Scores Obtained from a Simple Cognitive Test of Visuospatial Episodic Memory Performed Decades before Death Are Associated with the Ultimate Presence of Alzheimer Disease Pathology

Background: Community- or population-based longitudinal studiesof cognitive ability with a brain donation end point offer an opportunity to examine relationships between pathologyand cognitive state prior to death. Discriminating the earliest signs of dementing disorders, such as Alzheimer disease (AD), is necessary to undertake early interventions and treatments. Methods: The neuropathologicalprofile of brains donated from The University of Manchester Longitudinal Studyof Cognition in Normal Healthy Old Age, including CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) and Braak stage, was assessed by immunohistochemistry. Cognitive testscores collected 20 years prior to death were correlated with the extent of AD pathologypresent at death. Results: Baseline scores from the Memory Circle test had the ability to distinguish between individuals who developed substantial AD pathologyand those with no, or low, AD pathology. Predicted testscores at the age of 65 years also discriminated between these pathologygroups. The addition of APOE genotype further improved the discriminatory ability of the model. Conclusions: The results raise the possibility of identifying individuals at future risk of the neuropathologicalchanges associated with AD over 20 years before death using a simple cognitive test. This work may facilitate early interventions, therapeutics and treatments for AD by identifying at-risk and minimally affected (in pathologicalterms) individuals.