Between SNAP and a hard Aβ rock: Characterizing the fate of preclinical Alzheimer's disease

Objectives The objective of the study was to characterize a two-imaging marker construct in the preclinical stages of Alzheimer disease

Methods 497 cognitively unimpaired individuals (HC, 73.0±6.2years; 56%female) were included in the study. Aβ status (A) was determined with either PiB, flutemetamol or florbetapir, while neurodegeneration (N) was established using hippocampal volume. Following Jack et al (2012) individuals were categorized as either A-N-, A+N-, A+N+, or suspected non-Alzheimer disease pathophysiology (SNAP, A-N+). Clinical progression, cognitive domain-specific trajectories, global composite scores, and brain volumetrics were assessed

Results 64% of HC were classified as A-N-, 18% as A+N-, 6% as A+N+, and 12% as A-N+. Participants in the A-N- group were significantly younger, and while males were more prevalent among A+N+ and A-N+, females were more prevalent among A+N- and A-N-. ApoE4 carriage was more frequent in A+N-(46%) and A+N+(58%) than in A-N-(19%) and A-N+(24%). While no Significant differences were observed in baseline scores significantly faster cognitive decline was observed in A+N+(-0.30SD/yr) and A+N-(-0.08SD/yr) when compared to A-N-(+0.02SD/yr). The A-N- and A-N+ groups did not show significant decline over time, although A-N+ was associated with a lower baseline cognitive performance. Within 1.5-4.5 years, 22.2% of A+N+ progressed to amnestic MCI/AD, compared to only 7.3% of A-N+(2MCI, 1AD, 1VaD)

Conclusions Increasing marker abnormality was reflected in faster cognitive decline. Compared to A+N+, the different cognitive trajectories of subjects with neurodegeneration but no AD pathology suggest distinct underlying pathophysiological mechanisms

Research Support Supported in part by NHMRC Project Grants 1011689 & 1071430