PROMINENT NON-MEMORY DEFICITS IN AD ARE ASSOCIATED WITH A FASTER DISEASE PROGRESSION

Abstract

There is considerable heterogeneity in clinical manifestation and rate of decline among patients with Alzheimer's disease (AD). We previously identified two distinct cognitive subtypes in four large AD cohorts: the first characterized by prominent memory impairment, and the second by more prominent impairment of non-memory domains. Non-memory AD was associated with younger age, APOE e4 negative genotype, and atrophy of the posterior cortex with relative spared hippocampi. Taking these cognitive subtypes as a starting point, we now evaluated whether AD patients with a non-memory phenotype are prone to faster disease progression. We included 1067 probable AD patients from the Alzheimer Dementia Cohort (n=290), Alzheimer's Disease Neuroimaging Initiative (n=269), Dementia Competence Network (n=226), and University of California, San Francisco (n=282) with available clinical follow-up. Subjects were labelled as memory (n=663) or non-memory (n=404) based on a data-driven clustering approach as described in our previous study. Associations between cognitive phenotype and disease progression as measured with repeated Mini-Mental State Examination (MMSE) scores and repeated Clinical Dementia Rating scale sum of boxes (CDR sob) scores were estimated using age and sex adjusted linear mixed models (LMM). In addition and for ADC only, we estimated associations between cognitive phenotype and mortality rate with Cox proportional hazards models. Patients were 71±9 years old; 541 (51%) were female. LMM showed that patients with non-memory AD performed slightly worse on MMSE at baseline (21.8±0.7 vs memory AD 22.8±0.7; p<0.001). Moreover, patients with non-memory AD showed a steeper annual decrease in MMSE (-2.8±0.2) than memory AD (-1.9±0.1; pinteraction<0.001). We found similar results for CDR-sob, as LMM showed a slightly worse baseline score for non-memory AD (5.1±0.9) than memory AD (4.8±0.9; p<0.001). In addition, non-memory AD subjects showed a steeper annual increase in CDR sob (1.3±0.1) than memory AD (1.8±0.1; p<0.001). Finally, non-memory AD was associated with a higher risk of mortality than memory AD (HR 1.56, 95%CI 1.14–2.15; p<0.01). Non-memory AD is associated with faster disease progression than memory AD.