HETEROGENEITY IN NEUROIMAGING PATTERNS PRESENT THROUGHOUT THE CLINICAL SPECTRUM OF TYPICAL LATE-ONSET AMNESTIC AD

Abstract

Although heterogeneity in Alzheimer's disease (AD) has been appreciated in atypical patient presentations, the role of disease heterogeneity in “typical” AD has been underexplored and remains unclear. (Experiment 1) Heterogeneity in atrophy patterns were explored using a data-driven Bayesian model on structural MRIs of AD dementia patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Resulting latent atrophy factors were extracted for Aβ+ mild cognitive impairment (MCI) and cognitively normal (CN) participants. (Experiment 2) Longitudinal decline across multiple cognitive domains was explored in Aβ+ clinically normal individuals from the Harvard Aging Brain Study (HABS). (Experiment 1) We identified a medial temporal latent atrophy factor, a subcortical atrophy factor, and a cortical atrophy factor that were expressed to varying degrees within individual ADNI AD patients. All three atrophy factors were associated with memory decline across the disease spectrum, whereas the cortical factor was associated with executive function decline in Aβ+ MCI and AD dementia patients. (Experiment 2) Aβ+ clinically normal individuals showed independent longitudinal decline in episodic memory and language. Decline in episodic memory was associated with reduced gray matter thickness in medial temporal lobe whereas decline in language was associated with reduced gray matter thickness in lateral temporal cortex. These results across ADNI and HABS highlight that disease heterogeneity is an important feature of typical AD, and that this heterogeneity emerges during the preclinical stage of the disease. Quantification of heterogeneity in patterns of atrophy and cognitive decline throughout the AD spectrum will improve our ability to predict disease risk at the individual-level and shed insight into mechanisms underlying disease heterogeneity.