Neil Skolnik, MD
DISCLOSURES | September 10, 2024
This transcript has been edited for clarity.
I’m Dr Neil Skolnik and today I’m going to talk about the Revised criteria for diagnosis and staging of Alzheimer’s disease (AD) from the Alzheimer’s Association Workgroup. This is a big deal that will fundamentally change the way we will be approaching diagnosis and treatment of AD.
Diagnosing Alzheimer’s Disease
Until recently, AD was the diagnosis that remained after we ruled out other causes of dementia with blood tests and imaging. It turns out that we weren’t very accurate at making the diagnosis; in fact, according to a recent paper, we get this diagnosis right only about 60% of the time. This is no longer going to be the case. Moving forward, AD will be ruled in using blood-based biomarkers. When patients come to us concerned about mild cognitive impairment (MCI) or mild dementia, we will be able to tell them whether they have early AD by ordering a simple blood test.
This is becoming more important because we now have two FDA-approved monoclonal antibodies to slow the progression of cognitive impairment in individuals with MCI or mild dementia from AD, and many more medicines are in the pipeline.
AD has three phases: preclinical (which is without symptoms), MCI (the individual has cognitive impairment that doesn’t interfere with daily activities), and dementia (cognitive impairment that interferes with daily activities).
The key principle that this guideline lays out is that AD is defined by biology — neuropathologic changes in the brain (deposition of amyloid and tau protein). Previously, those findings could be seen only during autopsy. Currently, biomarkers for accurate diagnosis are available only by testing cerebrospinal fluid — which requires a lumbar puncture — or by PET scan. Those tests can be invasive and expensive and usually require specialist referral. We are now on the cusp of having blood-based biomarkers that will enable us to diagnose AD with a high degree of accuracy.
Blood-Based Biomarkers
These blood-based tests reflect underlying pathophysiologic changes, but do not tell us anything about symptoms, which are assessed clinically. The tests include :
Amyloid beta 42
Hybrid amyloid beta 42/40
Phosphorylated-tau protein (p-tau)
Calculated ratios of the different tests to yield a validated likelihood of the person having AD
A recent paper in JAMA showed that blood-based biomarkers, using the ratio of two tau proteins and two amyloid proteins, were accurate in identifying AD more than 90% of the time, with positive and negative predictive values both exceeding 90%.
Major labs such as Quest and LabCorp have developed their own blood-based biomarker tests, and patients have started asking about them. Diagnostic accuracy varies among these different assays, but this should improve when regulatory approved biomarker tests become available, which is anticipated to be soon. These biomarker tests are expected to have at least 90% accuracy compared with amyloid PET scanning.
The significance of blood-based tests for results depends on the clinical context in which the test is ordered. These tests are not recommended for use in asymptomatic individuals.
Primary Care Clinical Approach
How does this information change our clinical approach? When patients come to us with a concern about AD, the first step, as always, is determining whether they have cognitive impairment. If they do, then the next step will be blood tests and an MRI. In the past, the goal of blood tests and imaging was to rule out other causes of dementia, including B12 and folate deficiency, hypothyroidism, multi-infarct dementia, and normal pressure hydrocephalus, as well as other causes.
Once these blood-based biomarker tests are regulatory approved, they can be added to the initial panel of laboratory tests typically ordered when working up dementia. If those biomarkers for AD are positive and the patient likely has MCI or mild dementia, they can be referred to neurology to determine whether they are candidates for the new monoclonal antibodies.
This is an enormous conceptual and practical change in our understanding of and our approach to AD, and I suspect that we will be increasingly asked about these new tests by patients and their families.
Leave a Reply