The objective of this study was to evaluate novel plasma p-tau231 and p-tau181, as well as Aβ 40 and Aβ 42 assays as indicators of tau and Aβ pathologies measured with positron emission tomography (PET), and their association with cognitive change, in cognitively unimpaired older adults. Methods: In a cohort of 244 older adults at risk of Alzheimer's disease (AD) owing to a family history of AD dementia, we measured single molecule array (Simoa)-based plasma tau biomarkers (p-tau231 and p-tau181), Aβ 40 and Aβ 42 with immunoprecipitation mass spectrometry, and Simoa neurofilament light (NfL). A subset of 129 participants underwent amyloid-β ( 18 F-NAV4694) and tau ( 18 F-flortaucipir) PET assessments. We investigated plasma biomarker associations with Aβ and tau PET at the global and voxel level and tested plasma biomarker combinations for improved detection

ObjectiveTo investigate relationships between flortaucipir (FTP) uptake, age, and established Alzheimer disease (AD) markers in asymptomatic adults at increased risk of AD.MethodsOne-hundred nineteen individuals with a family history of AD (Presymptomatic Evaluation of Experimental or Novel Treatments of Alzheimer’s Disease [PREVENT-AD] cohort, mean age 67 ± 5 years) underwent tau-PET ([18F]FTP), β-amyloid (Aβ)-PET ([18F]NAV4694 [NAV]), and cognitive assessment. Seventy-four participants also had CSF phosphorylated tau and total tau data available. We investigated the association between age and FTP in this relatively young cohort of older adults. We also investigated regional FTP standardized uptake value ratio (SUVR) differences between Aβ-positive and Aβ-negative individuals and regional correlations between FTP and NAV retention. In cortical regions showing consistent associations across analyses, we assessed whether FTP was in addition related to CSF tau and cognitive performance. Lastly, we identified the lowest FTP value at which associations with Aβ-PET, CSF, and cognition were detectable.ResultsIncreased age was associated only with amygdala and transverse temporal lobe FTP retention. Aβ-positive individuals had higher FTP SUVR values in several brain regions, further showing correlation with NAV load through the cortex. Increased FTP SUVRs in medial temporal regions were associated with increased CSF tau values and worse cognition. The SUVRs at which associations between entorhinal FTP SUVR and other AD markers were first detected differed by modality, with a detection point of 1.12 for CSF values, 1.2 for Aβ-PET, and 1.4 for cognition.ConclusionsRelatively low FTP-PET SUVRs are associated with pathologic markers of AD in the preclinical phase of the disease. Adjustment in the tau threshold should be considered, depending on the purpose of the tau classification.

ImportanceNational Institute on Aging–Alzheimer’s Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD).ObjectiveTo assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD.Design, Setting, and ParticipantsThis longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years.ExposuresBased on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T−, A−T+, A−T−). Presence (+) or absence (−) of neurodegeneration (N) was assessed using temporal cortical thickness.Main Outcomes and MeasuresEach cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups.ResultsAmong 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable.Conclusions and RelevanceThe clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.

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