Abstract
The elusive relationship between underlying pathology and clinical disease hampers diagnosis of Alzheimer’s disease (AD) and preventative intervention development. We seek to understand the relationship between two classical AD biomarkers, amyloid-β1−42 (Aβ1−42) and total-tau (t-tau), and define their trajectories across disease development, as defined by disease onset at diagnosis of mild cognitive impairment (MCI). Using longitudinal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we performed a correlation analysis of biomarkers CSF Aβ1−42 and t-tau, and longitudinal quantile analysis. Using a mixed effects model, with MCI onset as an anchor, we develop linear trajectories to describe the rate of change across disease development. These trajectories were extended through the incorporation of data from cognitively normal, healthy adults (aged 20–62 years) from the literature, to fit sigmoid curves by means of non-linear least squares estimators, to create curves encompassing the 50 years prior to MCI onset. A strong right-angled relationship between the biomarkers Aβ1-42 and t-tau is detected, implying a highly non-linear relationship. The rate of change of Aβ1-42 is correlated with the baseline concentration per quantile, reflecting a reduction in the rate of loss across disease within subjects. Regression models reveal significant amyloid loss relative to MCI onset (− 2.35 pg/mL/year), compared to minimal loss relative to AD onset (− 0.97 pg/mL/year). Tau accumulates consistently relative to MCI and AD onset, (2.05 pg/mL/year) and (2.46 pg/mL/year), respectively. The fitted amyloid curve shows peak loss of amyloid 8.06 years prior to MCI diagnosis, while t-tau exhibits peak accumulation 14.17 years following MCI diagnosis, with the upper limit not yet reached 30 years post diagnosis. Biomarker trajectories aid unbiased, objective assessment of disease progression. Quantitative trajectories are likely to be of use in clinical trial design, as they allow for a more detailed insight into the effectiveness of treatments designed to delay development of biological disease.
Highlights
In 2015, the World Alzheimer Report estimated there to be 46.8 million people globally living with dementia, with projections suggesting that this figure will increase to 131.5million by 2050 [1]
Through segmentation of CSF Ab1-42 and CSF t-tau correlation plot into four compartments, utilising threshold values developed by Shaw et al [12], four ‘stereotypical’ biological profiles of spanning Alzheimer’s disease (AD) development are constructed, enabling subjects to be described based on their clinical diagnoses as well as their biological profiles
A second determinant may be necessary in combination with the presence of amyloid plaques to trigger tau conversion, a hypothesis which is supported by the molecular work of Li et al [20] in mice, which demonstrates that amyloid is necessary, but not sufficient, for pathological conversion of tau
Summary
In 2015, the World Alzheimer Report estimated there to be 46.8 million people globally living with dementia, with projections suggesting that this figure will increase to 131.5million by 2050 [1]. In 2015, the World Alzheimer Report estimated there to be 46.8 million people globally living with dementia, with projections suggesting that this figure will increase to 131.5. A diagnosis of probable or possible AD can be made. The former meets the criteria for dementia which specifies a worsening in cognition (amnestic and/or nonamnestic), in combination with onset over a time period of months to years [6]. The latter may present with an atypical course concomitant with disease presentation [6]
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