Objective:To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease (AD) pathogenesis in cognitively normal aging individuals at increased risk of AD dementia.Methods:In 274 members of the PREVENT-AD cohort of healthy aging persons with a parental or multiple-sibling history of AD dementia, we assessed the cross-sectional association of OI with potential indicators of presymptomatic AD. Some 101 participants donated CSF, thus enabling assessment of AD pathology with the biomarkers total tau (t-tau), phospho-tau (P181-tau), and their ratios with β-amyloid (Aβ1-42). Adjusted analyses considered age, cognition, APOE ε4 status, education, and sex as covariates. We measured OI using the University of Pennsylvania Smell Identification Test and cognitive performance using the Repeatable Battery for Assessment of Neuropsychological Status. Standard kits provided assays of the AD biomarkers. Analyses used robust-fit linear regression models.Results:Reduced OI was associated with lower cognitive score and older age, as well as increased ratios of CSF t-tau and P181-tau to Aβ1-42 (all p < 0.02). However, the observed associations of OI with age and cognition were unapparent in adjusted models that restricted observations to CSF donors and included AD biomarkers. OI showed little association with CSF Aβ1-42 alone except in APOE ε4 carriers having lowest-quartile Aβ1-42 levels.Conclusions:These findings from healthy high-risk older individuals suggest that OI reflects degree of preclinical AD pathology, while its relationships with age and cognition result from the association of these latter variables with such pathology. Diminished OI may be a practical and affordable biomarker of AD pathology.

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

Conflict of interest statement AL has served at scientific advisory boards of Fujirebio Europe, Eli Lilly, Novartis and Nutricia and is the inventor of a patent on synaptic markers in CSF. LP has received honoraria as member of advisory boards from Fujirebio Europe, IBL International, Merck, Roche and Biogen.

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