by Miguel Silva Miranda
As disease-modifying therapies move from clinical trials into routine practice, neurologists are being forced to rethink one of the most fundamental questions in dementia care: what exactly is Alzheimer’s disease? This Focused Workshop tackled that question head-on, bringing together experts with different perspectives on how advances in biomarkers should reshape diagnosis. Rather than becoming a debate over competing criteria, the session offered a thoughtful exploration of how decades of scientific discoveries have led to today’s changing clinical landscape.
Kristian Steen Frederiksen set the stage with what was perhaps the clearest historical overview of Alzheimer’s disease I have heard. He traced how major scientific discoveries have continually reshaped diagnostic criteria, from Alois Alzheimer’s original description and the first NINCDS-ADRDA criteria in 1984 to the discovery of β-amyloid and tau, the amyloid cascade hypothesis, the first symptomatic treatments, and the biomarker revolution. These milestones ultimately paved the way for today’s disease-modifying monoclonal antibodies and rapidly emerging blood-based biomarkers.
Frederiksen organised this evolution into three generations of diagnostic criteria. The first relied solely on clinical symptoms and recognised Alzheimer’s disease only at the dementia stage. The second incorporated biomarkers through the International Working Group (IWG) and NIA-AA criteria, while the newest Alzheimer’s Association framework defines the disease primarily by the presence of biological pathology. Despite this progress, he reminded the audience that major challenges remain, including explaining clinical heterogeneity, understanding co-pathologies, and recognising that current therapies slow rather than stop disease progression. His clear historical perspective provided the perfect introduction to the workshop.
Charlotte Teunissen then made a persuasive case for the Alzheimer’s Association criteria and the concept of Alzheimer’s disease as a biological condition. Beginning with plasma phosphorylated tau—playfully described as an “Alzheimer’s diagnostic superhero”—she showed how closely blood biomarkers correlate with amyloid and tau PET imaging, brain atrophy and future cognitive decline. Her enthusiasm for blood-based biomarkers was evident throughout.
Teunissen argued that biological diagnosis has been instrumental to the success of recent clinical trials and the development of disease-modifying therapies. In this framework, symptoms are the consequence of disease rather than a prerequisite for diagnosis. Individuals with positive biomarkers but no cognitive symptoms already have Alzheimer’s disease, even if they remain clinically unimpaired.
Addressing one of the main criticisms of this approach, she noted that not everyone with positive biomarkers will develop dementia, comparing Alzheimer’s biomarkers with HbA1c in diabetes. A biological diagnosis does not imply inevitable clinical progression, nor does it justify population-wide screening. Both the Alzheimer’s Association and IWG criteria discourage biomarker testing in asymptomatic individuals and acknowledge the importance of co-pathologies and risk stratification. Her presentation convincingly demonstrated that biological definitions and thoughtful clinical practice can coexist.
If Teunissen championed biomarkers, Giovanni Frisoni passionately defended the clinical perspective underpinning the IWG criteria. His central message was simple but thought-provoking: not everything that is biologically detectable is necessarily clinically meaningful.
Frisoni argued that the two frameworks have different goals. The Alzheimer’s Association criteria primarily facilitate drug development through a straightforward biological definition, whereas the IWG criteria focus on improving care for individual patients. For Frisoni, the clinical narrative shared with patients is just as important as the biomarker profile.
He argued that Alzheimer’s disease should begin with mild cognitive impairment rather than in cognitively unimpaired individuals with abnormal biomarkers. This distinction has enormous practical implications: defining every biomarker-positive person as having Alzheimer’s disease would increase the affected population from tens of millions living with dementia to hundreds of millions of cognitively normal individuals.
One of the most interesting parts of his presentation explored why pathology and symptoms often do not match. Additional pathologies—including TDP-43, α-synuclein and vascular disease—can worsen cognition despite relatively modest Alzheimer’s pathology, while greater brain reserve may explain why some individuals remain remarkably resilient despite a heavy tau burden. Understanding these factors, he suggested, may become essential for predicting who responds best to anti-amyloid therapies.
Rather than presenting opposing camps, the workshop showed that both diagnostic frameworks are responding to the same rapidly evolving evidence, albeit with different priorities. As Alzheimer’s care enters the era of disease-modifying therapies, neurologists will increasingly need to combine sophisticated biomarkers with careful clinical judgement. This excellent workshop demonstrated that defining Alzheimer’s disease is no longer simply an academic exercise—it is becoming central to how patients are diagnosed, counselled and treated.
