Cognitive trajectories preluding the imminent onset of Alzheimer's disease dementia in individuals with normal cognition: results from the HELIAD cohort

Background The cognitive trajectories of cognitively normal (CN) individuals rapidly progressing to Alzheimer's disease dementia (AD) have not been investigated. Aim To explore the preclinical pattern of cognitive performance heralding the rapid progression from normal cognition to AD. Methods The HELIAD cohort underwent comprehensive neuropsychological assessments (memory, language, attention, executive and visuo-perceptual functions) at baseline and after approximately 3-year intervals. The cognitive trajectories of those with normal cognition at baseline were explored according to the follow-up diagnosis using adjusted generalised estimating equations analyses. Results A total of 932 predominantly female (61%), older (72.9 +/- 4.9), CN participants were followed for 3.09 (+/- 0.83) years. Among them, 761 individuals remained CN, 29 progressed to AD and 142 developed MCI (33 single-domain amnestic, 41 multidomain amnestic, 37 single-domain non-amnestic and 31 multidomain non-amnestic). Those progressing to AD were already performing worse than the healthy reference in every single cognitive domain at baseline. Cognitive deficits ranged between similar to 0.5SD (attention, executive function and language) and similar to 1.0SD (memory and visuo-perceptual skills). Throughout the 3-year follow-up, memory constantly exhibited the most prominent impairment compared to the remaining cognitive domains while executive function diminished in the most abrupt fashion (similar to 0.19SD yearly) separating from the remaining three cognitive functions before the development of full-blown AD. Heterogeneous patterns of cognitive decline clearly differentiated those progressing to MCI from those rapidly converting to AD, as well. Discussion Poor performance in every cognitive domain may characterise cognitively normal individuals at high risk of fast progression to AD. Conclusion Strict neuropsychological cut-offs fail to detect a considerable number of individuals at high risk of rapid progression to AD.

Automated summary

This study aimed to explore the preclinical patterns of cognitive performance heralding the rapid progression from normal cognition to Alzheimer's disease. The results showed that individuals progressing to AD already exhibited worse performance in every cognitive domain at baseline, with memory being the most prominently impaired. Executive function showed the most abrupt decline before the development of AD. Additionally, distinct patterns of cognitive decline differentiated those progressing to mild cognitive impairment (MCI) from those rapidly converting to AD.