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| PET or PET/CT, for Alzheimer's Disease, Dementia, or Cognitive Impairment | |
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| Description: |
Coverage policies 2004047 and 2012026 have been combined into one policy with no change to coverage intent. CP 2012026 has been archived.
Note: This policy is intended for those members with contracts that do not have requirements for prior approval for imaging procedures through an independent imaging review organization.
Alzheimer disease (AD) is a fatal neurodegenerative disease that causes progressive loss in memory, language, and thinking, with the eventual loss of ability to perform social and functional activities in daily life. Survival after a diagnosis of dementia due to AD generally ranges between 4 and 8 years; however, life expectancy can be influenced by other factors, such as comorbid medical conditions. It is estimated that 6.5 million Americans aged 65 and older are currently living with AD dementia, and the number is projected to reach over 13.8 million by 2060 (Alzheimer’s disease facts and figures, 2024).
The pathologic hallmarks of AD are extracellular deposits of amyloid beta, referred to as amyloid plaques, and intracellular aggregates of hyperphosphorylated tau in the form of neurofibrillary tangles. There are different forms of amyloid such as plaques, oligomers, and monomers, and the roles of these different forms and how specifically they are pathophysiologically associated with AD is not well understood. Generally referred to as “amyloid hypothesis”, it is believed that aggregation of amyloid beta oligomers in the brain leads to amyloid plaques and is thought to be the primary driver of the disease process. These changes in the brain result in widespread neurodegeneration and cell death and ultimately cause the clinical signs and symptoms of dementia (Alzheimer’s Association, 2021; Roberts, 2018).
Because clinical diagnosis can be difficult, particularly early in the course of the disease or with atypical dementia, there has been considerable interest in developing biomarkers for AD that can be imaged through positron emission tomography (PET). These biomarkers include amyloid beta plaque, tau pathology, and glucose metabolism in the brain. PET images biochemical and physiologic functions by measuring concentrations of radioactive chemicals that have been partially metabolized in a particular region of the body. Radiopharmaceuticals used for PET imaging may be generated in a cyclotron or nuclear generator and introduced into the body by intravenous injections.
Demonstration of amyloid beta plaque is a requirement for the diagnosis of definite AD, but may also be present in individuals without dementia, in patients with mild or subjective cognitive impairment who may or may not progress to dementia, and in patients with other types of dementia. Conversely, it may be absent in a substantial proportion of patients with clinical features of AD (Vallabhajosula, 2011; Ossenkoppele, 2015; Jansen, 2015).
The other defining pathologic hallmark of AD is tau neurofibrillary tangles (NFTs). Postmortem studies have found that NFTs more directly correlate to the severity of dementia and neurodegeneration compared to amyloid beta plaques (Tian, 2022).
18-F fluorodeoxyglucose PET (18-F FDG PET) quantifies brain function by measuring glucose levels. Through identifying distinct regions of hypometabolism, FDG-PET is proposed as a method to distinguish AD from other dementias, especially in patients with atypical presentations (e.g., younger age) (Wolk, 2025).
PET imaging in patients with mild cognitive impairment (MCI) or dementia is intended to provide a more accurate diagnosis earlier in the disease course than clinical diagnosis alone, resulting in earlier, appropriately targeted treatment and other management approaches.
Regulatory Status
The following PET radiopharmaceuticals have been evaluated and approved as drugs by the FDA for use as diagnostic imaging agents in individuals with cognitive impairment. These radiopharmaceuticals are approved for specific conditions.
