Tau Protein is Associated with Longitudinal Memory Decline in Cognitively Healthy Subjects with Normal Alzheimer’s Disease Cerebrospinal Fluid Biomarker Levels

Abstract

Background: We investigated a sample of cognitively healthy subjects with normal Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker levels to identify the earliest variables related to longitudinal memory changes. Objective: Employing a new highly demanding learning and memory test (the Ancient Farming Equipment Test; AFE-T), we aimed to investigate whether a biomarker related to neurodegeneration (i.e., CSF tau) was associated with longitudinal memory decline.Methods: Thirty-two cognitively and biologically normal (CBN) subjects underwent MRI, neuropsychological assessment, and the AFE-T at baseline and 18 months later. To explore the relationship between cognitive performance and relevant factors, a linear model was set up. For a secondary analysis that further explore the effect of tau, the subjects were divided into CBN-Tau ↓ (tau < 228.64 pg/ml; n = 16) and CBN-Tau ↑ (tau > 228.64 pg/ml; n = 16). We also performed voxel-based morphometry (VBM) to identify regions of grey matter volume that would predict both baseline and longitudinal cognitive performance. Results: Our main finding was an association between CSF tau and longitudinal memory decline measured with AFE-T (B = -0.17, p < 0.05; r = -0.414; p < 0.01), and further analyses showed different evolvement between subgroups, with an accelerated decline in individuals with higher tau (F(1,31) = 8.37; p < 0.01). VBM results suggested that AFE-T performance is related to grey matter volume in a medial temporal, middle frontal, and posterior cerebellar network at baseline, and that there are strategic brain areas driving the longitudinal cognitive changes. Conclusions: The present findings provide evidence for structural and biological markers linked to cognitive aging by highlighting the role of tau, a marker of neurodegeneration, which can be related with the earliest memory changes in healthy subjects.

A computerized version of the Short Form of the Face-Name Associative Memory Exam (FACEmemory®) for the early detection of Alzheimer’s disease

“…This result is consistent with those of other studies reporting a link between performances on episodic memory tests, such as the original FNAME [4], the S-FNAME [8], the PAL CANTAB [1], or the Ancient Farming Equipment Test [43], and biomarkers of AD pathology, either PET imaging or CSF. Moreover, our results are consistent with the findings showing that CSF tau levels are more related to cognitive functioning, mainly memory, than CSF Aβ levels [43][44][45][46][47][48]. Additionally, the Aβ/p-tau ratio, which includes both AD biomarkers, was the CSF measurement that best correlated with performance on FACEmemory®, reinforcing the hypothesis that this test is a diagnostic tool that reflects AD pathology changes [49].…”

Accelerated long‐term forgetting in individuals with subjective cognitive decline and amyloid‐β positivity

“…Another important point regarding the nature of AFE‐T and its potential application in SCD concerns its neural correlates. Recently, the functional and structural brain correlates of the AFE‐T have been identified in cognitively unimpaired individuals 6,46 as well as in patients 8,47 . These studies have suggested that performance on this task depends on specific brain regions that are typically affected in AD, such as the medial temporal lobe (MTL).…”

Speech pause distribution as an early marker for Alzheimer’s disease

“…More recent studies have demonstrated that this particular cognitive profile in MCI is compatible with positive AD biomarkers [26,27,28,29,30], as well as abnormal neural connectivity [31,32,33] and cerebral perfusion patterns [34] during memory encoding tasks. Moreover, declines in memory encoding have been predicted in amyloid-positive cognitively-normal individuals [35,36,37] alongside downstream tau increases [38,39,40,41], as well as in patients with subjective cognitive complaint with positive AD biomarkers [42]. Abnormal cortical activity has also been observed in genetic carriers during memory encoding tasks [43,44], supporting the thesis of a preference of AD pathology for cortical areas devoted to memory processing and, more precisely, those involved in encoding and retrieval of newly learned information.…”