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

Abstract

Importance: Fluid and imaging biomarkers of Alzheimer disease (AD) are often used interchangeably, but some biomarkers may reveal earlier stages of disease.

Objective: To characterize individuals with tau abnormality indicated by cerebrospinal fluid (CSF) assay or positron emission tomography (PET).

Design, setting, and participants: Between 2010 and 2019, 322 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent CSF and PET assessments of tau pathology. Data-driven, clinically relevant thresholds for CSF phosphorylated tau (P-tau) (≥26.64 pg/mL) and flortaucipir-PET meta-regions of interest (ROI) (standard uptake value ratio ≥1.37) indicated participants' tau status as CSF-/PET-, CSF+/PET-, CSF-/PET+, and CSF+/PET+. Of 1659 ADNI participants with a CSF or flortaucipir assessment, 588 had both measures (1071 were excluded). Among these, 266 were further excluded because they did not have flortaucipir and CSF testing within less than 25 months, leaving 322 for analysis. Of these, 213 were cognitively unimpaired (CU); 98 had mild cognitive impairment (MCI); and 11 had AD dementia.

Main outcomes and measures: We compared tau-positive vs tau-negative groups as indicated by either modality or demographic and clinical variables, amyloid β-PET burden, and flortaucipir-PET binding across Braak stage-related ROIs. We also compared 5-year rates of CSF P-tau accumulation and cognitive decline prior to flortaucipir-PET scanning.

Results: Among the 322 study participants, 180 were women (56%), and the mean (SD) age was 73.08 (7.37) years. Two hundred ten participants were CSF-/PET- (65%); 63 were CSF+/PET- (19.5%); 15 were CSF-/PET+ (4.6%); and 34 were CSF+/PET+ (10.5%). Most CSF-/PET+ participants had measures near CSF or PET tau thresholds. The CSF+/PET- participants showed faster 5-year accrual of P-tau and increased flortaucipir-PET binding in early Braak ROIs but similar memory decline compared with CSF-/PET- participants. Tau-positive individuals by either measure showed increased amyloid β-PET burden. All CSF+/PET+ individuals were amyloid-positive, and 26 had MCI or AD dementia (76%). Compared with the CSF-/PET- group, CSF+/PET+ individuals had experienced faster 5-year accrual of CSF P-tau and decline in memory and executive function, resulting in reduced cognitive abilities at the time of flortaucipir-PET assessment.

Conclusions and relevance: Suprathreshold CSF P-tau without flortaucipir-PET abnormality may indicate a stage of AD development characterized by early tau abnormality without measurable loss in cognitive performance. Persons with both tau CSF and PET abnormality appear to have reduced cognitive capacities resulting from faster antecedent cognitive decline. Elevation of CSF P-tau appears to precede flortaucipir-PET positivity in the progression of AD pathogenesis and related cognitive decline.

Figure 1.. Classification of Alzheimer’s Disease Neuroimaging Initiative (ADNI) Participants in Tau Cerebrospinal Fluid/Positron Emission Tomography (CSF/PET) Groups

We classified ADNI participants into tau CSF/PET categories based on their CSF phosphorylated tau (P-tau; positivity ≥26.64 pg/mL) and meta–regions of interest (meta-ROI) flortaucipir-PET binding (standard uptake value ratio [SUVR] threshold ≥1.37) measures. Color code represents the tau CSF/PET groups and shape indicates clinical diagnosis. Dotted lines delineate a 5% interval around tau CSF/PET thresholds. Faded dots indicate participants who would fall within this interval. CU indicates cognitively unimpaired; MCI, mild cognitive impairment; AD, Alzheimer disease.

Figure 2.. Demographic and Cross-Sectional Biomarker Characteristics of Tau Cerebrospinal Fluid/Positron Emission Tomography (CSF/PET) Groups

A, The proportion of APOE ε4 carriers was different among CSF/PET groups. In post hoc analyses, CSF⁺/PET⁻, CSF⁻/PET⁺, and CSF⁺/PET⁺ had a higher proportion of APOE ε4 carriers than the CSF⁻/PET⁻ group. B, The proportion of cognitively impaired participants was increased in PET⁺ groups when compared with PET⁻ groups, regardless of CSF status. C, There was a marked difference in the frequency of florbetapir and florbetaben-PET (amyloid β)⁺ individuals across groups. Post hoc analyses suggested that all tau⁺ groups on either modality had a higher proportion of florbetapir or florbetaben-PET–(amyloid β)⁺ participants compared with the CSF⁻/PET⁻ group. D, All 3 tau⁺ groups also had higher mean cortical florbetapir-PET uptake. The CSF⁻/PET⁺ and CSF⁺/PET⁺ groups had measurably lower executive function (E) and memory performance (F) compared with the CSF⁻/PET⁻ and CSF⁺/PET⁻ groups. Bars indicate group median (red line), 1st and 99th percentiles (small black line) and 25th and 75th percentiles (thick black lines). ^aP < .05 ^bP < .01 ^cP < .005

Figure 3.. Retrospective Trajectories of Cerebrospinal Fluid (CSF) Phosphorylated Tau (P-Tau), Memory and Executive Function

We investigated CSF P-tau and cognitive performance (memory and executive function) in the 5 years (60 months) preceding flortaucipir–positron emission tomography (PET) scanning (time 0) as a function of PET/CSF status. A, Individual trajectories and measures of CSF P-tau during the 5 years preceding the flortaucipir-PET scan. B, Results from linear mixed-effects analyses where 5-year change in CSF P-tau was estimated for each tau CSF/PET group. When compared with the CSF⁻/PET⁻ groups, both CSF⁺ groups had higher intercept values and faster rates of CSF P-tau accrual over the 5-year interval. C and D indicate the same information for the performance on the ADNI memory composite scale. All 3 tau⁺ groups tended to have faster rates of memory decline over the 60 months antecedent to flortaucipir-PET scanning than the CSF⁻/PET⁻ group. However, only the CSF⁺/PET⁺ group had a lower intercept when compared with the CSF⁻/PET⁻ group, thereby suggesting that their memory decline had started earlier. D and F indicate the results of an identical analysis considering the Alzheimer’s Disease Neuroimaging Initiative executive function composite. Concordant negative and discordant tau biomarker groups had similar intercept values for their performance on the executive function composite. When compared with the CSF⁻/PET⁻ group, only the CSF⁺/PET⁺ group had faster decline in executive function over the 5-year period preceding flortaucipir-PET scanning.