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

Abstract

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/Aβ40, 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.

Medial temporal lobe structure, mnemonic and perceptual discrimination in healthy older adults and those at risk for mild cognitive impairment

“…Although the magnitude of decline in mnemonic discrimination performance was equivalent across task formats among at-risk older adults, our results suggest that the interpretation of these deficits should be considered carefully, because task formats could have a major influence on the underlying processes that give rise to such deficits. Perceptual discrimination deficits may contribute to decline in mnemonic discrimination observed in high risk individuals, both in our study and in previous work, regardless of task format (Berron et al, 2019; Sinha et al, 2018; Stark et al, 2013; Trelle et al, 2021; Webb et al, 2020; Yassa et al, 2010). This is likely because less detailed perceptual representations not only hamper hippocampal pattern separation but also weaken the distinctiveness of a cortical strength-based memory signal by virtue of leaving memory representations more vulnerable to interference (Kent et al, 2016; Ly et al, 2013; Monti et al, 2014; Muecke et al, 2018; Newsome et al, 2012; Ryan et al, 2012).…”

Novel approaches to measuring neurocognitive functions in Alzheimer's disease clinical trials

“…This task has alternate forms and is robust to practice effects [32], making it also suitable for serial assessments. Worse performance on the associative memory task and MST correlated with higher levels Alzheimer's disease biomarkers, such as CSF Aβ42/Aβ40 and Aβ+ status, though associations were small [27 ▪ ]. Both tasks were more sensitive to Aβ than the Logical Memory test from the Wechsler Memory Scale.…”

Advances in brain barriers and brain fluids research in 2021: great progress in a time of adversity

“…There continues to be enormous interest in the use of CSF proteins as biomarkers, particularly in relation to dementia [ 51 – 54 ]. The use of CSF biomarkers to distinguish between Alzheimer’s disease and frontotemporal lobar degeneration has been examined by Cousins et al [ 55 ].…”