New blood tests are set to change the way diagnose and treat dementia.
The month of June was a momentous milestone in the fight against Alzheimer’s disease. Regardless of your stance on the conditional approval of Aducanumab by the Food & Drug Administration, we clearly have the ability to reverse the pathology thought to be the major instigator in the devastating effects of Alzheimer’s. If administered at the right moment, to the correct individuals, there is real optimism that we are edging closer to a solution for a disorder that affects millions worldwide.
The “right moment” and “correct individuals” is seemingly an obvious statement to make but it is a complex and relevant question in dementias like Alzheimer’s disease.
We now know that Alzheimer’s disease has a “silent phase”, a period of time when the harmful pathology is developing in the brain but the symptom onset can be more than 10 years away. Thus, the “right moment” would be in this silent phase, before symptoms appear and pathology is developing and could cleared without causing long-term damage. However, trialling a drug in those with no symptoms and waiting to see if they develop Alzheimer’s, or not, has many financial and ethical complications. The majority of trials in Alzheimer’s have therefore been in the later phases of the disorder and has only shown minimal benefit but has established target engagement (e.g., cleared harmful pathology from the brain).
Next, the “correct individuals”. Drug trials like Aducanumab specifically target a protein called amyloid-β and not all dementias are caused by amyloid-β (e.g., Frontotemporal dementia, Lewy Body dementia or Vascular Dementia). In fact, a proportion of patients diagnosed with Alzheimer’s by specialists do not have amyloid-β simply because the clinician cannot observe the brain pathology, and only have a detailed account of symptoms from the patient and carer to guide their decision. Therefore, it is of paramount importance that we find people with the right pathology and early as possible for these drugs to be the most effective.
As I mentioned, this “right place at the right time” approach is very difficult when you cannot biopsy the diseased organ (the brain) of a patient and even more difficult if individuals are not experiencing any symptoms — thus, are not voluntarily walking into GP clinics complaining of memory problems. In the last two decades, we have developed extremely accurate tests to monitor the brain using molecular brain imaging and lumbar puncture examinations. These inform us, with very high confidence, if amyloid-β pathology is present in someone’s brain. However, these tests are not trivial and it is hard to envisage these being widely used for the general population to screen for dementia due to the cost and the specialism that it requires.
A biological marker (biomarker) in the blood is the only way to engage a large enough population, sometimes those without symptoms, so that the correct people are recruited into these trials and, in the future, are prescribed the correct treatment for maximum benefit. We have to be realistic though, a blood test is not going to be 100% accurate. Blood is a complex matrix, receiving information from all organs in the body, not just the brain, but these tests will act as a triage to highlight potential issues which can be confirmed with more advanced techniques.
The development of blood tests for dementia is a real neuroscience success story — progressing rapidly from academic curiosity to clinical utility. I often think back to standing in a half-empty room — mostly made up of supportive colleagues — at a late session of the 2014 Alzheimer’s Association International Conference, describing the potential of relationships between blood proteins with clinical symptoms in patients with dementia. Never did I think medical science could evolve so quickly — where a blood test for Alzheimer’s disease is no longer described as being “on the horizon” or “just not possible” by the majority but is now on the verge of widespread clinical routine in Europe. However, these early efforts I was describing in 2014 generated enthusiastic interest and persuaded a large research study to include standardised blood collections in their protocols. Now, it has certainly paid off. But, 2014 was not the start of this process.
My mentors and PhD supervisors at the time, Dr. Abdul Hye and Professor Simon Lovestone, had already hinted that a blood biomarker could be a realistic possibility in a series of publications between 2006–2010. They described that proteins linked to biological processes like immune response are changed in the blood of Alzheimer’s disease patients. Importantly, these proteins are closely linked to Alzheimer’s pathology found at post-mortem and were later found to be genetic risk factors for Alzheimer’s. Although these reported blood tests did not have the required accuracy needed to be clinically relevant, they generated the necessary interest that propelled this area of neuroscience to where it is now.
So, what has changed in such a short time? Well, certainly the intended targets have not. The “new” generation of blood biomarkers we talk about today are the classical candidates we have known about for many decades in the brains and cerebrospinal fluid (CSF) of Alzheimer’s disease patients. I believe there are three fundamental changes responsible for this rapid development of a blood test for Alzheimer’s.
Firstly, we have recently begun to change the way we think about Alzheimer’s disease. In 2018, the National Institute on Ageing and Alzheimer’s Association (NIA-AA) defined Alzheimer’s disease as a biological construct — simply meaning, you must have evidence of Alzheimer’s disease biology in the brain related to the observed cognitive symptoms for the disease to be called “Alzheimer’s”.
Secondly, there are now large well-characterised research cohorts (e.g., Swedish BioFINDER, the Alzheimer’s Disease Neuroimaging Initiative and Translational Biomarkers in Aging and Dementia, to name but a few) which have scrupulous details about their participants' biology, e.g., molecular imaging for tau and amyloid in the brain. These large studies gave us the best chance to see if our blood tests really reflect brain pathology.
Lastly, our technology. These proteins exist at super-small concentrations in the blood — femtomolar: one millionth of a billionth! Previously we could only detect them in extreme cases. Owing to these advancements we can detect these proteins in all people, of any age.
So, what are the next steps? Well, a blood test for neurofilament (NfL), a protein indicative for non-specific brain injury, has crucially been implemented into clinical routine in Sweden, and can now be requested by clinicians all around the country — other countries will rapidly follow suit. Blood NfL is also being used as a primary end-point in drug trials for multiple sclerosis and likely other disorders in the future. This blood test has wide implications for many disorders e.g., motor neurone disease, frontotemporal dementia and depression, as we have just reported in an article in Nature Communications. Importantly, it also works to identify dementia in people with Down’s syndrome, where wide varying intellectual ability can mask or confuse subtle cognitive changes — the NfL blood test is extremely useful in this context.
A specific blood test for Alzheimer’s disease, p-tau, has also received a lot of attention in the last 18 months, with some high-profile publications in the Lancet, Nature and JAMA (Karikari TK et al; Janelidze S et al; Thijssen EH et al; Palmqvist S et al). Already, international efforts are underway to validate these p-tau blood tests for clinical use with the field unanimously convinced of their value to the clinical examination of dementia patients and the potential benefit to aid therapeutic trials.
For those suffering with dementia, or caring for someone with dementia, an important question is always — is this Alzheimer’s disease or something else? Accurately knowing your diagnosis is often an important step to facing the years ahead for all concerned. It is also fundamentally important for the clinician to accurately prescribe symptomatic treatment.
The new blood tests are a necessary tool to rapidly get an accurate diagnosis — in a way we haven’t been able to do before. More optimistically, while we now have one approved disease-modifying drug available, more will certainly follow, and we already have the tools available to ensure that these drugs are given to the correct people without delay.
