CONy – News Nugget 1 – Too early for mass testing of biomarkers in patients with subjective cognitive decline

By Lucy Piper, medwireNews reporter

medwireNews: Biomarkers could be useful for helping patients with subjective cognitive decline (SCD) better understand the pathology associated with their symptoms, but consensus suggests that more work is needed before they are tested in every patient.

This was the outcome of a debate at the 18th World Congress on Controversies in Neurology in London, UK, between Paul Edison (Imperial College London), who argued in favor of the use of biomarkers in patients with SCD, and Zvezdan Pirtošek (University of Ljubljana, Slovenia), who argued against their use.

Before the discussion, delegates were evenly split, but by the end there was an 80% majority in favor of not testing for biomarkers in every patient with SCD.  

Why should we test for biomarkers?

Edison’s argument was that the current availability of biomarkers, compared with 2 decades ago, means clinicians can now investigate underlying pathologies in patients who present with SCD, which may enable them to determine if the symptoms are associated with an increased risk for mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD), or due to non-neurodegenerative causes, such as depressive symptoms, anxiety, personality traits, or failing physical health.

Such biomarkers include amyloid positivity on positron emission tomography (PET), which he pointed out can be detected and quantified in the early stages of MCI decades before symptoms appear, something that has only been possible since 2004.

Indeed, he quoted the findings from one of his studies from 2009 showing that around 50% of patients with MCI who have high amyloid loads will progress to AD within 2 years and 80% within 3 years, adding that amyloid positivity is more common in older individuals and those with the apolipoprotein (APO)E Ɛ4 allele, according to a study published in JAMA in 2015 .

So what does this mean for people with SCD? Edison referred to a meta-analysis published in 2015 that showed amyloid positivity is present in 10ꟷ44% of cognitively healthy individuals aged 50 to 90 years, 12ꟷ43% of patients with SCD, and 27ꟷ71% of those with MCI. With the likelihood of amyloid positivity estimated to be two-to-three times higher among APOE Ɛ4 allele carriers versus noncarriers.

He said: “If you were to see high amyloid, we know that these patients are, unfortunately, in the trajectory of Alzheimer’s disease.

“What we don’t know is at what point they are going to covert to having Alzheimer’s disease.”

Other biomarkers include reduced 18F-fludeoxyglucose, which is a more “functional biomarker,” Edison commented. This significantly correlates with Mini-Mental State Examination (MMSE) scores as well as measures of immediate recall and the recognition memory test for words. And the cerebrospinal fluid (CSF) markers β-amyloid 1–42 and tau, the former of which is significantly decreased in patients with AD versus controls, while the latter significantly increased, Edison explained.

He concluded that, ultimately, “it is the patient’s choice.” For those with SCD who want “a better understanding of the pathological processes and underlying causes,” of their symptoms, “these pathological markers are available.”

Just because we can, should we test for biomarkers?

Putting forward the case for not testing for biomarkers in every patient with SCD, Pirtošek argued, that “aggressive assessment of older adults in the community could trigger a health crisis in the ‘worried well’, creating unnecessary anxiety in individuals who are otherwise aging normally.”

He made the point that SCD is common, with studies suggesting prevalence rates of 50ꟷ80% in elderly individuals, it increases with age and it is unspecific. Around 60% of individuals with SCD decline to MCI and AD over a 15-year period, said Pirtošek, which means that “the remaining 40% of [patients are] presenting with SCD due to conditions other than AD.”

Identifying SCD is important, he said, as “longitudinal studies do show that it does predict MCI.” For example, “a meta-analysis of 28 studies showed that [patients with] SCD have twice the risk of progressing to dementia,” than those without, the presenter reported. It can also affect emotional and social functioning and overall quality of life.

Pirtošek therefore agreed with his opposition that “it is critical to find sensitive, low-cost methods for early detection of individuals at risk for incident dementia.”

However, he highlighted that there are currently no standardized assessments or thresholds for clearly diagnosing SCD, which is heterogenous and influenced by numerous factors. And while some factors associated with an increased likelihood of preclinical AD are known, such as age at onset at 60 years or older, subjective decline in memory specifically, and biomarker evidence, the ability to predict who will and who will not progress is “inconsistent.”

With regards to biomarkers, he admits that SCD is related to key biomarkers, as discussed by Edison, but current research is contradictory and there is “not a clear pattern.”

Pirtošek believes that biomarkers “are useful” and should be used for “the identification of underlying causes, early detection, differential diagnosis, and treatment planning.”

But he stressed that “before rushing to the indiscriminate use of biomarkers in all SCDs,” a lot more research is needed to find the right biomarkers or improve the ones we have, and this should be a priority.

Key considerations he highlighted include the potential benefits versus the cost, the ethical aspect if there are no specific treatments, the problem of false positives and negatives leading to unnecessary worry or a missed diagnosis, and patient preferences.

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CONy 2024; London, UK: March 21–23