Aims

Blood-based Alzheimer’s disease (AD) biomarkers provide opportunities for community studies and across ethnic groups.

We investigated blood biomarker concentrations in the Washington Heights, Inwood, Columbia Aging Project (WHICAP), a

multi-ethnic community study of aging and dementia. The goal was to determine the effectiveness of state-of-the-art ADrelated

plasma biomarkers, including Aβ40 and ββ42 as markers of amyloid pathology, total tau and neurofilament light

chain (NfL) as markers of neurodegeneration, and phospho-tau (P-tau) 181 and 217 as markers of tau pathology. We

compared plasma biomarker concentrations between clinically- and pathologically-defined diagnostic groups and

examined differences by race/ethnicity groups.

Methods

We measured plasma Aβ40, Aβ42,T-tau, P-tau181 and P-tau217, and neurofilament light chain (NfL) in 113 autopsied

participants, (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical

AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as

predictors of incident clinical AD.

Results

P-tau181, P-tau217 and NfL concentrations were elevated in pathologically diagnosed AD and to a lesser extent in

clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased P-tau217 and P-tau181 were associated with

subsequent AD diagnosis in a follow-up of previously unaffected individuals.

Conclusions

Blood-based AD biomarker concentrations of the Aβ42/Aβ40 ratio, P-tau217 and P-tau181 are associated with

pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be

incorporated into multi-ethnic, community-based studies.

Aims

We assessed the utility of plasma phosphorylated tau (P-tau) 181 and 217 as biomarkers of AD pathophysiology in a population-based setting and examined interclass correlation coefficients (ICC) to determine intra-individual variability over serial samples.

Methods

We included 1,329 Mayo Clinic Study on Aging participants (1,161 cognitively unimpaired, 153 MCI, 15 dementia), median age of 69 (range 30-98); 1,066 had amyloid PET and 495 tau PET. P-tau 181 and 217 was measured on the MSD platform; previous cutpoints were used for analyses. Elevated amyloid (A+) was defined as SUVR≥1.48 using PiB PET; elevated tau (T+) as SUVR≥1.25 using F-18-AV-1451. Area under the Receiver Operating Curve (AUROC) and diagnostic statistics were used to assess the accuracy of plasma P-tau for amyloid and tau PET. ICCs of P-tau levels were calculated.

Results

Among all participants, plasma P-tau181 predicted A+ with an AUROC of 0.71, 51% sensitivity, 92% specificity, and 81% positive predictive value (PPV). For P-tau217 and A+, the AUROC was 0.74, 51% sensitivity, 96% specificity, 90% PPV. Plasma P-tau181 predicted T+ with an AUROC of 0.59, 22% sensitivity, 95% specificity, 54% PPV. For P-tau 217, the AUROC was 0.63, 34% sensitivity, 92% specificity, 53% PPV. Both P-tau181 and 217 levels increased with clinical severity (CU<MCI<dementia, p<0.001). The ICC (95% CI) for Ptau181 was 0.92 (0.92, 0.93) and for Ptau217 was 0.95 (0.95, 0.96).

Conclusions

In this population-based sample, both plasma P-tau181 and 217 had good discrimination for A+, but discrimination for T+ was lower. There was low intra-individual variability over serial samples.