Hanna-Maria Roitto

When clinical Alzheimer's symptoms outpace biology – What does it really mean? New insight from JAMA Neurology. We’ve long relied on biomarker staging, particularly tau-PET and amyloid-PET scans, to tell us where a person is on the Alzheimer’s disease continuum. But what happens when a person looks clinically worse than their biomarkers suggest? Key Points: - A study by Pichet Binette and colleagues tried to get closer to the answer. - The authors used ~1,200 participants across the BioFINDER-2 and ADNI cohorts. - They compared clinical stage (cognitive symptoms) vs. biological stage (amyloid + tau-PET). - The authors identified three groups: 1- clinical and biological stages matched, 2- clinical was worse than biological 3- biological was worse than clinical. - Those whose clinical symptoms were more severe than their biological AD stage frequently manifested: α-synuclein pathology (suggesting possible Lewy body disease), cerebral small vessel disease (vascular), signs of TDP-43 pathology, higher neurodegeneration markers like neurofilament light, and greater vascular burden (WMHs, infarcts, ischemic heart disease). My take: I think there are 5 main takeways for clinicians, researchers and families. 1️⃣ Don’t assume all cognitive decline is due to Alzheimer’s pathology. Many folks may present with non-AD pathologies driving the decline; clues may be present on tau-PET. 2️⃣ A mismatch (clinical > biological) should raise red flags for co-pathologies. Think Lewy bodies, vascular lesions, or TDP-43. This could alter your treatment path and prognosis. 3️⃣ Biological staging alone doesn’t always capture disease complexity. It turns out a 'robust diagnosis' still requires integrating clinical assessment, imaging, and other potentially other biomarkers. 4️⃣ Resilience can be a real thing. Some folks w/ high tau loads remain clinically intact. Are there protective factors? 5️⃣ Will precision medicine in Alzheimer’s become essential in the future as we develop more treatments? I hope so. We must move beyond a one-pathology model and embrace individualized diagnostics to optimize care and clinical trial outcomes. If you (or your patient) look worse than the brain scan, dig deeper. Don’t treat images, treat people. Ex pede herculem , don't judge the whole by the part (of the story). jamanetwork.com/journals/jam… #Neurology #Alzheimers #PrecisionMedicine #Neurodegeneration #ClinicalPearls @alzassociation @FixelInstitute