Open AccessAPOE ε4/ε4 homozygotes with early Alzheimer's disease show accelerated hippocampal atrophy and cortical thinning that correlates with cognitive decline
Author(s) -
Abushakra Susan,
Porsteinsson Anton P.,
Sabbagh Marwan,
Bracoud Luc,
Schaerer Joel,
Power Aidan,
Hey John A.,
Scott David,
Suhy Joyce,
Tolar Martin
Publication year - 2020
Publication title -
alzheimer's and dementia: translational research and clinical interventions
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.49
H-Index - 30
ISSN - 2352-8737
DOI - 10.1002/trc2.12117
Subject(s) - apolipoprotein e , atrophy , magnetic resonance imaging , alzheimer's disease neuroimaging initiative , psychology , medicine , cognitive decline , neuroimaging , alzheimer's disease , brain size , dementia , cognition , cardiology , neuroscience , disease , radiology
Hippocampal volume (HV) and cortical thickness are commonly used imaging biomarkers in Alzheimer's disease (AD) trials, and may have utility as selection criteria for enrichment strategies. Atrophy rates of these measures, in the high‐risk apolipoprotein E (APOE) ε4/ε4 homozygous AD subjects are unknown. Methods Data from Alzheimer's Disease Neuroimaging Initiative (ADNI‐1) and a tramiprosate trial were analyzed in APOE ε4/ε4 and APOE ε3/ε3 subjects with mild cognitive impairment (MCI) or mild AD. Magnetic resonance imaging (MRI) data were centrally processed using FreeSurfer; total HV and composite average cortical thickness were derived and adjusted for age, head size, and education. Volumetric changes from baseline were assessed using Boundary Shift Integral, and correlated with cognitive changes. Results APOE ε4/ε4 MCI subjects showed significantly higher % HV atrophy and cortical thinning at 12 months (4.4%, 3.1%, n = 29) compared to APOE ε3/ε3 subjects (2.8%, 1.8%, n = 93) and similarly in mild AD (7.4%, 4.7% n = 21 vs 5.4%, 3.3% n = 29). Differences were all significant at 24 months. Over 24 months, HV atrophy and cortical thinning correlated significantly with Alzheimer's Disease Assessment Scale‐Cognitive subscale worsening in APOE ε4/ε4 MCI subjects, but not in mild AD. Discussion Correlation of volumetric measures to cognitive change in APOE ε4/ε4 subjects with early AD supports their role as efficacy biomarkers. If confirmed in a Phase 3 trial with ALZ‐801 (pro‐drug of tramiprosate) in APOE ε4/ε4 early AD subjects, it may allow their use as surrogate outcomes in future treatment or prevention trials in AD.