A Blood Test for Alzheimer’s Disease? Breakthroughs and Limitations

Recently, researchers at Washington University, St. Louis made a significant breakthrough in developing a blood test for early indications of Alzheimer’s disease. But what exactly is Alzheimer’s disease, how prevalent is it, and why do we seem to be so far away from a treatment or cure? In this post, I provide an overview of the disease, describe why this blood test is important and mention a few caveats for interpreting the result.

What is Alzheimer’s disease?

Researchers and clinicians define dementia as a cognitive decline that starts mild, but ultimately progresses in severity until the person can no longer operate independently. Alzheimer’s disease is the leading cause of dementia, accounting for 50%–75% of cases³. What distinguishes it from other forms of dementia is what happens in the brain to cause cognitive decline. Essentially, patients with Alzheimer’s disease have two particular features: amyloid-ß “plaques,” and tau “tangles.” The plaques accumulate outside the neurons, affecting neuron-to-neuron communication. The tangles accumulate inside the cells, blocking transport of essential nutrients and molecules within the cell. Both ultimately lead to neuron death.

A remarkable property about the brain is that its neural communication is highly redundant — often, not one but many cells and many pathways are thought to simultaneously represent similar information. In addition, the brain often represents the same information with multiple “addresses” — for example, you might remember a person by the way you met, the last thing you spoke about, the person’s name, their height, their hair color, etc. With so many pathways, and redundant representations of the same information, most people can manage fairly well even when they lose some neurons. But eventually, as the disease progresses, neural loss becomes increasingly impossible to overcome.

While amyloid-ß plaques and tau tangles are hallmark features of Alzheimer’s disease, it is important to note that the picture is not simple. For example, the presence of amyloid-ß alone is not sufficient to cause Alzheimer’s disease³. There are also individuals who are cognitively normal despite exhibiting plaques or tangles. These findings call for a nuanced perspective, where Alzheimer’s disease is part of a continuum, rather than a specific set of clinical features. In addition, amyloid-ß and tau are not the only key players in Alzheimer’s disease pathology. Microglia, cells that are part of the brain’s immune response, are another. These cells initially act in a helpful way to clear amyloid-ß, but they switch to an aggressive state later in the disease and start promoting inflammation, which, in turn, kills neurons.

How prevalent is Alzheimer’s disease?

Roughly 5.5 million people in the U.S. have Alzheimer’s disease, and about 44 million people live with dementia worldwide³. Standing behind these already staggering numbers are the countless hours of care devoted to those with Alzheimer’s disease, as well as a significant health care expense — in 2016, the cost of care for persons 65 and above with Alzheimer’s disease was estimated at $236 billion¹. The prevalence of Alzheimer’s disease increases with age — roughly 1 in 9 people age 65 and older have Alzheimer’s disease, while roughly 1 in 3 people age 85 and older have the disease¹. As the global population gets older, the number of people with Alzheimer’s disease is expected to triple by 2050³, with a commensurate toll on care.

These numbers explain why most people know someone who has had experience with dementia or Alzheimer’s disease. As such a significant public health issue, there has been a substantial effort on behalf of research institutions to better understand the disease, and on behalf of pharmaceutical companies to come up with treatments or preventive care options. Yet, at present there are no cures to the disease, and treatment options lead to modest improvements at best.

What have been the main challenges to developing treatments for Alzheimer’s disease?

There is particular interest in developing treatments for patients at the earliest stages of Alzheimer’s disease to stop the progressive decline in its tracks. But getting an accurate diagnosis of Alzheimer’s disease is challenging, especially in the early stages. As many as 40% of patients with mild cognitive impairment will not develop Alzheimer’s disease. Some clinical trials have failed in the past because the recruits ultimately did not have Alzheimer’s disease pathology. Moreover, tau and amyloid-ß deposits may begin well before any cognitive impairment. Thus, a significant challenge to developing appropriate treatments has been an inability to diagnose sufficient recruits accurately at an early stage of the disease.

Evaluating the presence of amyloid-ß plaques has largely been done by PET scans, yet these are expensive — for pharmaceutical company research and development teams and for patients interested in the diagnostic. MRI may be used to track the progression of disease with respect to neural loss, but again, will be most powerful in late stages of the disease. Researchers at The Johns Hopkins University have been involved in developing imaging scans for tau, but this technology is still relatively new. The best option up until recently was to look for tau and amyloid-ß in cerebrospinal fluid (CSF) — the fluid that floats around the brain and spinal cord. This fluid is accessible via lumbar puncture, and since it floats around the brain, is a good indicator of processes occurring in the brain itself. Blood tests have been called the “holy grail” of tests that could be performed to screen for Alzheimer’s disease, but until recently, sufficiently sensitive blood tests had not been developed.

