Can a person with impaired cognition but a negative Amyloid (Positron Emission Tomography) PET scan still have Alzheimer's disease?

Negative Amyloid PET in Alzheimer's Disease: Diagnostic Implications

Yes, a person with impaired cognition but a negative amyloid PET scan can still have Alzheimer's disease, particularly in cases with atypical presentations or when amyloid oligomers are present that may not be detected by current PET technology. 1, 2

Understanding Amyloid PET Limitations

• A negative amyloid PET scan significantly reduces the likelihood of Alzheimer's disease but does not completely rule it out, especially in patients with clinical symptoms strongly suggestive of AD 1
• Amyloid PET detects fibrillar amyloid plaques but may not detect other forms of amyloid pathology such as soluble oligomers that could contribute to cognitive impairment 3
• The 2024 ACR Appropriateness Criteria states that while a negative brain amyloid PET/CT usually excludes a diagnosis of AD, other forms of neurodegenerative conditions may still be present 1

Scenarios Where AD May Exist Despite Negative Amyloid PET

• Discordance between CSF amyloid markers and amyloid PET has been documented, with some patients showing abnormal CSF Aβ42/Aβ40 ratios despite negative amyloid PET scans 2
• In these discordant cases, other biomarkers such as FDG-PET and CSF tau markers may still support an AD diagnosis 2
• The variability in amyloid plaque conformation may affect PET tracer binding, resulting in false-negative scans in some symptomatic patients 2

Clinical Decision-Making Algorithm

1. Initial assessment: Evaluate clinical presentation and cognitive testing results

   • If typical AD presentation but negative amyloid PET, consider:
     • Patient age (younger patients may have atypical presentations) 1
     • Alternative biomarkers such as CSF Aβ42/Aβ40 ratio 2

2. Additional biomarker testing:

   • Consider CSF analysis for Aβ42/Aβ40 ratio and tau markers 2
   • Evaluate FDG-PET for AD-typical hypometabolism patterns 1
   • Consider tau PET if available 1

3. Interpretation of conflicting results:

   • When amyloid PET is negative but other biomarkers suggest AD:
     • CSF Aβ42/Aβ40 ratio may have better agreement with pathology in some cases 2
     • Combined assessment of multiple biomarkers increases diagnostic accuracy 1

Important Considerations and Caveats

• Equivocal amyloid PET findings occur in approximately 13% of cases and represent an intermediate state between positive and negative scans 4
• The 2024 ACR Appropriateness Criteria notes that when amyloid and FDG-PET results are incongruent, mixed dementia should be considered 1
• Recent research suggests that only about one-third of persons with AD diagnoses follow the classic amyloid cascade hypothesis precisely, indicating significant heterogeneity in disease presentation 5
• The Society of Nuclear Medicine and Molecular Imaging guidelines suggest that amyloid PET is most appropriate for patients with persistent or progressive unexplained mild cognitive impairment or possible AD with atypical presentations 1

Emerging Perspectives

• The revised 2024 Alzheimer's Association criteria recognize a biological-clinical staging framework that accounts for variations in disease presentation and progression 5
• Research on soluble amyloid-β oligomers suggests they may play a pathogenic role very early in AD, potentially before they can be detected by current amyloid PET technology 3
• The relationship between neuropathology and cognitive impairment in AD is complex, with both amyloid plaques and neurofibrillary tangles contributing to cognitive decline through mechanisms that may not always be captured by current imaging techniques 6