Detecting early changes in cognition in people who have a high risk of developing Alzheimer’s dementia

EPAD is a pan-European study led from the Centre for Dementia Prevention at the University of Edinburgh that aims to build a platform for delivering proof of concept drug trials for the prevention of Alzheimer’s dementia. The study has now taken off across Europe and just as we are nearing the time point when the first follow-up visits are due there have been two key papers that the EPAD consortium have published.

The two linked papers published in the journal Alzheimer’s and Dementia review current neuropsychological assessment measures that are used to observe changes in cognition in both longitudinal and neuroimaging studies and propose a selection of measures best suited to detection of cognitive changes in the pre-clinical period. The measures recommended are those which best predict future dementia and reflect underlying brain changes. While significant progress has been made in characterizing the biological changes that occur decades before Alzheimer’s dementia develops, cognitive dysfunction has been viewed as something that happens at a late-stage and has therefore not been focused on in the “at risk“ preclinical population. However, there is increasing evidence that suggests cognitive changes may be detected decades before dementia develops. The review confirms this view and suggests that future work not only focus on those testing methods which have been demonstrated by research to pick up very early changes, but also suggests the need for futher cognitive test development with novel methods designed to target very specific brain areas first affected.

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The two papers are authored by the EPAD consortium. Prof Karen Ritchie who is the lead neuropsychologist in the consortium and will soon be joining the Centre for Dementia Prevention noted that until recently Alzheimer’s disease has been thought of as a late life disease beginning with dementia, we now can think of this disease developing from a much younger age, probably middle-age, with brain changes which are not noticed in everyday life and therefore will not be picked up by complaints to a doctor. It has been a major challenge to the EPAD Clinical and Cognitive Outcomes Scientific Advisory Group (Work Package 1) to demonstrate how such clinically silent changes may be detected by neuropsychological testing at this early stage, and to recommend the best available measures. Co-author Prof Craig Ritchie who is the co-ordinator for the EPAD study and one of the Directors of the CDP says: "To test new drugs for preventing Alzheimer’s dementia, we needed to develop a cognitive outcome measure that reflected an impact on disease pathology of the drug. This needed to be linked to the disease in the brain and also be sensitive to change over time. This work in developing the cognitive outcome battery for EPAD is core to the whole projects success”. The papers published this week summarise current assessment measures that are used for detecting cognitive decline – and highlight the lack of evidence-based guidelines for measuring cognitive change in a preclinical population where the cognitive decline is “silent” and occurring years before memory problems arise. Beyond the EPAD work but stimulated by it; Karen stated that she would like to see more of the new technologies being developed in cognitive psychology to explore normal functioning in specific brain structures which may be adapted to detection of preclinical Alzheimer’s disease – particularly the new computerised methods and perhaps eventually virtual reality methods which are able to target even specific sub-regions of the hippocampus. It is anticipated that these methods would help detect cognitive decline earlier than current methods allow.

The authors emphasise the importance of having valid assessment measures that would reliably detect which individuals would be at risk of developing Alzheimer’s dementia as well as tracking changes over time. Based on the literature review, episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large-scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. However, these studies have mostly concerned persons who are only a few years away from developing dementia. EPAD sets out to cover a much longer clinical period, going back perhaps decades before dementia when only subtle brain changes are evident. This will involve a new generation of testing procedures focusing particularly on spatial navigation skills. These methods are not currently used to assess changes in dementia but will be incorporated as experimental measures for the first time within EPAD along with more conventional testing procedures implicating primarily episodic memory.

The consensus statement from the EPAD consortium provides recommendations for both future drug trials and research into preclinical Alzheimer’s disease and therefore provides a key milestone for designing future dementia studies. “There is no doubt that we are on the verge of a paradigm shift in conceptualisation of Alzheimer’s disease as a disease that has numerous stages with the last stage being dementia, to prevent dementia we have to have the tools to identify people at risk, be able to accurately measure an impact on disease course and of course develop interventions (including drugs) that will have that impact” commented Prof Craig Ritchie.

The full text papers are available online:

Mortamais, M., Ashc, J.A., Harrison, J., Kaye, J., Kramer, J., Randolph, J., Pose, C., Albala, B., Ropacki, M., Ritchie C.W., Ritchie, K., (2016). Detecting cognitive changes in preclinical Alzheimer’s disease: A review of its feasibility. Alzheimer’s & Dementia, 1-25

Ritchie, K., Ropacki, M., Albala, B., Harrison, J., Kaye, J., Kramer, J., Randolph, C., Ritchie, C.W. (2016). Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project. Alzheimer’s & Dementia, 1-10