Radioactive Tracers Approved by the FDA for Amyloid Beta PET Imaging in Patents with Cognitive Impairment
florbetapir F18 (Amyvid), manufactured by Avid Radiopharmaceuticals (subsidiary of Eli Lilly) (NDA 202008) was approved in 2012 for the following indications:
flutemetamol F18 (Vizamyl), manufactured by GE Healthcare, (NDA 203137) was approved in 2013 for the following indications:
florbetaben F18 (Neuraceq), manufactured by Life Molecular Imaging (formerly Piramal Life Sciences), (NDA 204677) was approved in 2014 for the following indications:
Radioactive Tracers Approved by the FDA for Tau PET Imaging in Individuals with Cognitive Impairment
flortaucipir F18 (Tauvid), manufactured by Eli Lilly and Company, (NDA 212123) was approved in 2020 for the following indications:
In 1994, the fludeoxyglucose (FDG) F18 radiotracer was originally approved by the FDA through the New Drug Application (NDA) process (NDA20306). The original indication was for "the identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures." Added indications in 2000 were for "Assessment of glucose metabolism to assist in the evaluation of malignancy…" and "Assessment of patients with coronary artery disease and left ventricular dysfunction…." FDA approval of FDG does not include the evaluation of patients with cognitive decline. Multiple manufacturers have approved NDAs for FDG.
Coding
Prior to 2013, there was no code specific to florbetapir, and HCPCS code A4641 would have been used to report this tracer. The PET scan would be reported using the CPT codes for PET or PET/CT scanning (i.e., 78811 or 78814).
Effective in 2013, a HCPCS code specific to florbetapir was introduced:
A9586: Florbetapir F18, diagnostic, per study dose, up to 10 millicuries
Effective July 2016 the following HCPCS for Flutemetamol and Florbetaben F18 were introduced:
Q9982 – Flutemetamol F18, diagnostic, per study dose, up to 5 millicuries
Q9983 – Florbetaben F18, diagnostic c, per study dose, up to 8.1 millicuries
Related policies:
2009004_Biochemical Markers, Alzheimer’s Disease
1998137_Genetic Test: Alzheimer’s Disease
2007001_Magnetic Resonance Imaging (MRI), Functional
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Policy/ Coverage: |
Coverage policies 2004047 and 2012026 have been combined into one policy with no change to coverage intent. CP 2012026 has been archived.
Effective August 01, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Amyloid beta imaging with positron emission tomography (PET) to select individuals with mild cognitive impairment or mild dementia due to Alzheimer disease for amyloid beta targeting plaque-therapy meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered when the following criteria are met:
Member receives a “recommended” determination from criteria review in InterQual® for Amyloid beta imaging with positron emission tomography (PET) based on diagnosis and requested product.
Click the following link to view the specific criteria in InterQual®:
https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
Amyloid beta imaging with positron emission tomography (PET) for determination of cessation of Donanemab therapy meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered when the following is met:
Member receives a “recommended” determination from criteria review in InterQual® for Amyloid beta imaging with positron emission tomography (PET) based on diagnosis and requested product.
Click the following link to view the specific criteria in InterQual®:
https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
See Criteria below.
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
1. Amyloid beta imaging with positron emission tomography (PET) to predict conversion to Alzheimer disease does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described above.
For members with contracts without Primary Coverage Criteria, amyloid beta imaging with positron emission tomography (PET) to predict conversion to Alzheimer disease, is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance not described above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
2. Amyloid beta imaging with PET as an adjunct to clinical diagnosis in individuals with dementia does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described.
For members with contracts without Primary Coverage Criteria, amyloid beta imaging with PET as an adjunct to clinical diagnosis in individuals with dementia, is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
3. All other uses of amyloid beta imaging with PET, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described above.
For members with contracts without Primary Coverage Criteria, all other uses of amyloid beta imaging with PET, are considered not Medically Necessary or is investigational and is not covered for any indication or circumstance not described above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
4. Tau imaging with PET for all indications including but not limited to dementia, mild cognitive impairment and Alzheimer disease does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance.
For members with contracts without Primary Coverage Criteria, Tau imaging with PET for all indications including but not limited to dementia, mild cognitive impairment and Alzheimer disease is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance not described above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
5. The use of PET using FDG for the evaluation of Alzheimer's or dementia (e.g., multi-infarct dementia, Pick disease, frontotemporal dementia, dementia with Lewy bodies, presenile dementia) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance.
