Alzheimer disease is the most common cause of dementia in older individuals. Cerebrospinal fluid biomarkers and amyloid positron emission tomography (PET) can accurately detect Alzheimer disease brain pathology, but the perceived risks, costs, and limited availability have contributed to low rates of biomarker testing in the clinic.1 With recent approvals of disease-modifying, amyloid-targeting therapies, incorporation of biomarkers into clinical practice has become more important for medical decision-making. Fortunately, blood-based biomarkers of Alzheimer disease pathology have advanced rapidly in recent years and are now increasingly used in research, clinical trials, and clinical practice.2 Blood-based biomarkers are highly scalable and promise to improve accurate diagnosis of Alzheimer disease, with the potential for much greater reach than cerebrospinal fluid or PET tests.2 Among the blood-based biomarkers, plasma phosphorylated tau 217 (p-tau217) has demonstrated the highest accuracy in detecting amyloid pathology and also reflects tau pathology to some degree.3-5
Although Alzheimer disease biomarkers are increasingly being incorporated into clinical practice in patients with mild cognitive impairment or mild dementia (the populations for which amyloid-targeting therapies have demonstrated clinical benefit), these measures are also sensitive to early biological changes associated with Alzheimer disease that precede the onset of clinical symptoms.6 Indeed, these biological changes are thought to begin a decade or more prior to the onset of cognitive decline, during an asymptomatic phase of disease that has often been referred to as preclinical Alzheimer disease.7 Importantly, current Alzheimer’s Association clinical practice guidelines limit testing for Alzheimer disease pathology using blood-based and other Alzheimer disease biomarkers to individuals with objective cognitive impairment undergoing diagnostic evaluation in specialty care; clinical testing of cognitively unimpaired older adults is not recommended at this time.2
However, in the research setting, unimpaired individuals with biomarker evidence of Alzheimer disease pathology have been the focus of numerous natural history studies and, more recently, secondary prevention trials testing whether targeting pathology can forestall the onset of cognitive impairment.8 Studies have demonstrated that higher plasma p-tau217 levels in cognitively unimpaired individuals are associated with higher risk for future cognitive decline and progression to mild cognitive impairment or dementia.9-11 The ability of blood-based biomarkers to detect early Alzheimer disease pathology in cognitively unimpaired individuals with high sensitivity has already been translated to clinical trials of amyloid-targeting therapies. The TRAILBLAZER-ALZ 3 clinical trial enrolled cognitively unimpaired individuals with elevated p-tau217 and is evaluating whether donanemab reduces progression to cognitive impairment.
