Uncovering heterogeneous cognitive trajectories in mild cognitive impairment: a data-driven approach

Abstract

Background Given the complex and progressive nature of mild cognitive impairment (MCI), the ability to delineate and understand the heterogeneous cognitive trajectories is crucial for developing personalized medicine and informing trial design. The primary goals of this study were to examine whether different cognitive trajectories can be identified within subjects with MCI and, if present, to characterize each trajectory in relation to changes in all major Alzheimer’s disease (AD) biomarkers over time. Methods Individuals with a diagnosis of MCI at the first visit and ≥ 1 follow-up cognitive assessment were selected from the Alzheimer’s Disease Neuroimaging Initiative database (n = 936; age 73 ± 8; 40% female; 16 ± 3 years of education; 50% APOE4 carriers). Based on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13) total scores from baseline up to 5 years follow-up, a non-parametric k-means longitudinal clustering method was performed to obtain clusters of individuals with similar patterns of cognitive decline. We further conducted a series of linear mixed-effects models to study the associations of cluster membership with longitudinal changes in other cognitive measures, neurodegeneration, and in vivo AD pathologies. Results Four distinct cognitive trajectories emerged. Cluster 1 consisted of 255 individuals (27%) with a nearly non-existent rate of change in the ADAS-Cog-13 over 5 years of follow-up and a healthy-looking biomarker profile. Individuals in the cluster 2 (n = 336, 35%) and 3 (n = 240, 26%) groups showed relatively mild and moderate cognitive decline trajectories, respectively. Cluster 4, comprising about 11% of our study sample (n = 105), exhibited an aggressive cognitive decline trajectory and was characterized by a pronouncedly abnormal biomarker profile. Conclusions Individuals with MCI show substantial heterogeneity in cognitive decline. Our findings may potentially contribute to improved trial design and patient stratification.

The Contribution of Functional Near-Infrared Spectroscopy (fNIRS) to the Study of Neurodegenerative Disorders: A Narrative Review

“…The construct of MCI has been specifically designated to describe an early stage of clinically measurable cognitive impairment that, however, does not interfere with the daily activities of an individual [ 24 ]. Apart from cognitive impairment, greater neuropsychiatric burden and accelerated courses of cognitive decline and conversion into dementia have been related to this minor neurocognitive entity [ 25 , 26 , 27 , 28 ]. The concept of MCI has both research and clinical applications, allowing physicians to recruit individuals at high risk of progressing to dementia and apply early preventive strategies [ 3 ].…”

Association between neuropsychological assessment and amyloid status in a clinical setting.

“…One of the major challenges in clinical neuropsychological practice is differential diagnosis of the etiology of cognitive impairment on the individual patient level. This is particularly relevant given the heterogeneity of individual cognitive trajectories observed among AD biomarker positive individuals (Giorgio et al, 2020; Wang et al, 2023). As previously reported, there is relatively poor correspondence between amyloid biomarkers and cognitive status, despite amyloid biomarkers being most available in clinical practice at this time (Ackley et al, 2021; Aschenbrenner et al, 2018; Brier et al, 2016; Kester et al, 2009; Mielke et al, 2016; Ossenkoppele et al, 2013).…”

Developing a core outcome set for interventions in people with mild cognitive impairment: study protocol

“…However, what matters to those with MCI may vary to those with a diagnosis of dementia. Not all individuals with MCI progress to dementia and the rate of cognitive decline can vary substantially 16 . MCI also often affects people of working age or in early retirement and clinical symptoms differ significantly from people with dementia.…”