# Amyloid and Tau PET Imaging ## Introduction Amyloid and tau PET imaging represent a paradigm shift in the evaluation of Alzheimer disease and other neurodegenerative conditions. These tracers enable direct visualization of the two hallmark pathological proteins of Alzheimer disease -- amyloid-beta plaques and neurofibrillary tau tangles -- in living patients. ## Amyloid PET Imaging ### Pathological Basis Amyloid-beta plaques accumulate in neocortical gray matter years to decades before clinical symptoms emerge. Amyloid deposition follows a predictable pattern described by Thal phases. Amyloid PET detects fibrillar amyloid plaques rather than soluble oligomers. It is important to recognize that a positive amyloid PET does not equate to an Alzheimer disease diagnosis, as amyloid positivity increases with age in cognitively normal individuals. ### FDA-Approved Amyloid Tracers Three F-18 labeled amyloid tracers are FDA-approved. Florbetapir (Amyvid) is administered at 10 mCi with a 30 to 50 minute uptake period and a 10-minute scan. Florbetaben (Neuraceq) is given at 8.1 mCi with a 45 to 130 minute uptake period and a 15 to 20 minute scan. Flutemetamol (Vizamyl) is given at 5 mCi with a 90 minute uptake period and a 20-minute scan. All three bind to beta-sheet fibrillar amyloid with high affinity. Pittsburgh Compound B (PiB), a C-11 labeled research tracer, has limited clinical utility due to its 20-minute half-life. | Tracer | Trade Name | Dose (mCi) | Uptake Period (min) | Scan Duration (min) | Label | |---|---|---|---|---|---| | Florbetapir | Amyvid | 10 | 30–50 | 10 | F-18 | | Florbetaben | Neuraceq | 8.1 | 45–130 | 15–20 | F-18 | | Flutemetamol | Vizamyl | 5 | 90 | 20 | F-18 | | Pittsburgh Compound B (PiB) | Research only | 15 | 40–70 | 20 | C-11 | | Flortaucipir (tau) | Tauvid | 10 | 80 | 20 | F-18 | ### Interpretation of Amyloid PET A negative scan shows gray matter uptake that is less than or equal to white matter uptake, with distinct gray-white matter contrast preserved. A positive scan shows cortical gray matter uptake that equals or exceeds adjacent white matter, with loss of the normal gray-white matter distinction. The scan should be evaluated in axial, sagittal, and coronal planes. Key regions to assess include the frontal, temporal, and parietal cortex, the posterior cingulate, precuneus, and striatum. ### Appropriate Use Criteria Amyloid PET is appropriate for patients with persistent or progressive unexplained mild cognitive impairment, patients with atypical clinical presentations of possible Alzheimer disease, and patients with progressive dementia and an atypically early age of onset (under 65 years). It is not appropriate for asymptomatic individuals, those with family history alone, for determining dementia severity, or for non-medical purposes. ## Tau PET Imaging ### Pathological Basis Neurofibrillary tangles composed of hyperphosphorylated tau protein follow a predictable distribution described by Braak staging: transentorhinal regions in stages I and II, limbic regions in stages III and IV, and neocortical regions in stages V and VI. Tau burden correlates more closely with cognitive decline than amyloid burden does. Different tau isoforms (3R, 4R, and mixed) are associated with different tauopathies. ### FDA-Approved Tau Tracer Flortaucipir (Tauvid) is the first and only FDA-approved tau PET tracer, approved in 2020. It is administered at 10 mCi intravenously with an 80-minute uptake period and a 20-minute acquisition. It binds primarily to paired helical filament (PHF) tau, which contains mixed 3R/4R isoforms as found in Alzheimer disease. It is less reliable for non-AD tauopathies involving 4R tau, such as progressive supranuclear palsy and corticobasal degeneration. ### Interpretation of Tau PET Visual assessment evaluates tracer uptake relative to reference regions. Normal findings include uptake limited to the choroid plexus, basal ganglia, and substantia nigra, which represent off-target binding. Abnormal findings include neocortical uptake, particularly in the temporal, parietal, and frontal regions. The distribution pattern correlates with Braak stage and clinical phenotype. ### Off-Target Binding The choroid plexus demonstrates frequent off-target binding that may obscure the hippocampal signal. The basal ganglia and substantia nigra show common non-specific uptake. Flortaucipir has some affinity for monoamine oxidase B (MAO-B). Newer tau tracers such as MK-6240, PI-2620, and GTP1 aim to reduce these off-target binding issues. ## Clinical Integration ### Amyloid and Tau Together Within the AT(N) biomarker framework, amyloid positive plus tau positive supports an Alzheimer disease diagnosis. Amyloid positive with tau negative may represent preclinical Alzheimer disease or non-AD amyloidosis. Amyloid negative with tau negative makes Alzheimer disease unlikely. The AT(N) framework classifies patients based on amyloid (A), tau (T), and neurodegeneration (N) biomarkers. ### Comparison with FDG PET FDG PET shows the functional consequence of neurodegeneration through hypometabolism. Amyloid PET shows the pathological substrate, specifically amyloid plaques. Tau PET shows pathological progression, as neurofibrillary tangles correlate with symptoms. These modalities are complementary rather than redundant. ## Emerging Applications Anti-amyloid therapies such as lecanemab and donanemab have made amyloid PET critically important for confirming eligibility and assessing amyloid clearance. Both amyloid and tau PET serve as tools for clinical trial enrollment and endpoint measurement. Tau PET shows promise as a prognostic biomarker for the rate of cognitive decline. Investigation of non-AD tauopathies using next-generation tau tracers is an active area of research. ## Pitfalls and Limitations Amyloid positivity increases with age, and approximately 30% of cognitively normal individuals over 70 are amyloid positive. A positive amyloid scan therefore does not confirm Alzheimer disease as the cause of current symptoms. Tau tracer off-target binding may complicate interpretation. Cost and limited availability remain barriers to widespread clinical use. Insurance coverage is variable, and CMS covers amyloid PET under Coverage with Evidence Development. ## Clinical Pearls A negative amyloid PET effectively excludes Alzheimer disease as the cause of cognitive impairment, with a negative predictive value exceeding 95%. Tau PET correlates more strongly with cognitive symptoms and disease stage than amyloid PET, making it a better biomarker for disease progression. With the advent of anti-amyloid immunotherapies, amyloid PET has gained critical importance for patient selection and treatment monitoring. ## References 1. Johnson KA, et al. Appropriate Use Criteria for Amyloid PET. *Alzheimer's & Dementia*. 2013;9(1):e1-e16. 2. Jack CR, et al. NIA-AA Research Framework: Toward a Biological Definition of Alzheimer's Disease. *Alzheimer's & Dementia*. 2018;14(4):535-562. 3. Fleisher AS, et al. Flortaucipir PET in Alzheimer Disease. *JAMA Neurology*. 2020;77(11):1388-1398. 4. Ossenkoppele R, et al. Tau PET Patterns Mirror Clinical and Neuroanatomical Variability in Alzheimer's Disease. *Brain*. 2016;139(5):1551-1567.