Association of CSF Biomarkers With Hippocampal-Dependent Memory in Preclinical Alzheimer Disease

Abstract

<h3>Objective</h3> To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF β-amyloid (Aβ)₄₂/Aβ₄₀ and phosopho-tau₁₈₁ (p-tau₁₈₁) in cognitively unimpaired older adults (CU). <h3>Methods</h3> CU enrolled in the Stanford Aging and Memory Study (n = 153; age 68.78 ± 5.81 years; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ₄₂, Aβ₄₀, and p-tau₁₈₁ were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word–picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied “target” objects, novel “foil” objects, and perceptually similar “lure” objects. Analyses examined cross-sectional relationships among memory performance, age, and CSF measures, controlling for sex and education. <h3>Results</h3> Age and lower Aβ₄₂/Aβ₄₀ were independently associated with elevated p-tau₁₈₁. Age, Aβ₄₂/Aβ₄₀, and p-tau₁₈₁ were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target–lure similarity). P-tau mediated the effect of Aβ₄₂/Aβ₄₀ on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF Aβ₄₂ was not significantly associated with p-tau₁₈₁ or memory. <h3>Conclusions</h3> Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying CU with preclinical AD pathology.