For members with contracts without Primary Coverage Criteria, the use of PET using FDG for the evaluation of Alzheimer's or dementia (e.g., multi-infarct dementia, Pick disease, frontotemporal dementia, dementia with Lewy bodies, presenile dementia) is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
6. PET Scans (Positron Emission Tomography) for any diagnosis other than those that are addressed through specific policy does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described.
For members with contracts without Primary Coverage Criteria, PET Scans (Positron Emission Tomography) for any diagnosis other than those that are addressed through specific policy is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Click the following link to view the specific criteria in InterQual®:
https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
Effective July 24, 2026 to July 31, 2026
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Amyloid beta imaging with positron emission tomography (PET) to select individuals with mild cognitive impairment or mild dementia due to Alzheimer disease for amyloid beta targeting plaque-therapy
meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered.
Amyloid beta imaging with positron emission tomography (PET) for determination of cessation of Donanemab therapy meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered when the following is met:
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
1. Amyloid beta imaging with positron emission tomography (PET) to predict conversion to Alzheimer disease does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described above.
For members with contracts without Primary Coverage Criteria, amyloid beta imaging with positron emission tomography (PET) to predict conversion to Alzheimer disease, is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance not described above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
2. Amyloid beta imaging with PET as an adjunct to clinical diagnosis in individuals with dementia does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described.
For members with contracts without Primary Coverage Criteria, amyloid beta imaging with PET as an adjunct to clinical diagnosis in individuals with dementia, is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
3. All other uses of amyloid beta imaging with PET, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described above.
For members with contracts without Primary Coverage Criteria, all other uses of amyloid beta imaging with PET, are considered not Medically Necessary or is investigational and is not covered for any indication or circumstance not described above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
4. Tau imaging with PET for all indications including but not limited to dementia, mild cognitive impairment and Alzheimer disease does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance.
For members with contracts without Primary Coverage Criteria, Tau imaging with PET for all indications including but not limited to dementia, mild cognitive impairment and Alzheimer disease is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance not described above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
5. The use of PET using FDG for the evaluation of Alzheimer's or dementia (e.g., multi-infarct dementia, Pick disease, frontotemporal dementia, dementia with Lewy bodies, presenile dementia) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance.
For members with contracts without Primary Coverage Criteria, the use of PET using FDG for the evaluation of Alzheimer's or dementia (e.g., multi-infarct dementia, Pick disease, frontotemporal dementia, dementia with Lewy bodies, presenile dementia) is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
6. PET Scans (Positron Emission Tomography) for any diagnosis other than those that are addressed through specific policy does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described.
For members with contracts without Primary Coverage Criteria, PET Scans (Positron Emission Tomography) for any diagnosis other than those that are addressed through specific policy is considered not Medically Necessary or is investigational and is not covered for any indication or circumstance. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective February 2022 - July 23, 2026
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
The use of PET using FDG for the evaluation of Alzheimer's or dementia (e.g., multi infarct dementia, Pick disease, frontotemporal dementia, dementia with Lewy bodies, presenile dementia) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without Primary Coverage Criteria, the use of PET using FDG for the evaluation of Alzheimer's or dementia (e.g., multi infarct dementia, Pick disease, frontotemporal dementia, dementia with Lewy bodies, presenile dementia) is considered Not Medically Necessary or is investigational and is not covered. Not Medically Necessary or investigational services are specific contract exclusions in most member benefit certificates of coverage.
PET Scans (Positron Emission Tomography) for any diagnosis other than those that are addressed through specific policy do not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without Primary Coverage Criteria, PET Scans (Positron Emission Tomography) for any diagnosis other than those that are addressed through specific policy are considered Not Medically Necessary or are investigational and are not covered. Not Medically Necessary or investigational services are specific contract exclusions in most member benefit certificates of coverage.
Specific coverage policies are listed individually.
Effective September 2004 through January 2022
The use of PET using FDG for the evaluation of dementia or Alzheimer's does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, the use of PET for the evaluation of dementia or Alzheimer's is considered investigational. Investigational services are an exclusion in the member certificate of coverage.
PET Scans (Positron Emission Tomography) for any diagnosis other than those that are addressed through specific policy are not covered based on benefit certificate primary coverage criteria for effectiveness.
For contracts without primary coverage criteria, PET Scans (Positron Emission Tomography) for any diagnosis other than those that are addressed through specific policy are considered investigational and are not covered. Investigational services are exclusion in the member certificate of coverage.
Specific coverage policies are listed individually.
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| Rationale: |
Literature on the use of florbetapir-PET imaging to aid in the diagnosis of patients with suspected Alzheimer’s disease is limited. The pivotal phase III trial, although to be commended for its use of the gold standard of histopathology, has a number of limitations including small sample size, use of a majority rating of three physicians, and having few patients in the mildly impaired category. This study reported a moderately high correlation of amyloid plaque with histopathologic examination. The sensitivity and specificity of this test have not yet been adequately determined in an appropriate population, including a larger number of patients with mild cognitive impairment.
The clinical utility of this technology is uncertain. The test is not likely to be useful for confirming AD in patients who present with cognitive impairment. It may have a role in ruling out AD, but this has yet to be established with certainty. Questions also remain about the use of this test outside of the investigational setting, particularly regarding the accuracy of visual interpretation of images and how best to apply this test in routine clinical practice.
Evidence about the clinical utility of amyloid beta PET imaging to select patients for treatment with amyloid beta targeting therapy is available from 4 studies conducted as part of the clinical development program for aducanumab. PRIME was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging, staggered study conducted in the United States with the primary objectives of safety and tolerability. The phase 3 studies were multicenter, global, randomized, double-blind, placebo-controlled studies of identical design with the primary objective of efficacy and safety. In all 3 studies, the diagnosis of AD was confirmed by presence of amyloid pathology measured by 18-florbetapir PET imaging. The pivotal trials ensured enrollment of patients at an earlier stage of their disease; MCI due to AD or mild AD dementia based on an entry criterion (FDA/PCNS, 2020).
The phase 3 studies randomized patients to aducanumab low dose (3 or 6 mg/kg for
ApoE ε4 carriers and noncarriers, respectively), aducanumab high dose (10 mg/kg), or placebo every 4 weeks for 18 months, followed by an optional, dose-blind, long-term extension period. Due to early termination and consequent administrative censoring, data was missing for up to 45% of patients randomized in the 2 trials. Approximately 60% of patients had the opportunity to complete week 78 of the trial before the trials were terminated for futility (FDA/PCNS, 2020).
Study 302 (N=1638 randomized patients) met the primary endpoint in patients treated with high-dose aducanumab (10 mg/kg) with an absolute difference of -0.39 in favor of aducanumab on the 18-point CDR-SB scale (a relative 22% less decline in high dose aducanumab group compared to placebo, p=.0120). The reported MCID is generally considered to be 1 to 2 points on a scale from 0 to 18 (Andrews, 2019). Results of responder analysis describing the proportion of individuals who achieved a predefined level of improvement was not reported. Results in the low-dose aducanumab (3 or 6 mg/kg for
ApoE ε4 carriers and noncarriers, respectively), group were not statistically significant compared with placebo (absolute difference
‐0.26, relative difference
‐15%, p=.0901) and therefore no statistically valid conclusions can be made for any of the secondary endpoints for either treatment arm.
Study 301 (N=1647 randomized patients) did not meet its primary end point of a reduction relative to placebo in the CDR-SB score. For the high-dose arm, an absolute difference of 0.03 and a relative difference of 2% favored placebo (p=.8330). For the low-dose arm, an absolute difference of -0.18 and a relative difference of 12% favored aducanumab (p=.8330). Because of the pre-specified plans to control for type I error for multiple comparisons, no statistically valid conclusions can therefore be made for any of the secondary endpoints (FDA/PCNS, 2020).
