Characterization of Alzheimer Disease Biomarker Discrepancies Using Cerebrospinal Fluid Phosphorylated Tau and AV1451 Positron Emission Tomography

1. Flortaucipir-PET and CSF modalities for assessing tau pathology not only differ in results in early Alzheimer’s dementia (AD) but suprathreshold CSF P-tau may be indicative of early AD that is unrecognizable via cognitive testing.

2. CSF P-tau may provide evidence of disease progression that early fortaucipir-PET cannot sufficiently detect.

Evidence Rating Level: 1 (Excellent)

Both amyloid-β (Aβ) and tau pathologies are characteristic biomarkers of Alzheimer’s disease (AD). Aβ accumulation is evaluated through cerebrospinal fluid (CSF) and positron emission tomography (PET), with results from these two modalities often being used interchangeably. Due to the similar but unidentical information obtained from these procedures, this cohort study sought to evaluate tau pathology with CSF and fluorine 18-labeled flortaucipir (AV1451) PET to determine whether or not they offer different information related to disease progression and cognitive decline in AD. A total of 322 participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent both CSF and PET evaluations of tau pathology within 25 months of analyses (mean [SD] age = 73.08 [7.37] years, 56% female). Of these, 66.1% were cognitively healthy, 30.4% had mild cognitive impairment (MCI), and 3.4% had AD dementia. PET regions of interest (ROI) were established to determine positivity (standard uptake value ratio ≥1.37) and included the bilateral entorhinal, amygdala, fusiform, inferior, and middle cortices due to evidence supporting their roles in AD. Thresholds were calculated for CSF phosphorylated tau (P-tau; ≥26.64 pg/mL). Approximately 65% of participants were CSF^–/PET^–, 19.5% CSF⁺/PET^–, 4.6% CSF^–/PET⁺, and 10.5% CSF⁺/PET⁺. Findings suggested that a categorization of CSF⁺/PET^– resulted in a significantly faster five-year accumulation of P-tau and increased PET binding in RIOs compared to CSF^–/PET^– participants (CSF+/PET- time-by-group interaction β [SE] 0.06 [0.03] pg/mL/mo, p = 0.02; CSF⁺/PET⁺ time-by-group interaction β [SD] 0.11 [0.03] pg/mL/mo, p<0.001). When either measure indicated tau positivity, there was evidence of elevated Aβ-PET burden. Estimated model intercepts suggested that P-tau may precede the five-year period during which these analyses began (CSF⁺/PET^– β [SD] 17.65 [2.82], p<0.001; CSF⁺/PET⁺ β [SE] 29.45 [3.33], p<0.001). Further all CSF⁺/PET⁺ participants were Aβ positive and 76% were diagnosed with either MCI or AD. This study provides evidence that flortaucipir-PET and CSF modalities for assessing tau pathology not only differ but also that suprathreshold CSF P-tau may be indicative of early AD dementia  unrecognizable via cognitive testing. Essentially, CSF P-tau may provide evidence of disease progression that early fortaucipir-PET cannot sufficiently detect. 

Click to read the study in JAMA Neurology

Image: PD

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