In June, the Alzheimer’s Association controversially revised its diagnostic criteria.

From now on Alzheimer’s disease (AD) “should be defined biologically, not based on a clinical syndrome(s)”.

In other words, a patient’s behaviour, mood and cognitive decline are now irrelevant when diagnosing the most common form of dementia.

In fact, diagnosis can now be done in the absence of any clinical symptoms.

To this end, AD diagnosis should rely solely on the presence of biomarkers, such as amyloid β and tau protein – those plaques and tangles that gum up the brain.

This means that cognitive function tests don’t factor in diagnosing AD, and would no longer be taken into account.

All that’s needed is a sample of cerebral spinal fluid or a blood test revealing the presence of these damaging proteins.

This is a radical shift based on advice from a team of US experts. They effectively challenge the idea of when Alzheimer’s sets in – and even perhaps what is Alzheimer’s.

How? Because the new criteria would diagnose Alzheimer’s with the arrival of these plaques and tangles brain changes well before clinical symptoms appear.

It also considers dementia as the catastrophic end-stage – evidence of damage beyond repair – rather than the main event.

The upside? If AD is a disease with a long symptom-free early stage,  then maybe those symptoms can be permanently delayed.

Imagine that!

You’re functionally healthy but you’re told that you have Alzheimer’s disease, asymptomatic for the moment. But if you live long enough, mild cognitive impairment (MCI) would eventually take hold.

Over time, full-blown dementia would rob you of you.

This has tremendous moral and ethical implications. Are you obliged to tell your boss? Your insurance company?

A global expert panel led by Hôpitaux universitaires de Genève this week published a paper that rejected the new criteria, saying:

“This may lead to a problematic over-diagnosis if this is incorrectly interpreted.”

To counter this, in the Journal of the American Medical Association, they “advocate that clinical signs as well as biomarkers must be taken into account”.

Which is, in fact, the standard way of reaching a clinical diagnosis of Alzheimer’s.

The search for reliable diagnosis

Generally, when you visit the doctor with concerns that you might be developing dementia, it’s because you feel you’re not the person you’ve long trusted yourself to be.

You’ve noticed changes in your memory, thinking, behaviour and mood. They encourage you to have these changes investigated. It’s scary stuff.

For a long time, a diagnosis of dementia, or more specifically, Alzheimer’s disease, was based on a doctor’s judgement, following a review of your medical history, and a series of tests, including for cognitive impairment.

The most common test for cognitive changes due to Alzheimer’s disease is the Standardised Mini-Mental State Examination, (SMMSE) which was first developed in 1975. It takes about five minutes and tests your reading, writing, orientation and short-term memory.  

Nearly, 50 years old, the SMMSE remains a key tool in clinical diagnosis. But there was a problem with this and other standard clinical tests. 

Professor Ralph Martins is Director of Research at Alzheimer’s Research Australia. Martins is Chair in Ageing and Alzheimers Disease at Edith Cowan University, and Professor in Biomedical Sciences at Macquarie University.

He was the first to propose and demonstrate that the Alzheimer brain was under oxidative stress, which is now widely recognised by the Alzheimer research community.

He was also the first to isolate and characterise the molecular components of the neuropathological hallmarks of Alzheimer’s disease.

Martins told The New Daily that because there are overlaps in determining different kinds of pathology, “a probable diagnosis of Alzheimer’s – based solely on clinical assessment – is about 70 per cent accurate”.

“Until recently, that’s been the situation,” he said.

The diagnosis could only be reliably confirmed post-mortem.

The rise of the biomarker

Then, in recent years, several biomarkers for Alzheimer’s disease (AD) were developed, including assays for amyloid β and tau in the cerebral spinal fluid (CSF).

Martins said that these biomarkers lifted diagnostic accuracy for Alzheimer’s from 70 per cent to near 100 per cent.

A 2015 paper, co-authored by Giovanni B Frisoni from the University of Geneva, noted that:

“Clinicians can use biomarkers to diagnose the disease at the mildly symptomatic stage of mild cognitive impairment or even at the completely asymptomatic stage.

“Drug developers can use them in clinical trials as indicators of the ability of drugs to halt or reverse neuro-degeneration and the build-up of what are believed to be the neurotoxic culprits of Alzheimer’s disease (amyloid β and hyper-phosphorylated tau).”

Great stuff. But already, they were a source of argument.

“Alzheimer’s disease biomarkers still stir up great controversy and the debate between enthusiasts and opponents sometimes takes radical tones,” the authors wrote.

