Day, Gregory S

Abstract Background Plasma p ‐tau217 represents a promising alternative to PET‐ and CSF‐based biomarkers of AD in well‐characterized research cohorts. However, the performance of this accessible biomarker in outpatient clinics comprised of patients with multiple causes of cognitive impairment has yet to be established. Method Plasma Aβ42/40 and p ‐tau217 concentrations were measured using Fujirebio Lumipulse assays in patients evaluated within a subspecialty memory clinic at Mayo Clinic in Florida. Syndromic and etiologic diagnoses were established by consensus, integrating clinical data and findings from MRI ( n = 484), FDG‐PET ( n = 117), and CSF AD biomarkers ( n = 440). Plasma biomarker performance was evaluated using established diagnostic cutpoints to identify patients with “positive/elevated”, “intermediate”, or “negligible” levels of cerebral amyloid pathology on amyloid‐PET. Result Plasma AD biomarkers were measured in 509 patients (mean 68.6±9.3 years; 47% female; 91.3% non‐Hispanic White), including patients with typical amnestic AD ( n = 237, 46.6%), non‐amnestic presentations of AD ( n = 48, 9.4%), and non‐AD causes of cognitive concerns ( n = 224, 44.0%). “Intermediate” plasma p ‐tau217 and p ‐tau217/Aβ42 concentrations were reported in <15% of patients (43% of patients with Aβ42/40), implying the need for further testing to inform the likelihood of AD neuropathologic change in these patients. After excluding these patients, plasma p ‐tau217 reliably distinguished patients with symptomatic AD with 95% sensitivity and 82% specificity. Integration of Aβ42 measures (ptau217/Aβ42) incrementally improved specificity (86%). Diagnostic performance was unaffected by age (> vs < 65‐years). Plasma p ‐tau217 (AUC: 0.94; 95%CI: 0.91‐0.96) and p ‐tau217/Aβ42 performance (AUC: 0.96; 95%CI: 0.94‐0.98) were closely aligned with results of established CSF AD biomarkers ( p ‐tau181/Aβ42), outperforming Aβ42/40 (AUC: 0.78; 95%CI: 0.74‐0.83). Reduced kidney function was associated with elevated plasma p ‐tau217 and p ‐tau217/Aβ42 concentrations in patients without AD (referencing CSF AD biomarkers). Conclusion Concentrations of plasma p ‐tau217, but not Aβ42/40, strongly associated with clinical diagnoses of symptomatic AD and CSF AD biomarker results. Integration of Aβ42 measures yielded marginal improvements in performance, with increased complexity and cost. These findings support the use of plasma p ‐tau217 in heterogeneous clinical cohorts, including patients with multiple causes of cognitive impairment. Caution is advised when interpreting p ‐tau217 concentrations in patients with decreased kidney function, due to potential elevations in plasma biomarker concentrations.

Abstract Background Black and Latino Americans experience a disparate dementia burden yet remain underrepresented in dementia research, including clinical trials designed to slow or prevent symptomatic Alzheimer's disease (AD). Accessible and non‐invasive AD blood biomarkers may improve identification and recruitment of underrepresented participants into AD clinical trials. There is a clear need to assess the performance of emergent plasma AD biomarkers for the detection of AD neuropathology in cognitively normal Black and Latino Americans. Method Cognitively normal Black and Latino participants underwent cognitive evaluations and PET (amyloid‐PiB, tau‐flortaucipir) imaging at Mayo Clinic in Florida. Plasma p ‐tau217 was measured using Fujirebio Lumipulse assays. We evaluated the diagnostic performance of a p ‐tau217 threshold (≥0.186 pg/mL) known to identify non‐Hispanic White participants with cognitive impairment and “positive” amyloid PET scans (>25 Centiloids). Next, we derived an optimized threshold to identify participants with “positive” amyloid PET using Youden's method. Result The cohort included 58 Black (55%) and 47 Latino‐White (45%) well‐educated (mean 16.1±2.3 years) individuals, with mean age 64.7±8.8 years, and slight female bias (63%). Plasma p ‐tau217 concentrations increased with age (rho=0.269, p = 0.004) and declined with MoCA scores (rho=‐0.225, p = 0.027). Sixty‐nine participants completed amyloid‐ and tau‐PET imaging. Plasma p ‐tau217 concentrations increased with amyloid‐ (rho=0.254, p = 0.044) but not with tau‐PET standardized uptake value ratio (rho=0.127; p = 0.334). p ‐tau217 concentrations were ≥0.186 pg/mL in 10/69 participants (14%), including 3/3 amyloid‐ and tau‐PET positive (A+T+) participants, 3/8 A+T‐ participants (sensitivity: 55%), and 4/58 A‐T‐ participants (specificity 93%). An optimized p ‐tau217 threshold of ≥0.118 pg/mL identified 10/11 A+T± participants (sensitivity 91%), and 16/58 A‐T‐ participants (specificity 73%). In A‐T‐ participants, estimated glomerular filtration rate was lower in participants with ‘false positive’ elevations in plasma p ‐tau217 (mean difference: 67 vs 81 ml/min/1.73m 2 , p = 0.004), emphasizing the need for caution when interpreting plasma p ‐tau217 concentrations in patients with decreased kidney function. Conclusion Plasma p ‐tau217 thresholds validated in participants with symptomatic AD (≥0.186 pg/mL) failed to identify early AD neuropathology in 5/8 cognitively normal Black and Latino participants. Optimized thresholds are required to improve detection of preclinical AD in Black/Latino individuals.

Abstract Background The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory‐predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non‐amnestic‐predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. Method We included tau‐PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n = 139 posterior cortical atrophy/PCA‐AD; n = 103 logopenic variant primary progressive aphasia/lvPPA‐AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS‐AD) from 14 sites, with a subset of patients ( n = 78) having longitudinal tau‐PET data. As an independent sample, we further included regional post‐mortem tau stainings from 93 atypical AD patients from two sites ( n = 19 PCA‐AD, n = 32 lvPPA‐AD, n = 23 bvAD, n = 19 CBS‐AD). Gaussian mixture modeling was used to harmonize different tau‐PET tracers by transforming tau‐PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross‐sectional and longitudinal tau‐PET and post‐mortem tau pathology, and 2) functional connectivity of tau‐PET epicenters and tau‐PET accumulation epicenters was associated with cross‐sectional and longitudinal tau patterns. Result Tau‐PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA‐AD (“visual AD”) and left‐hemispheric temporal predominance in lvPPA‐AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau‐PET levels, which was confirmed with post‐mortem data (Figure 2). Moreover, the connectivity profile of tau‐PET epicenters and accumulation epicenters corresponded to tau‐PET progression patterns (Figure 3). Conclusion Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant‐specific endpoints in clinical trials.