Change in brain amyloid signal was measured by florbetapir fluorine 18 PET and quantified by a composite SUVR in a subset of sites and patients (n=488) at week 78. In study 302, adjusted mean change from baseline to week 78 relative to placebo showed a dose-dependent reduction in amyloid beta by -0.179 and -0.278 in the low- and high-dose arms, respectively. In study 301, adjusted mean change from baseline to week 78 relative to placebo showed a dose-dependent reduction in amyloid beta by -0.167 and -0.232 in the low- and high-dose arms, respectively. While aducanumab showed statistically significant dose dependent changes from baseline in amyloid beta plaques, there are no satisfactory data, clearly establishing individual changes in amyloid correlate with or predict long term cognitive and functional changes as measured by CDR-SB. The FDA statistical review reported no correlation in study 302 between reduction in amyloid plaque and long-term clinical change among the high-dose cohort or full 10 mg/kg dosed subgroup. In the absence of clinical data convincingly demonstrating a clinical effect, it cannot be concluded that observed reduction in amyloid will translate into a clinical benefit to patients (FDA, 2020).
Data with limited follow-up are available to analyze safety because the phase 3 trials were stopped prematurely due to futility. Pooled safety data from the 2 phase 3 clinical trials showed that about 35% (compared to 3% in the placebo arm) of patients on aducanumab experienced amyloid-related imaging abnormalities (ARIA), whose clinical effects can range from asymptomatic to severe. Although the majority of patients were asymptomatic or had symptoms such as headache, confusion, or dizziness that resolved with temporary stoppage of the drug, 6.2% of participants receiving the high dose of aducanumab discontinued the drug due to ARIA (Aduhelm, 2021).
An increase in falling adverse events was observed in the high dose as compared to placebo across the 2 phase 3 studies (15% vs. 12%, respectively). FDA statistical review reported a hazard ratio of 1.33 (p=.016) suggesting a 33% relative increase in hazard of falling for 10 mg/kg compared to placebo (FDA, 2020).
Pichet et al (2022) published the results of a study that was aimed at identifying which combinations of AD related plasma biomarkers and other assessments provide the best prediction of progression to AD dementia in patients with mild cognitive impairment (MCI). The results of this study included data from a clinical trial (NCT010280530) which was a principal open-label study to assessing the prognostic usefulness of Flutemetamol (18F) injection in identifying patients with amnestic MCI who will convert to probable Alzheimer's Disease.
Zhu et al (2022) conducted a meta-analysis of cerebral perfusion imaging methods (FDG-PET, SPECT, and MRI) in the assessment of MCI conversion to AD. A total of 16 studies were included (5 with FDG-PET). The authors found significantly higher sensitivity, specificity, and positive likelihood ratio with FDG-PET than SPECT or MRI. The studies for FDG-PET were determined to have low risk of bias.
The criterion standard for the diagnosis of AD is postmortem neuropathologic examination. In the absence of comparisons with the criterion standard, long-term clinical follow-up (e.g., conversion from MC] to probable AD) may be used as a surrogate end point to evaluate the diagnostic performance of beta amyloid imaging with positron emission tomography (PET).
Technical Performance
Evidence on technical performance of this test should demonstrate that the test measures what it is intended to measure, ie, beta amyloid plaque. The best evidence on this would be direct comparison with a criterion standard test for measuring amyloid plaque, which is histopathologic examination of tissue. Other important measures of technical performance are the reliability of testing, including both test-retest reliability and interobserver reliability in reading test results.
