Related Heterogeneity in Pathologically Confirmed Sporadic Alzheimer Disease.

Objective: To characterize age-related clinical heterogeneity in Alzheimer’s disease (AD) and determine if it is modified by APOE genotype or concomitant non-AD pathology, we analyzed data from 1750 patients with sporadic, pathologically-confirmed severe AD. Methods: In this retrospective cohort study, regression and mixed effects models assessed effects of estimated age of onset, APOE genotype, and their interaction on standardized clinical, cognitive and pathologic outcome measures from the National Alzheimer’s Coordinating Center (NACC) database. Results: A bimodal distribution of age of onset frequency in APOE e4- cases showed best separation at age 63. Using this age cut-off, cases were grouped as early onset (EO) AD e4- (n=169), EOAD e4+ (n=273), late onset (LO) AD e4- (n=511), and LOAD e4+ (n=797). EOAD were more likely than LOAD patients to present with non-cognitive behavioral or motor symptoms or non-memory cognitive complaints, and had more executive dysfunction, but less language impairment on objective cognitive testing. Age of onset and e4- genotype were independently associated with lower baseline MMSE and greater functional impairment, and EOAD had faster cognitive and functional decline than LOAD regardless of APOE genotype. EOAD were more likely than LOAD patients to receive a non-AD clinical diagnosis even though they were more likely to have “pure” AD without concomitant vascular or other non-AD neurodegenerative pathology. Conclusions: Early onset sporadic AD is associated with a greater likelihood of an atypical, non-memory dominant clinical presentation, especially in the absence of the APOE e4 allele, which may lead to misattribution to non-AD underlying pathology.