The Pathology of Rapid Cognitive Decline in Clinically Diagnosed Alzheimer's Disease

Background: Variable rate of cognitive decline among individuals with Alzheimer's disease (AD) is an important consideration for disease management, but risk factors for rapid cognitive decline (RCD) are without consensus. Objective: To investigate demographic, clinical, and pathological differences between RCD and normal rates of cognitive decline (NCD) in AD. Methods: Neuropsychology test and autopsy data was pulled from the National Alzheimer's Coordinating Center database from individuals with a clinical diagnosis of AD. Individuals with average decline of 3 or more points on the Mini-Mental Status Examination (MMSE) per year over 3 years were labeled RCD; all others were NCD. Results: Sixty individuals identified as RCD; 230 as NCD. These neuropsychology tests differed at baseline (RCD versus NCD): WMS-LM Immediate Recall (4.35[3.39] versus 6.31[3.97],p < 0.001), Animal Naming (12.1[4.83] versus 13.9[4.83], p = 0.007), TMT Part B (187[86.1] versus 159[79.0], p = 0.02), WAIS-Digit Symbol (29.5[11.3] versus 29.5[11.3], p = 0.04), and the BNT (21.5 [7.05] versus 23.6[5.09], p = 0.04). RCD had more thyroid disease (30% versus 16%, p = 0.01) and greater usage of AD medication at baseline (80% versus 62%, p = 0.01). RCD had more severe cerebral amyloid angiopathy 1.62[1.0] versus 1.13 [1.0], p = 0.002), more neocortical Lewy bodies (20% versus 10%, p = 0.04), and more atrophy (1.54[0.92] versus 1.17[0.83], p = 0.04). A model combining select variables was significant above chance (chi(2) = 25.8, p = 0.002), but not to clinical utility (AUC <0.70; 95% CI). Conclusion: Individuals with RCD have more severe pathology, more comorbidities, and lower baseline neuropsychology test scores of language and executive function.