Association of plasma biomarkers with longitudinal change in age- and Alzheimer's disease-related brain atrophy patterns.

INTRODUCTION: Determining whether plasma biomarkers are preferentially associated with Alzheimer's disease (AD)-related rather than age-related brain atrophy patterns may clarify their prognostic and diagnostic clinical use. METHODS: Using data from the Baltimore Longitudinal Study of Aging ( N =818), we examined cross-sectional plasma Aβ 42 /Aβ 40 , GFAP, NfL, p-tau181, and p-tau217 measurements obtained while participants were cognitively unimpaired (CU). During follow-up, 104 participants developed mild cognitive impairment (MCI)/dementia (74 due to AD, 24 due to non-AD, 6 unknown etiology). 2,293 longitudinal brain MRIs were used to quantify multidimensional atrophy pattern scores reflecting brain age (SPARE-BA), AD-like patterns (SPARE-AD), and five dominant dimensions of atrophy (R-indices). We investigated the associations of plasma biomarkers and atrophy pattern scores at index visit with conversion to MCI/dementia due to AD. We then examined the associations of plasma biomarkers with longitudinal change in pattern scores using linear mixed effects models. RESULTS: p-tau181, Aβ 42 /Aβ 40 (Lumipulse), and p-tau217 were associated with incident MCI/dementia due to AD but not non-AD etiologies, while GFAP was associated with incident MCI/dementia due to both AD and non-AD. All four biomarkers were associated with longitudinal SPARE-AD changes. Aβ 42 /Aβ 40 (Quanterix and Lumipulse), p-tau181, and p-tau217 were associated with longitudinal parieto-temporal atrophy. p-tau217 was the only biomarker associated with longitudinal medial temporal lobe atrophy. We did not find associations between plasma biomarkers and SPARE-BA or R-indices capturing subcortical, diffuse cortical, or perisylvian atrophy. DISCUSSION: Among CU individuals, plasma p-tau217 was associated with subsequent MCI/dementia due to AD and showed the most extensive associations with longitudinal AD-related brain atrophy.