Association of CSF Biomarkers with Hippocampal-dependent Memory in Preclinical Alzheimer Disease

Objective: To determine if memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer’s disease (AD) biomarkers, we examined associations between performance in three memory tasks and CSF Aβ₄₂/Aβ₄₀ and p-tau₁₈₁ in cognitively unimpaired older adults (CU).

Methods: CU enrolled in the Stanford Aging and Memory Study (N=153; age 68.78 ± 5.81 yrs; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ₄₂, Aβ₄₀, and phosopho-tau₁₈₁ (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 between memory performance, age, and CSF measures, controlling for sex and education.

Results: Age and lower Aβ₄₂/Aβ₄₀ were independently associated with elevated p-tau₁₈₁. Age, Aβ₄₂/Aβ_40, and p-tau₁₈₁ were each associated with a) poorer associative memory and b) 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 non-significant. CSF Aβ₄₂ was not significantly associated with p-tau₁₈₁ or memory.

Conclusions: 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 cognitively unimpaired older adults with preclinical AD pathology.