Abstract
BackgroundUnderstanding the earliest manifestations of Alzheimer’s disease (AD) is key to realising disease-modifying treatments. Advances in neuroimaging and fluid biomarkers have improved our ability to identify AD pathology in vivo. The critical next step is improved detection and staging of early cognitive change. We studied an asymptomatic familial Alzheimer’s disease (FAD) cohort to characterise preclinical cognitive change.MethodsData included 35 asymptomatic participants at 50% risk of carrying a pathogenic FAD mutation. Participants completed a multi-domain neuropsychology battery. After accounting for sex, age and education, we used event-based modelling to estimate the sequence of cognitive decline in presymptomatic FAD, and uncertainty in the sequence. We assigned individuals to their most likely model stage of cumulative cognitive decline, given their data. Linear regression of estimated years to symptom onset against model stage was used to estimate the timing of preclinical cognitive decline.ResultsCognitive change in mutation carriers was first detected in measures of accelerated long-term forgetting, up to 10 years before estimated symptom onset. Measures of subjective cognitive decline also revealed early abnormalities. Our data-driven model demonstrated subtle cognitive impairment across multiple cognitive domains in clinically normal individuals on the AD continuum.ConclusionsData-driven modelling of neuropsychological test scores has potential to differentiate cognitive decline from cognitive stability and to estimate a fine-grained sequence of decline across cognitive domains and functions, in the preclinical phase of Alzheimer’s disease. This can improve the design of future presymptomatic trials by informing enrichment strategies and guiding the selection of outcome measures.
Highlights
Understanding the earliest manifestations of Alzheimer’s disease (AD) is key to realising diseasemodifying treatments
Participants are eligible for inclusion in this ongoing study if they are over 18 years of age and have a parent with genetically confirmed familial Alzheimer’s disease (FAD) or a clinical diagnosis of FAD
We first describe the demographics of our study participants, present our experimental results on the sequence and timing of cognitive decline in presymptomatic FAD
Summary
Understanding the earliest manifestations of Alzheimer’s disease (AD) is key to realising diseasemodifying treatments. The critical step is improved detection and staging of early cognitive change. We studied an asymptomatic familial Alzheimer’s disease (FAD) cohort to characterise preclinical cognitive change. Alzheimer’s disease (AD) is clinically characterised by slowly progressive cognitive decline that leads to multidomain impairment and loss of independence. There is an urgent economic and social need for a treatment that can slow disease progression. Clinical trials in symptomatic AD have failed to identify a disease modifying treatment. The pathological process of AD begins over a decade prior to symptom onset [3]. This clinically silent period opens up a treatment window at a potentially more tractable stage of the disease
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