Non-linear relationships of cerebrospinal fluid biomarker levels with cognitive function: an observational study

We assessed cognitive function and assayed CSF Aβ and Tau biomarkers in 95 non-demented volunteers and 97 AD patients. We then tested non-linearities in their inter-relations.CSF biomarkers related to cognitive function in the non-demented range of cognition, but these relations were weak or absent in the patient range; Aβ1-40's relationship was biphasic.Major biomarker changes precede clinical AD and index cognitive impairment in AD poorly, if at all.The incidence and prevalence of Alzheimer's disease (AD) double every five years from age 65, to affect over one quarter of people aged over 85 [1,2]. AD pathology can develop long before clinical symptoms [3-5]. This means that, ideally, disease-modifying treatments should begin before diagnosis [6]. Consequently, there is much interest in finding biomarkers that can predict the onset of AD [7]. There is also much interest in finding biomarkers to assess treatment effects [8]. Leading candidates for these roles are β-amyloid (Aβ) and Tau proteins in the cerebrospinal fluid (CSF) [9-15]. To date, nearly all studies of CSF biomarkers have related them to diagnostic categories -AD and mild cognitive impairment (MCI). However, the boundaries of diagnostic categories, particularly MCI, are uncertain [16-18]. We, therefore, related CSF biomarkers directly to cognitive test scores.The form of the relationship between biomarker levels and cognitive scores is important. To predict the onset of AD, a biomarker should relate to cognitive decline pre-clinically. Conversely, to monitor disease progression and treatment response, a biomarker should relate to cognitive level in the range of clinical dementia. These relationships may be such that alterations in biomarker expression may precede, coincide with, or lag behind changes in cognitive status. The simplest assumption would be that the relation of CSF amyloid and Tau biomarkers with cognitive function is linear from cognitive normality through MCI to AD. If so, then these biom