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). 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) (Ն26.64 pg/mL) and flortaucipir-PET meta-regions of interest (ROI) (standard uptake value ratio Ն1.37) 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. DESIGN, SETTING, AND PARTICIPANTS MAIN OUTCOMES AND MEASURESWe 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.

Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer’s disease

“…However, other studies did not find a relationship between CSF p-tau and [ 18 F]flortaucipir within cognitively unimpaired controls [9][10][11], which could be related to the notion that individuals with SCD are at increased risk for AD [65,66,67]. However, p-tau may be more sensitive in early stages than [ 18 F]flortaucipir [11,26,52], as subtle increases in [ 18 F]flortaucipir binding has been shown in the preclinical stages of AD [15,19,60,68].…”

“…Ideally, CSF would be collected on the day of the PET scan, and although our results were comparable if we adjusted the time lag between CSF p-tau and tau PET to a maximum of 1 year and we entered the time lag as a covariate in our main analysis, this time lag may have affected our results. Since p-tau levels may rise before tau PET [11,26,52], associations may have been stronger when there was a greater time lag.…”

“…[ 18 F]flortaucipir PET is able to capture regional uptake patterns and mirrors established neuropathological staging schemes of tau [15,22], while correlations of CSF p-tau with neuropathological tau burden have been modest [23,24]. However, CSF p-tau may be more sensitive in detecting early changes in AD (tau) pathology [11,25,26]. Few studies have described the relationship between both CSF p-tau and [ 18 F]flortaucipir binding with proxies of disease severity, and it remains to be established whether [ 18 F]flortaucipir PET and p-tau can be viewed as equivalent markers for AD staging.…”

Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes

“…[36][37][38] Since AD pathology has accumulated for many years before apparent clinical symptoms occur, 39,40 the early identification of non-demented individuals at imminent risk of cognitive impairment would provide insights into intervention as well as new therapy approaches. 41 And the heterogeneity in the definition of neuronal injury is vital to clinical trials using biomarkers for enrollment or as alternative endpoint measures. In all groups, discordant individuals were intermediate to concordant-negative and concordant-positive persons in terms of cognitive performance, no matter in a non-demented (CN and MCI) population, or a separate CN or MCI population.…”

Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes in older adults without dementia

“…Since AD pathology has accumulated for decades before apparent clinical symptoms occur, the early identi cation of non-demented individuals at imminent risk of cognitive impairment would provide insights into intervention as well as new therapy approaches [32]. And the heterogeneity in the de nition of neuronal injury is vital to clinical trials using biomarkers for enrollment or as alternative endpoint measures.…”