commercialization of one of them: Aduhelm (aducanumab).
The company said in a press release that they made this decision to free up more resources for the other medication, Leqembi (lecanemab), and to develop different AD treatments, not because of safety or efficacy concerns with Aduhelm.
Despite the fact these anti-amyloid medications only modestly slow memory and thinking decline in people with early AD, they represent a significant turning point, because it is now possible to narrow down who they could potentially help.
“If the patient does not have Alzheimer’s disease, these drugs pose a risk of complications without any benefit,” Dr. Munoz said. “On the other hand, if you fail to make the diagnosis, then the individual misses the opportunity,” to benefit from treatment.
Given their limited benefit and significant cost – approximately US$26,000 to US$28,000 – these anti-amyloid drugs may not have an enormous impact in themselves.
What’s most promising about them is that with tests like CSF, it’s now possible to objectively measure their effects, which could prove particularly valuable in clinical trials in the future, not just of candidate drugs but non-drug therapies, too.
“These things are going to help us find out which interventions, or combinations of interventions, are helpful and start to align these lifestyle interventions with (how they are) modifying the underlying biochemistry,” said Dr. Borrie.
Similar advances may be on the horizon for other forms of dementia. For example, “we are starting to see publications of new biomarkers for Lewy body disease,” Dr. Borrie said. While there are no treatments for LATE as yet, “they’re just figuring out a blood test for that,” noted Dr. Chertkow.
“For people with just a tauopathy, there are experimental treatments against tau,” he said. “We’re transitioning into a time over the next ten to 15 years where we’ll have potentially disease-modifying drugs targeting these different proteins. Then it will make a big difference, with people being diagnosed at this level of precision.”
THE REAL GAME-CHANGER WILL BE BLOOD TESTS, WHICH HAVE NOT ARRIVED IN CANADA OUTSIDE OF RESEARCH.
Dr. Chertkow continued, “It’s predicted that within two to three years, blood tests will be available in Canada” for AD. Even now, “blood biomarkers in research are redefining the diagnosis of underlying Alzheimer’s disease in people with mild symptoms, or even those with no symptoms but a strong family history who are at risk of dementia in the future,” Dr. Borrie said. “The blood biomarkers will also be important for following treatment.”
HOW MACHINE LEARNING & LIFESTYLE CHANGES CAN HELP
According to Dr. Borrie, another area of research that holds promise for early detection of mild cognitive impairment and dementia is machine learning. A project at Baycrest that offers a free, evidence-based brain health assessment called Cogniciti “has about 130,000 people who have taken the test,” he said.
“If you get repeated measures over time, you can analyze many data points and possibly see subtle changes and patterns of different trajectories.” In the meantime, other research findings point to immediate steps people can take to improve their brain function and stave off or at least slow cognitive decline.
For example, “a study came out from Finland in 2015 that had people with two or more risk factors for cognitive impairment and randomized them to the treatment arm – which was exercise, mental stimulation, control of vascular risk factors, and dietary education – versus just giving people advice,” said Dr. Borrie.
“Both groups improved, but the people who got the more intensive program did better.” For instance, compared to the control group, participants in the intervention arm saw a 40% greater improvement on complex memory tasks and 83% greater improvement on tests of executive function (complex planning and thinking skills).
The results of this trial, dubbed FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability), were first published in The Lancet in March 2015.
There’s even evidence that this kind of intervention can bolster brain function. “Dr. Montero-Odasso, a geriatrician in our division who runs the Gait and Brain Lab, recently published results from the SYNERGIC Study, where they’ve shown people with mild cognitive impairment can improve their cognitive performance using exercise and mental stimulation,” Dr. Borrie said. (The study appeared in the July 2023 issue of JAMA Network Open.) “That’s really powerful – as powerful as any drug option.”
People can be doing things that might alter the trajectory of decline.
The measures may seem familiar – the same factors are linked with a reduced risk of developing dementia. Regular exercise appears to be the most powerful, said Dr. Munoz, “probably because it maintains the health of blood vessels.” Poor blood vessel health can lead to damage that can cause vascular dementia, which commonly overlaps with and can accelerate the progress of AD.
Other non-drug strategies Dr. Borrie recommends include eating a Mediterranean-style diet, staying socially active, engaging in mentally stimulating activities, restorative sleep, “and alcohol reduction or cessation,” he said. “Anything above two standard drinks per week increases the risk of all kinds of different conditions.”
Maximizing managing other vascular risk factors is also crucial, he added. This includes smoking cessation as well as recognizing and treating medical conditions, such as “hypertension, hyperlipidemia, diabetes, and atrial fibrillation,” Dr. Borrie said.
Detecting such treatable risk factors is one reason to see your doctor if you notice changes in your memory that affect your daily functioning, such as impaired work performance, “forgetting meetings, forgetting codes, or not being able to remember seven digits at a time,” Dr. Borrie said.
A CHECK-IN WITH YOUR DOCTOR ALSO PRESENTS THE OPPORTUNITY TO PICK UP AND ADDRESS OTHER POTENTIALLY REVERSIBLE CONDITIONS THAT CAN CAUSE DEMENTIA-LIKE SYMPTOMS.
“Some people dismiss memory impairment because they think it’s part of normal aging,” said Dr. Borrie. (And indeed, according to the “World Alzheimer Report 2021,” in high-income countries like Canada, an estimated 60% of people with dementia are undiagnosed.) He urges people to take potential warning signs seriously. “Try to get a diagnosis earlier, and address those risk factors that need attention.”