Summary of Evidence
For individuals who have mild cognitive impairment (MCI) who receive amyloid beta imaging with PET to predict conversion to AD, the evidence includes studies on diagnostic accuracy and a RCT that evaluated changes in diagnosis and management. Relevant outcomes are test validity, symptoms (cognitive and/or behavioral), change in disease status, functional outcomes, health status measures, and quality of life. Studies have been conducted to evaluate the diagnostic accuracy of amyloid beta PET in patients with MCI, using conversion to probable AD as a reference standard. Systematic reviews of these studies have concluded that limited data, varying sensitivity and specificity, and risk of bias limited confidence in conclusions. Direct evidence of improved health outcomes with this technology is lacking. A RCT tested immediate versus delayed reporting of amyloid beta test results for patients with MCI and AD. No differences between the groups were found for health outcomes, although the study was not powered for these outcome measures.
For individuals who have dementia who receive amyloid beta imaging with PET as an adjunct to clinical diagnosis, the evidence includes studies on diagnostic accuracy. Relevant outcomes are test validity, symptoms (cognitive and/or behavioral), change in disease status, functional outcomes, health status measures, and quality of life. One possible use of amyloid beta testing is as an adjunct to clinical diagnosis to rule out AD; this could lead to further diagnostic testing to determine the etiology of dementia and potentially facilitate avoidance of inappropriate presumptive medication use and/or appropriate use of medications for other types of dementia. The pivotal trials showed a sensitivity of 86% to 93% and a specificity of 86% to 100% compared with the criterion standard of amyloid beta plaque density on postmortem histology. However, the patients in these studies were at the end of life and not representative of the population of patients with suspected AD who present earlier in the course of the disease.
For individuals with MCI or mild dementia due to AD who receive amyloid beta imaging with positron emission tomography and who are being considered for an FDA-approved amyloid beta plaque-targeting therapy, the evidence includes RCTs. Relevant outcomes are test validity, symptoms (cognitive and/or behavioral), change in disease status, functional outcomes, health status measures, quality of life, disease-specific survival, and overall survival. The ClarityAD trial demonstrated a 27% (difference= -0.45; 95% Cl, -0.67 to -0.23) statistically significantly slower rate of decline on the CDR-SB for lecanemab versus placebo. The differences in rate of change over time consistently favored lecanemab across cognitive, functional, quality of life and caregiver burden outcomes. Amyloid-related imaging abnormalities (ARIA) was observed in 21% of individuals treated with lecanemab; 3% of individuals treated with lecanemab experienced symptomatic ARIA. Lecanemab and donanemab have received traditional FDA approval with a label indicating that the presence of amyloid beta pathology should be confirmed prior to initiating treatment.
For individuals with MCI or mild dementia due to AD who are being treated with amyloid beta plaque-targeting therapy and are being evaluated for continuation of therapy, no evidence was identified on the role of subsequent or repeat amyloid beta PET imaging or its correlation with clinical assessment of disease status. Relevant outcomes are test validity, symptoms (cognitive and/or behavioral), change in disease status, functional outcomes, health status measures, quality of life, disease-specific survival, and overall survival.
For individuals who have MCI who receive tau imaging with PET to predict conversion to AD, no studies were identified that report the sensitivity and specificity of flortaucipir F18 tau PET for predicting conversion of MCI to AD. Relevant outcomes are test validity, symptoms (cognitive and/or behavioral), change in disease status, functional outcomes, health status measures, and quality of life. Direct evidence that tau PET for predicting conversion to AD improves clinical outcomes is not available.
For individuals who have dementia who receive tau imaging with PET as an adjunct to clinical diagnosis, the evidence includes studies on diagnostic accuracy. Relevant outcomes are test validity, symptoms (cognitive and/or behavioral), change in disease status, functional outcomes, health status measures, and quality of life. Tau neurofibrillary tangles are one of several markers of AD on histopathology necessary for a diagnosis of AD. One study (n=64) was identified that used a reference standard of autopsy-confirmed diagnosis and reported sensitivities ranging from 92% to 100% with specificities ranging from 52% to 92% across 5 readers of tau PET imaging. In the largest study (n=719), the sensitivity for distinguishing AD dementia from non-AD neurodegenerative disorders was 90% or 97% depending on how the cut point was defined. Specificity was 91% or 88% depending on cut point. There is not yet a consensus on the appropriate regions of the brain and cut points for defining tau PET positivity for quantitative analysis. Direct evidence on clinical utility (ie, improvement in net health outcomes resulting from testing) is lacking.