Until participants are accurately and successfully recruited for clinical trials, not only will it be impossible for drug development to move forward, but even more fundamentally, it will be impossible to discern why clinical trials failed. Without this knowledge, clinical trials cannot help scientists improve their hypotheses about the underlying causes of the disease.

What is the recent breakthrough?

Researchers at Washington University, St. Louis developed a blood test to predict the accumulation of amyloid-ß in the brain⁴. Amyloid-ß comes in two varieties: one “sticky” and one soluble. The idea behind the blood test is that if there is less “sticky” amyloid-ß in the blood, then there is probably more of it in the brain². The research group tested 158 volunteers in their 60s and 70s. The blood test results were compared with PET scans of participants looking for ß-amyloid. In general, the blood test could predict the presence of amyloid-ß in the PET scan with 88% accuracy. Crucially, if the subject’s age and genetic predisposition to Alzheimer’s disease were known, the accuracy of the blood test improved to 94%. And, in cases where the blood test predicted the presence of amyloid-ß that was not confirmed by PET scans, those subjects had a fifteenfold increased risk for an amyloid-positive PET scan later, suggesting that the blood test might be more sensitive than PET scans.

This breakthrough is significant for identifying candidates for testing pharmaceutical interventions. With a blood test, large groups of potential candidates can be screened rapidly and at reasonable cost. Only those with a positive result from the blood test would move on to receiving a PET scan to confirm.

What are the caveats?

Although this blood test provides new ways to test for amyloid-ß accumulation in the brain, it’s important to remember that amyloid-ß accumulation alone is not sufficient to cause Alzheimer’s disease. So this blood test, on its own, is not a test for Alzheimer’s disease. A preclinical Alzheimer’s disease diagnosis would additionally require clinical levels of tau³, while a full Alzheimer’s disease diagnosis would require cognitive symptoms as well. In addition, participants in the Washington University, St. Louis study were generally not cognitively impaired, so more work is needed to determine how useful this blood test is for persons who already exhibit Alzheimer’s disease symptoms. In particular, the accumulation of amyloid-ß is thought to plateau once symptoms manifest, while tau pathology is thought to more closely track disease severity after symptoms manifest³. Moreover, so far this blood test has not been shown to be able to predict the development of cognitive impairment; it has only been shown to predict the presence of amyloid-ß accumulation, which, alone, is not a reliable predictor of subsequent cognitive decline. Therefore, pharmaceutical companies looking to use this blood test to identify potential participants for clinical trials should still combine this test with other measures, like CSF screening for tau^5,6. This will not only be necessary to recruit participants who are most likely to develop Alzheimer’s disease, but will also be important for developing drugs that target something more, or besides, amyloid-ß.

In all, more work needs to be done. Nevertheless, the ability to prescreen for amyloid-ß at a fraction of the cost of a PET scan is a significant step forward for pharmaceutical research. Hopefully, by helping pharmaceutical companies to more rapidly and accurately screen a larger population of possible participants for clinical trials, this tool will help accelerate drug research and development to prevent Alzheimer’s disease going forward.

Author’s note: Much of my understanding of this topic developed from watching Marilyn Albert, professor of neurology and director of the Johns Hopkins University Alzheimer’s Disease Research Center, speak about the disease in 2016. Watch Dr. Marilyn Albert speak about Alzheimer’s disease in 2016.

Further reading: The amyloid hypothesis on trial, Nature Outlook

References

2016 Alzheimer's disease facts and figures. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 12, Issue 4, 459 - 509
Bendlin, B.B., and Zetterberg, H. (2019). Screening with a high precision blood-based assay for Alzheimer disease. Neurology 10.1212/WNL.0000000000008080.
Lane, C.A., Hardy, J., and Schott, J.M. (2018). Alzheimer’s disease. European Journal of Neurology 25, 59–70.
Schindler, S.E., Bollinger, J.G., Ovod, V., Mawuenyega, K.G., Li, Y., Gordon, B.A., Holtzman, D.M., Morris, J.C., Benzinger, T.L.S., Xiong, C., et al. (2019). High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology 10.1212/WNL.0000000000008081.
Moghekar, A., Li, S., Lu, Y., Li, M., Wang, M.-C., Albert, M., O’Brien, R., and BIOCARD Research Team (2013). CSF biomarker changes precede symptom onset of mild cognitive impairment. Neurology 81, 1753–1758.
Pettigrew, C., Soldan, A., Moghekar, A., Wang, M.-C., Gross, A.L., O’Brien, R., and Albert, M. (2015). Relationship between cerebrospinal fluid biomarkers of Alzheimer’s disease and cognition in cognitively normal older adults. Neuropsychologia 78, 63–72.
Makin, S. (2018). The amyloid hypothesis on trial. Nature 559, S4–S7.