What are the biomarkers of Alzheimer’s really telling us?

From pandemics to wildfires, the past few years have given us all too much to think about. Add doom-scrolling and automatic refreshing and flicking between screens – no wonder many of us are distracted, or even forgetful. What’s the difference between this, and mild cognitive impairment presaging the ultimately fatal cognitive decline of Alzheimer’s disease?

Until recently, there was no way to say for sure if you were on the way to AD until someone had a peek at your cold, dead brain.

And until 2011, if you weren’t dead yet, Alzheimer’s was diagnosed suggestively, by accumulating cognitive tests; brain imaging, urine, cerebrospinal fluid and blood tests; asking the patient and family their perceptions of decline; clinician observation and excluding other possibilities.

But over the years, scientists have learned more about what physical markers – “biomarkers” – are associated with (though not yet proven causal of) Alzheimer’s. For example, people who go on to develop it have been found to have clumps of a protein called beta-amyloid in their brains. Such signs, it turns out, may precede by years – even decades – symptoms of major cognitive decline. Others may have such amyloid plaques but never end up suffering advanced Alzheimer’s. For years scientists have studied this association, hoping that by clearing these amyloid plaques from the brain, we might ultimately prevent the disease.

A new study published in Vascular Pharmacology in August looks at the relationship between beta-amyloid and age-related diseases beyond just Alzheimer’s. Dysfunction in amyloid, it seems, is linked to impaired action of blood vessels and their linings, to inflammation and to oxidative stress. While something is clearly going awry in the Alzheimer’s brain and with these other conditions, the peptide is involved in many beneficial roles in the body through our lives: regulating synaptic function, contributing to protection against infection and recovery from injury and fixing leaks in the blood-brain barrier.

Although the precise role of amyloid in the process leading to Alzheimer’s dementia is still unknown, amyloid is thus one of the signs now being used since 2011, to divide the disease into three stages.

Only the third of these stages is what most of us think of as Alzheimer’s; the other two phases, pre-clinical and mild cognitive impairment, don’t necessarily lead to the third, dementia, but are nevertheless characterized by the presence of that amyloid buildup and other brain changes seen to a more significant degree in Alzheimer’s dementia.

So in a 2018 research framework developed by the National Institute on Aging (NIA) of the US National Institutes of Health (NIH), authored with the Alzheimer’s Association, Alzheimer’s was re-conceptualized from a collection of symptoms (a syndrome) to an underlying pathological process that can be diagnosed in living people by the presence of one of three types of biomarkers such as amyloid plaques – no symptoms required. But this framework only applied in the context of research.

The Alzheimer’s Association hopes to see this finding sharpened into a new definition for AD in which you can be diagnosed as having the disease years before you show its classic symptoms.

“In 2011 and in 2018, we tried to really say, hey, we’ve come a long way, we can now measure biological changes because a disease that we are now currently calling only the symptomatic manifestation is actually starting decades before,” Dr. Maria Carrillo, chief science officer of the association, explained to Salon in a video interview.

Carrillo compared the change in understanding needed for Alzheimer’s to that which has occurred with cancer, where we can now find precancerous cells and effect cures well before symptoms of cancers previously diagnosed only at, for example, stage four. As cancer has become less of a death sentence in some cases, perhaps AD might also one day be a treatable chronic illness – rather than a sentence of senescence and death.

However, we’re not quite there yet. Indeed, the NIA continues to warn that the amyloid levels blood test, like testing cerebrospinal fluid, should not be used on its own to diagnose dementia or Alzheimer’s. Biomarkers, the NIA states, are not yet a validated clinical concept and should only be used diagnostically in research settings, although they may contribute to the clinical picture used for diagnosis. 

Even among those who develop plaques, some show cognitive resilience – ability to function normally despite such pathologies of the Alzheimer brain, probably thanks to complex brain connections as a result of a mentally active lifestyle, social connections and education. This could be the case with other biomarkers as well.

The authors of the 2018 research framework even wrote: “We appreciate the concern that this biomarker-based research framework has the potential to be misused.”

Jolien Schaeverbeke, a senior scientist and postdoctoral research fellow at the Laboratory for Cognitive Neurology & Laboratory of Neuropathology in Belgium, told Salon in a video interview that even though the process leading to Alzheimer’s dementia may start decades before its perceptible signs, there’s no guarantee you won’t die of something else before showing them. Or of getting them at all.

“We are not sure that a person [with amyloid plaques or other biomarkers] will have clinical symptoms,” says Dr. Schaeverbeke. Even into old age.

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There are thus ethical implications in revealing to patients whether they have AD biomarkers before we are sure they represent an inevitable future case of the advanced disease. And these relate not just to physical outcomes – the risks inherent in aggressively attacking a protein that is in fact necessary to some extent – but psychological ones, too.

Take medical assistance in dying, as modern forms of euthanasia are called in Canada, where existing rules are shortly to be extended to include mental health conditions as a reason for granting access to doctor-assisted death. While a person who finds out they have AD biomarkers might live deeply and fully in response, another individual might become depressed and seek early medical assistance in dying, when in fact they might otherwise have lived a long and happy life, dying of another condition before any serious cognitive decline could strike.

On the other hand, a 2021 review on the bioethics of disclosing pre-clinical biomarkers or genetic risk did find that while short-term worsened cognitive function can result from sudden awareness of risk, in general, more knowledge does not seem to negatively affect those with early Alzheimer’s pathology or gene variants linked to greater risk.

Who else gets to know about biomarkers is perhaps a more worrisome concern. In Belgium, where Dr. Schaeverbeke’s study population lives, she says there’s no risk of being denied health insurance because of a diagnosis of early stage AD. That’s not the case in the United States, where employer-paid or private life, health, or long-term disability insurance could be at risk as a result of early identification of biomarkers.

In some situations, the benefits might outweigh the risks: in a 2017 study on the bioethics of telling research subjects they show biomarkers for AD, Dr. Schaeverbeke and her colleagues found that 100 percent of nearly forty people who contacted a memory clinic wanted to be told their amyloid scan results when given the choice.

Since they were already concerned about their cognitive function, learning the cause of what they already knew was going awry was more a comfort than an additional stress for this group. They believed knowing the results of their scan would also help them make good decisions about, for example, drawing up end-of-life plans, early retirement, or moving to a smaller house.

“Some people, they just said, ‘Okay, we’re going to enjoy life,'” Schaeverbeke said, recalling her interviews with patients. And with about 25 percent of patients with amyloid plaques seen on a PET scan going on to develop Alzheimer’s dementia over the next five years, that may be wise.

But with genetic and environmental influences both at play in ways we don’t yet adequately understand, the risks of going too fast and furious with biomarkers and genetic testing alike are real. What is actually going to happen to you over the coming years, and the extent to which lifestyle changes a worrying biomarker test might spur could protect against eventual clinical symptoms, is still impossible to say.

Dr. Schaeverbeke points out that while one well-known genetic variant, APOE4, is known to increase amyloid deposits and your risk of Alzheimer’s Disease, there is actually another allele that is protective against it.

“Imagine,” she posits, “that your dad gives you APOE4 and your mom gives you E2”.

What if insurers only check for the better-known, risk-increasing allele – or for amyloid plaques, without considering cognitive resilience – and then deny coverage? That’s just one example of why bioethicists – and the public at large – must think carefully about who gets access to information about what might be going on, quietly, inside.