For individuals with MCI or mild dementia due to AD who receive tau imaging to select for an FDA-approved amyloid beta plaque-targeting therapy, the evidence includes an RCT. Relevant outcomes are test validity, symptoms (cognitive and/or behavioral), change in disease status, functional outcomes, health status measures, quality of life, disease-specific survival, and overall survival. TRAILBLAZER-ALZ 2 was a randomized, double-blind, placebo-controlled study that enrolled patients with early AD and evaluated the efficacy and safety of donanemab, an amyloid beta-targeting therapy. Confirmation of tau pathology using tau PET was required as an entry criterion to ensure that participants were early in the AD disease process. However, the FDA-label for donanemab does not require tau PET imaging prior to initiation of therapy.
For individuals who have suspected AD who receive Fluorine 18 fluorodeoxyglucose FDG-PET to diagnose AD, the evidence includes systematic reviews of nonrandomized studies. Relevant outcomes are test validity, symptoms (cognitive and/or behavioral), change in disease status, functional outcomes, health status measures, and quality of life. The studies included in the reviews were generally of poor quality. There is no standard cutoff for FDG-PET positivity for diagnosing AD, and many studies have not included postmortem confirmation of AD as the reference standard, leading to uncertainty about estimates of performance characteristics. FDG-PET may have high sensitivity and specificity for diagnosing AD, but there is little evidence comparing the performance characteristics of clinical diagnosis using FDG-PET with the clinical diagnosis not using FDG-PET. Therefore, the incremental value of adding FDG-PET to the standard clinical diagnosis is unclear. No studies have reported on clinical outcomes of patients diagnosed with and without FDG-PET.
Practice Guidelines and Position Statements
American College of Radiology
The American College of Radiology (ACR) have issued appropriateness criteria for dementia, revised in 2024, for various imaging procedures including amyloid PET, tau PET, and FDG-PET (ACR, 2025). The ACR appropriateness criteria are evidence-based guidelines reviewed by a multidisciplinary panel. These guidelines were developed through an analysis of current medical literature and the application of established methodologies like the RAND/UCLA Appropriateness Method and GRADE. When evidence was deemed insufficient, expert opinion was used as a supplement to recommend imaging or treatment procedures. A multidisciplinary panel rated 10 scenarios on a scale of 1 to 9, considering the benefits and risks to patients, including information on relative radiation levels, and classified the procedures as usually appropriate (score of 7-9), maybe appropriate (score of 4-6), or usually not appropriate (score of 1-3).
Below is a list of the appropriate scenarios (with score of 7-9) for Amyloid, Tau PET, and FDG-PET imaging.
American College of Radiology Appropriate Use Criteria for Amyloid PET, Tau PET, and FDG PET Imaging
Appropriate clinical scenarios for amyloid PET:
Variant 1: Adult. Mild cognitive impairment not meeting criteria for dementia. Initial imaging.
Variant 2: Adult. Cognitive impairment with memory deficits. Suspect Alzheimer disease with typical clinical presentation. Initial imaging.
Variant 3: Adult. Cognitive impairment with memory deficits. Suspect Alzheimer disease with atypical clinical presentation. Initial imaging.
Variant 4: Adult. Known Alzheimer disease considering therapy with antiamyloid monoclonal antibodies. Pretreatment imaging.
Appropriate clinical scenarios for Tau PET:
Variant 3: Adult. Cognitive impairment with memory deficits. Suspect Alzheimer disease with atypical clinical presentation. Initial imaging.
Appropriate clinical scenarios for FDG-PET:
Variant 1: Adult. Mild cognitive impairment not meeting criteria for dementia. Initial imaging.
