Testing for Early Diagnosis of Alzheimer’s Disease - Episode 7
Alireza Atri, MD, PhD, concludes with a discussion on how different testing methods impact the care of patients with AD.
Alireza Atri, MD, PhD: Timely detection, early and accurate diagnosis, and an appropriate disclosure is the very first tenet of appropriate best care for anybody who has a cognitive complaint. If you have a change and it can be shown objectively, it may be in the office through standard cognitive testing and brief tests, or it may require something more like neuropsychological evaluation, which I endorse for individuals in the mild to moderate stages to delineate the nature of the symptoms, the patterns, and the staging. No matter what that is, the underlying cause, causes, or contributors, we compare those one by one. It’s not mutually exclusive that an individual who may have Alzheimer changes in the brain could also have sleep apnea, B12 deficiency, thyroid deficiency, or may be on a medication that’s deleterious. Each component of these can be managed. It’s important that individuals have timely detection. That’s the first step to care. Detection and diagnosis denied are really care and justice denied.
We’re in a new era, because at least with biomarkers at our disposal now, we can show the diagnosis of Alzheimer disease [AD]. I can see a future with more options. We have PET [positron emission tomography] scans and spinal fluid, which are very important, but not everybody can have those. For example, if you’re on an anticoagulant, have had back surgery, or have difficult anatomy, that may not be an option. A PET scan may be an option. There are some cost and coverage considerations for those.
Ultimately, we’re coming to an era where we’re going to have blood [tests]. There already are some tests. There’s 1 available clinically, but it isn’t used much because some of these still have to be validated for us for clinical use. There are some tests available for the amyloid beta 42/40 ratio, and those kinds of things have been shown to correlate quite well with spinal fluid, abnormal AD levels, and amyloid plaque burden on PET scans. Those are highly correlated with neuropathological changes from autopsy studies. But as you get further away and you get to the blood, the area of the curve, the accuracy, sensitivity, specificity, and positive/negative predictive values are different. They’re not perfect by any means.
There are blood tests for amyloid, but in research, we also have phospho-tau [ptau]. There are different tests for abnormal forms of ptau that are being used, and they’re in some ways downstream but show a component of Alzheimer disease. You can get the A or you can get the T, and if you have the T, which is abnormal ptau ratios in blood in these research tests or in the spinal fluid, those correlate highly with advanced levels of Braak staging and nerve neurofibrillary tangles in the brain, stages 4, 5, and 6.
We’re not there yet, because the blood has to be validated, but I can see a future where individuals come in when they have a complaint, go through the algorithm, get their phenotype delineated, look at the patterns of where their vulnerabilities and strengths are, and we take care and manage all the things that we can. We mitigate cognitive decline, sleep apnea, excessive alcohol use, comorbid conditions, low thyroid, low B12, etc. We buff those things up and then include a diagnosis of Alzheimer disease, first by the blood as a screening, and then possibly confirmatory with other things like spinal fluid or PET scans. I can see a future where this is going to be very important for induction of therapy, monitoring therapy, and whether you get amyloid drugs. Aducanumab is the first in some ways; it’s the tip of the spear for others coming along. We don’t know. Do we do induction therapy? Do we reduce amyloid levels to normal levels? And for how long before we can then show effects on ptau and then down the line on cognition?
Evidence is accumulating every day; some of it was presented at CTAD [Clinical Trials on Alzheimer’s Disease conference] in Boston in November, including with aducanumab. We saw that as you’re lowering and removing amyloid from the brain, the blood level markers were highly correlated with the amyloid PET scans, and then there was a correlation between amyloid removal and ptau levels downstream. By removing amyloid, you’re affecting tau downstream, which biologically makes sense in the model. And then there were small but significant correlations with changing tau, with the individuals who had their ptau change in the right directions, having shown more benefit in cognitive and other measures.
We have a long way to go to tweak these with our different biomarkers, but I’m excited for the years to come to validate these, how we can do it, and change management and dosing based on these blood biomarkers. Because you can imagine that you can give the drug and remove amyloid, and you might not have to give the drug for a while. Who knows? We don’t know. How long do they have to be negative? And then in the future, what other drugs can we add? Because we know amyloid isn’t the only factor. How can we have an effect on tau, on inflammation? We have drugs that work on symptoms and don’t stop working, it’s just the degree that the disease progresses. That’s also part of appropriate management.
We have a lot to learn, but it’s an exciting era for us on the biomarker side and having these first-in-class drugs like aducanumab, with hopefully others to follow that we’re going to learn from. Hopefully we’ll look back in 20 or 25 years and think about how this was an era where we started affecting the pathophysiology of Alzheimer disease, moving this disease from something that has been brewing in the brain for 20 or 25 years to something that’s much more manageable.
This transcript has been edited for clarity.