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INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co‐expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically‐relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p‐tau181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = −2.00, p = 0.005, M7: β = −2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post‐translational modifications for early cognitive and pathological changes. [ABSTRACT FROM AUTHOR]

Background: Recent advances demonstrate utility in blood‐based phosphorylated tau (pTau) as a diagnostic biomarker for Alzheimer's disease (AD). While several platforms show high diagnostic and prognostic performance, most assays rely on antibody combinations that require long tau peptides for their detection. The Lumipulse G Plasma pTau 181 assay (Fujirebio) instead uses an antibody combination targeting epitopes proximal to Thr181 and therefore can detect shorter tau peptides. This allows for a wider array of expressed plasma pTau 181 peptides to be measured. Method: Plasma pTau 181 was measured in three cohorts using the modified Lumipulse G Plasma pTau 181 assay: cohort 1 included 269 cognitively unimpaired (CU), 109 mild cognitively impaired (MCI), and 80 AD participants from the Stanford Alzheimer's Disease Research Center (ADRC); cohort 2 included 192 CU from the Stanford Aging and Memory Study (SAMS); and cohort 3 a third, independent plasma cohort from the Yale University ADRC included 20 CU and 20 AD participants. Outcome measures included discriminative accuracy of the modified assay for clinical AD diagnosis, association with amyloid and tau pathology determined using CSF biomarkers or positron emission tomography (PET), and ability to predict longitudinal cognitive change. Result: Plasma pTau 181 showed robust clinical performance in differentiating AD from CU participants in cohort 1 (AUC = 0.934) and cohort 3 (AUC = 0.845). In cohort 1, the analyte associated with CSF pTau 181 (β=+0.543 and P<0.001), CSF Aβ42/Aβ40 ratio (β=‐0.349 and P<0.001), and amyloid‐PET global SUVRs (β=+0.494 and P<0.001). Associations between plasma P‐tau181 with CSF and PET biomarkers were significant when examined in Aβ+ and Aβ‐ groups separately. Plasma pTau181 was also found to associate with inferior temporal tau‐PET in the subset of CU in cohort 2 (N=35, β=+0.393 and P=0.016). Finally, in cohort 1 baseline plasma pTau 181 predicted change in MoCA over 2‐year follow‐up, controlling for clinical diagnosis, age, sex, and education (β=‐0.211 and P=0.009). Conclusion: The results across these 3 participant cohorts revealed the modified Lumipulse G pTau 181 assay discriminates AD pathology in clinical and preclinical AD, strongly associates with CSF and PET imaging in Aβ+ and Aβ‐ participants and predicts longitudinal cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Heterogeneity in the clinical presentation of Alzheimer's disease (AD) underscores the importance of biomarker‐defined diagnosis for use in medicine, research and clinical trials. Therefore, CSF measurement of amyloid and tau is an important tool in the diagnostic toolbox for inferring AD‐related brain pathologies. Because differences in preanalytical handling and in study population demographics render it difficult to apply a set of global concentration cut points for defining normal/abnormal for each analyte, it is critical that analyte cut points representing normal/abnormal be determined in a center‐specific manner. Method: This is a cross‐sectional analysis of CSF collected from participants enrolled in the ongoing prospective cohort study of the Stanford Alzheimer's Disease Research Center. Participants underwent lumbar puncture and cognitive evaluation to receive a diagnosis of cognitively unimpaired (CU), mild cognitive impairment (MCI) or AD. The current study included cognitively normal adults (n=78), individuals with MCI (n=36), and individuals with AD (n=26). Core CSF AD biomarkers p‐tau181, total tau, Aβ42 and Aβ40 were measured (Lumipulse G1200 platform, Fujirebio US, Inc). Cutpoints identifying normal/abnormal amyloid and tau were generated using the Youden method and Amyloid+ was defined as abnormally low CSF Aβ42/Aβ40 while Tau+ was defined as abnormally elevated CSF p‐tau181 and/or total tau. Result: Classification by amyloid and tau biomarkers revealed that in this population, 64.1% (n=50) CU were biomarker negative for tau or amyloid pathology. However, 28.2% (n=22) of the CU were Amyloid+, 5.1% (n=4) were Amyloid+ and Tau+, and 2.6% (n=2) were Tau+ alone. In the MCI diagnostic group, 33.3% (n=12) were Amyloid+ alone, while 30.6% (n=11) were both Amyloid+ and Tau+, and 5.6% (n=2) were Tau+ alone. 30.6% (n=11) were both Amyloid‐ and Tau‐. Within those receiving an AD diagnosis, 23.1% (n=6) had CSF biomarker evidence for being Amyloid+ only, 65.4% (n=17) were both Amyloid+ and Tau+, and 11.5% (n=3) participants had no biomarker evidence for Amyloid+ or Tau+. Conclusion: These results highlight the heterogeneity underlying amyloid and tau pathology in clinically defined diagnostic groups. Biomarker‐defined diagnosis using center‐specific cut points will support accurate diagnosis, treatment, clinical research and enrollment in clinical trials. [ABSTRACT FROM AUTHOR]