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

Neurology. 2021 Mar 9;96(10):e1470-e1481. doi: 10.1212/WNL.0000000000011477. Epub 2021 Jan 6.


Objective: 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).

Methods: 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.

Results: 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.

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 CU with preclinical AD pathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / psychology
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / physiopathology
  • Alzheimer Disease / psychology
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Association Learning
  • Biomarkers / cerebrospinal fluid*
  • Cross-Sectional Studies
  • Cues
  • Discrimination, Psychological
  • Female
  • Hippocampus / physiopathology*
  • Humans
  • Male
  • Memory
  • Memory Disorders / cerebrospinal fluid*
  • Memory Disorders / physiopathology
  • Memory Disorders / psychology*
  • Memory, Episodic
  • Mental Recall
  • Middle Aged
  • Neuropsychological Tests
  • Peptide Fragments / cerebrospinal fluid
  • Psychomotor Performance
  • tau Proteins / cerebrospinal fluid


  • Amyloid beta-Peptides
  • Biomarkers
  • MAPT protein, human
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins