Modeling the pathological cascade of Alzheimer’s disease and related dementia markers: The MEMENTO cohort

Abstract

AbstractBackgroundAlzheimer’s disease and related dementia (ADRD) are characterized by a progressive alteration of clinical (Cognitive and Physical functions) and subclinical (Neuroimaging, blood and CSF markers) features. Understanding the sequence and timing of these alterations is of primary importance to understand the natural history of ADRD and ultimately change its course. Pathological processes underlying ADRD evolve over years prior to dementia diagnostic on a time scale that is still hypothetical before any diagnosis is made. The objective of this work was to describe the sequence of markers changes in the Memento cohort by realigning the individual marker trajectories according to a latent disease time to overcome this issue.MethodMemento cohort is a French nationwide clinic‐based study which aims at better understanding the natural history of ADRD. Participants with mild cognitive impairment or subjective cognitive complaint were enrolled and followed‐up intensively for a maximum of 5 years. In an analytical sample of 2186 participants, we considered repeated measures of 12 ADRD markers including cognitive performances (memory, verbal fluency, executive function), neuroimaging measures (hippocampal volume, cortical thicknesses, white matter hyperintensities, glucose metabolism of region of interest of FDG‐PET), and CSF (Aβ42, p‐tau, t‐tau). We defined the latent disease time by an individual shift of the observed time, and simultaneously analyzed the ADRD marker trajectories according to this latent disease time using a multivariate mixed model adjusted on potential confounders.ResultAfter individual realignment of the trajectories according to the latent disease time, the temporal sequence of alterations suggested that neurodegeneration preceded cognitive decline. However, such sequence largely depended on education and ApoE4 status as illustrated in the figure. Cognitive decline appeared to be delayed among participants with high level of education, whereas changes in Aβ42 and tau proteins levels in CSF seemed to appear prior to neurodegeneration and cognitive decline mainly among ApoE ε4 carriers.ConclusionUsing longitudinal multidimensional data from a large cohort, we were able to stage participants along the pathological progression of ADRD. Our results show a large heterogeneity in temporal order markers changes which could suggest the existence of several subtypes of ADRD.