Your dad has started losing his car keys, forgetting important dates, and, even more alarming, getting lost on the way to the grocery store. You’re thinking, “Is it Alzheimer’s?” Maybe it’s time for a trip to the doctor’s office. Unfortunately, that trip may prove frustrating because diagnosing Alzheimer’s disease (AD) isn’t straightforward. First, cognitive decline in general, and dementia more specifically, have many possible causes. Second, there’s no one test for AD. That’s increasingly a problem. About five million people in the US now suffer from AD. As of 2023, more than 6.7 million Americans age 65 and older are living with AD. If the current trends continue and barring any significant medical breakthroughs, by 2050, the number of Americans age 65 and older with AD is projected to rise to nearly 12.7 million (Alzheimer’s Association). This condition poses a profound public health threat and a formidable challenge to biopharma companies. Previously we looked at AD’s underlying pathologies and explored the latest pharmaceutical interventions. Let’s turn to the other half of the battle against this painful condition: creating accurate, minimally-invasive diagnostics. Who knows, maybe one day, a simple blood test or retinal scan will reveal the presence of AD soon enough for early intervention. 

Back to the doctor’s office. If the doctor suspects AD, she may assess your dad’s cognitive function or check his reflexes. If he performs poorly, the doctor must rule out other possible causes, such as a vitamin B-12 deficiency, depression, or stroke. She may order brain imaging to check for abnormalities such as high levels of amyloid-beta protein, a hallmark of AD. However, brain imaging is pricey. Further, most insurance plans won’t reimburse them because current AD treatments don’t differ from those for other types of dementia. Patients sometimes qualify for a spinal tap to detect tau or amyloid-beta proteins in their blood, which can indicate AD. But no one wants a spinal tap. These tests may provide helpful information. Unfortunately, the only way to truly diagnose AD is by autopsy.

The need to develop accurate, minimally-invasive diagnostics is clear. Better tests will, in turn, support improved clinical testing of potential drugs as identifying patients becomes easier. Recognizing the need for better AD diagnostics, the Alzheimer’s Drug Discovery Foundation (New York, NY) launched a Diagnostics Accelerator in July 2018. With backing from the Gates Foundation (Seattle, WA) and other philanthropic donors, they so far have committed $100 million to funding research at the cutting edge of AD diagnostics development. The foundation has developed a test for microRNA biomarkers in blood plasma that can predict who will progress from mild cognitive impairment to Alzheimer’s disease from DiamiR (New Jersey). The foundation is also working on a retinal test and digital technology as diagnostic tools for AD. Here’s an overview of some of the research they are funding. 

AD has long been associated with the abnormal buildup of two neurological proteins: amyloid-beta plaques (Aβ) and tau. Damaged neurons release a third, called neurofilament. It may also be an early indicator of AD if it appears with the others. Several research groups are developing blood tests for these proteins. They’re validating the tests by comparing samples from cognitively normal and AD patients of the same age and correlating them with brain scans. 

• The University of Gothenburg (Sweden) is a hotbed of research into next-generation protein-based AD diagnostics. Drs. Kaj Blennow and Henrik Zetterberg’s work led to the use of spinal taps to detect AD-associated proteins. Now, teams in their labs are developing and validating similar tests from blood samples. Dr. Zetterberg’s lab is partnering with Roche Diagnostics (Rotkreuz, Switzerland) on a test to detect Aβ40 and Aβ42 protein fragments. When present in high amounts, these proteins cluster to form amyloid plaques. The Gothenburg researchers are also looking into spotting these proteins in saliva. A novel blood test for AD has been developed by researchers at the University of Gothenburg. This novel test quantifies a particular tau protein variant, specifically the P-tau181 variant, in routine blood samples. The Single Molecule Array (Simoa) testing method is well-known for its ultra-sensitivity, which enables it to identify far lower protein biomarker levels than other techniques.
• Eisai (Tokyo, Japan) is also developing blood tests for Aβ40 and Aβ42. In particular, its researchers are looking at the ratio of the two proteins. They suspect that reduced levels of Aβ42 may indicate early AD. Eisai and Biogen jointly developed a humanized monoclonal antibody, Lecanemab (Leqembi), that reduced cognitive decline. The drug was approved by FDA in July 2023.
• Randy Bateman at Washington University (St. Louis, MO) is also leading studies examining ratios between these two proteins as an early AD marker. In one study, some patients were initially classified as false positives based on comparing blood tests and brain imaging results. The blood test suggested they had AD; the brain image said they didn’t. Four years later, repeated brain imaging studies showed signs of Aβ plaques, suggesting the blood test may detect AD in its early stages— potentially a big boon to treating the disease. Another study conducted up to 2020 by Frank de Wolf and colleagues concluded that plasma biomarkers, including total-tau, neurofilament light chain (NfL), and amyloid-β, are becoming instrumental in defining and staging Alzheimer’s disease. A notable finding is that a higher baseline plasma NfL level is associated with a higher risk of developing Alzheimer’s disease.
• The University of California, San Diego neuroscientist Doug Galasko is collaborating with ADX Neurosciences (Ghent, Belgium) on a blood test to identify low concentrations of the tau and neurofilament proteins.