Nine years later, the controversy is hotter than ever.

Frisoni is a co-author of the paper published this week that flagged the Alzheimer’s Association’s new diagnostic criteria as problematic.

Where the real trouble lies

As Scientific American noted, in a piece published in August: “Incorporating biomarkers into clinical care was envisioned as a way of reducing that uncertainty in the diagnosis of AD.”

In 2018, researchers sponsored by the Alzheimer’s Association and the National Institute on Ageing (NIA) first proposed that: “Biomarkers didn’t confirm a diagnosis of AD; they were a diagnosis of AD.”

This was more useful for researchers than doctors dealing with flesh and blood people.

Professor Ralph Martins. Photo: Alzheimer’s Research Australia

As the researchers describe it, in the new Alzheimer’s Association criteria:

“The disease is a continuum that begins with the appearance of changes in the brain associated with the disease processes in asymptomatic individuals.”

That is, the plaques and tangles and other brain abnormalities are the disease “which progresses through stages of increasing levels of disease-related brain changes”.

This eventually leads “to the appearance and progression of clinical symptoms”. In other words, the disease has been at work for years before the individual has those first worries about memory, behaviour and mood.

Some people will die before they develop symptoms.

So, as the Geneva paper claims, will this new criteria lead to an over-diagnosis of the disease among asymptomatic people?

What Australian researchers say

Professor Scott Ayton is dementia mission lead at The Florey Institute of Neuroscience and Mental Health. In an email responding to questions, he said:

“The discussion of these criteria is mostly about academic research. Clinicians only diagnose people who present with symptoms.

“We don’t give the blood tests unless they have symptoms that resemble Alzheimer’s disease, and currently this is almost exclusively done in research settings.”

He said there is “the potential that one day in the future people will be diagnosed with Alzheimer’s disease without cognitive symptoms, for example by a screening blood test”.

But he said such patients would be treated “very differently than if they presented with symptoms”.

Real-world relevance

The argument would have real-world relevance if the only thing that would change this would be if the drug Lecanemab “is approved for ‘pre-symptomatic’ Alzheimer’s disease, but these trials have not been done, and we don’t screen people for Alzheimer’s disease – so this is years into the future”.

Lecanemab is a monoclonal antibody that “reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function”.

“We are certainly not over-diagnosing people with dementia, we are under-diagnosing,’’ Professor Ayton said.

‘‘There is a huge population in aged care who don’t have a diagnosis of dementia, and the increased care and funding that comes with that.”

Researchers believe that amyloid plaques are central to Alzheimer’s disease. Photo: Getty

Professor Martins told The New Daily that the brain amyloid and CSF biomarkers are only used in diagnosis of dementia in people who exhibit symptoms.

He said people are not ‘diagnosed’ as having Alzheimer’s dementia if they have no symptoms.

He said people who are amyloid positive but have no symptoms “are considered to be ‘high risk’ and are said to have the preclinical form of the disease but are not ‘diagnosed’ with Alzheimer’s dementia.

This stands in contradiction to the American criteria.

Asymptomatic people and research

However, “cognitively normal amyloid positive individuals” are highly useful for research into slowing or even stopping the disease from progressing.

“It is widely believed that the earlier one intervenes the more effective the drug treatment will be,” Martins said.

He noted that “while no diagnosis of Alzheimer’s dementia [are] made … there are currently clinical trials on these cognitively normal individuals with amyloid lowering drugs”.

If these trials demonstrate that intervention at this stage delays or prevents the onset of symptoms “then it is warranted this cohort be offered preclinical diagnosis”.

A new Australian trial

Martins is leading a new trial called AU-ARROW that investigates whether a healthy lifestyle is a protective measure against Alzheimer’s.

The two-year multi-domain lifestyle intervention program comprises physical exercise, computerised brain training, social engagement, diet and medical counselling.

The study will randomise 600 participants aged 60-79 into two groups: A group that will receive health education and support; and a multi-domain intervention group.

Martins still needs to recruit 200-plus participants.

“We get many wanting to participate but not eligible as they are too healthy,” he said.

“We are seeking participants who do not have a healthy lifestyle such as a poor diet and little exercise and those with a family history.”

Participants as part of their selection are tested for their memory and cognition to determine if they are cognitively normal. All participants recruited are cognitively normal.

He said once recruited, participants will get an amyloid scan of which about 30 per cent are amyloid positive.

“We include all eligible participants whether they are positive or negative for amyloid.”

If you’re interested, contact Professor Martins here.