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 Ab₄₂/Ab₄₀ 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 Ab₄₂, Ab₄₀, and phosopho-tau₁₈₁ (p-tau₁₈₁) were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a 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 Ab₄₂/Ab₄₀ were independently associated with elevated p-tau₁₈₁. Age, Ab₄₂/Ab_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 Ab₄₂/Ab₄₀ on memory. Relationships between CSF proteins and delayed recall were similar but non-significant. CSF Ab₄₂ 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.

Supplemental Data 

Method e-1. Tau PET imaging

Figure e-1: SAMS Participant Flowchart

Figure e-2: Gaussian Mixture Modelling

Figure e-3: CSF Proteins vs. Medial Temporal Lobe Tau 

Figure e-4: CSF Ab₄₂ Sample Characteristics

Figure e-5: CSF Proteins vs. Associative d’ by Stimulus Category

Figure e-6: CSF Proteins vs. Lure Discrimination Difference Scores

Table e-1: Relationships between CSF Proteins and Individual Standardized Delayed Recall Test Scores