Washington University researcher Dr. Laura Ibanez has identified 25 different types of protein-coding mRNA associated with an increased risk of AD. She’s now working to see if a blood test that analyzes these RNA molecules can predict the disease’s onset.

Another kind of RNA—microRNA—forms the basis of two blood tests now developed by Amoneta Diagnostics (Huningue, France) and DiamiR Biosciences (Monmouth Junction, NJ). These detect differences in specific microRNA levels in people with AD.

The retina connects directly to the brain via the optic nerve. Thus, it potentially serves as a sort of window into the brain. At Australia’s Center for Eye Research (CERA; Melbourne), researchers zoom in on an eye scan to diagnose AD early. Developed in Dr. Peter van Wijngaarden’s lab, the test detects amyloid-beta deposits in the retina of healthy adults. It’s being developed for people with a family history of AD. One day it may replace costly brain imaging studies. Dr. Tom MacGillivray at the University of Edinburgh and the medical imaging company RetiSpec (Toronto, CA) are conducting similar research.

The range of basic science researchers and biopharma companies working on minimally invasive, less expensive tests for AD provides hope that one day soon, people at risk for or in the early stages of AD can more easily be identified. This should help with more efficient drug discovery for AD and, ultimately, a way to treat patients before the disease progresses.

The fight against Alzheimer’s disease is not just about treating its symptoms but also about diagnosing it early and accurately. From the lab benches in Gothenburg to the examination rooms in Tokyo, scientists and clinicians are making profound strides in understanding this debilitating condition. The diagnostic landscape is expanding, with promising breakthroughs on the horizon – from blood tests that detect minuscule protein levels to retinal scans that might one day replace expensive and invasive brain imaging techniques. This intensive research paints a hopeful picture for the future, one where Alzheimer’s can be detected early, offering a better chance for timely interventions and, perhaps, even prevention. As our understanding deepens and our diagnostic tools become more precise, the potential to change millions of lives becomes ever more palpable. In the end, the ultimate victory against Alzheimer’s may lie not just in treating it but in catching it before it ever takes hold.

1. IS ALZHEIMER’S DISEASE EASILY DIAGNOSABLE CURRENTLY?

No, diagnosing Alzheimer’s Disease isn’t straightforward. Currently, it requires a range of tests, and the only definitive diagnosis can be made posthumously through autopsy.

2. WHY IS THERE A PRESSING NEED FOR BETTER DIAGNOSTIC TOOLS FOR ALZHEIMER’S DISEASE?

With the number of individuals who have Alzheimer’s projected to rise significantly, it is essential to have minimally-invasive, accurate diagnostic tools. Early detection can lead to timely interventions, slowing down the disease’s progression.

3. WHAT PROMISING ADVANCEMENTS HAVE BEEN MADE IN THE FIELD OF AD DIAGNOSTICS?

There have been significant strides in blood tests for neurological proteins associated with AD, detecting protein-coding mRNA associated with AD, and retinal scans, which might serve as windows to the brain. These approaches offer hope for easier and earlier detection.

4. WHO ARE SOME OF THE KEY PLAYERS IN AD DIAGNOSTIC RESEARCH?

Multiple entities are at the forefront, including the University of Gothenburg, Eisai, Washington University, University of California, Amoneta Diagnostics, DiamiR Biosciences, and the Center for Eye Research in Australia.

5. HOW DO RETINAL SCANS FIT INTO THE FUTURE OF AD DIAGNOSTICS?

The retina, being directly connected to the brain, potentially serves as a window to detect early signs of AD. Tests are being developed to identify amyloid-beta deposits in the retina, which may one day replace the need for costly brain imaging for AD diagnosis.