Variant 2: Adult. Cognitive impairment with memory deficits. Suspect Alzheimer disease with typical clinical presentation. Initial imaging.
Variant 3: Adult. Cognitive impairment with memory deficits. Suspect Alzheimer disease with atypical clinical presentation. Initial imaging.
Variant 6: Adult. Cognitive impairment with behavioral abnormalities or progressive aphasia. Suspect frontotemporal dementia. Initial imaging.
Variant 7: Adult. Cognitive impairment with visual hallucinations or Parkinsonian symptoms. Suspect dementia with Lewy bodies. Initial imaging.
In 2025, the Alzheimer’s Association (AA) and Society of Nuclear Medicine and Molecular Imaging (SNMMI) published updated appropriate use criteria (AUC) for amyloid PET and developed AUC for tau PET (Rabinovici, 2025). A multidisciplinary workgroup compiled 17 clinical scenarios based on key patient groups where amyloid or tau PET might be used in diagnostics. Similar to the ACR process, using a method adapted from the RAND and UCLA approach for AUC development, the workgroup reviewed and updated the 2013 amyloid PET AUC scenarios refining existing ones and adding new scenarios, resulting in a comprehensive set of criteria for considering amyloid and tau PET in clinical practice (Johnson, 2013). The workgroup employed a modified Delphi approach, using surveys and scoring rounds, to evaluate the clinical scenarios involving amyloid and tau PET imaging for AD diagnosis. Members rated scenarios on a scale of 1 to 9, considering the benefits and risks to patients, and classified them as appropriate (score of 7-9), uncertain (score of 4-6), or rarely appropriate (score of 1-3).
"The following general principles served as the “litmus test” for appropriateness of amyloid or tau imaging across all clinical scenarios:
The AA and SNMMI workgroup recommends that these principles be met in all patients referred for clinical amyloid/tau PET across all clinical scenarios."[PMID: 39776249]
For amyloid PET, seven scenarios were rated as appropriate, two as uncertain, and eight as rarely appropriate. For tau PET, five scenarios were rated as appropriate, six as uncertain, and six as rarely appropriate. Below is a list of the appropriate scenarios (with score of 7-9) for Amyloid and Tau PET imaging.
Alzheimer’s Association and Society of Nuclear Medicine and Molecular Imaging Appropriate Use Criteria for Amyloid and Tau PET Imaging
Appropriate clinical scenarios for amyloid PET:
Clinical Scenario 5: Patients presenting with MCI or dementia who are younger than 65 y and in whom AD pathology is suspected
Clinical Scenario 6: Patients presenting with MCI or dementia syndrome that is often consistent with AD pathology (amnestic presentation) with onset at 65 y or older
Clinical Scenario 7: Patients presenting with MCI or dementia syndrome that could be consistent with AD pathology but has atypical features (e.g., nonamnestic clinical presentation, rapid or slow progression, etiologically mixed presentation)
Clinical Scenario 11: Patients with MCI or dementia with equivocal or inconclusive results on recent CSF biomarkers
Clinical Scenario 12: To inform the prognosis of patients presenting with MCI due to clinically suspected AD pathology
Clinical Scenario 14: To determine eligibility for treatment with an approved amyloid-targeting therapy
Clinical Scenario 15: To monitor response among patients who have received an approved amyloid-targeting therapy
Appropriate clinical scenarios for tau PET:
Clinical Scenario 5: Patients presenting with MCI or dementia who are younger than 65 y and in whom AD pathology is suspected
Clinical Scenario 7: Patients presenting with MCI or dementia syndrome that could be consistent with AD pathology but has atypical features (e.g., nonamnestic clinical presentation, rapid or slow progression, etiologically mixed presentation)
Clinical Scenario 12: To inform the prognosis of patients presenting with MCI due to clinically suspected AD pathology
Clinical Scenario 13: To inform the prognosis of patients presenting with dementia due to clinically suspected AD pathology
Clinical Scenario 14: To determine eligibility for treatment with an approved amyloid-targeting therapy
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