Fleisher, Adam

BackgroundApolipoprotein E ɛ4 (APOE ɛ4) allele carrier status has been well established as a risk factor for developing Alzheimer's disease. However, the specific influence of APOE ɛ4 allele status on cognitive and functional rates of decline in mild cognitive impairment (MCI) is poorly understood. We examine the prospective association of APOE ɛ4 allele status on measures of cognitive and functional decline in subjects with amnestic MCI (aMCI).MethodsA total of 516 aMCI participants aged 55–90 years who received placebo or vitamin E from the Alzheimer's Disease Cooperative Study's MCI treatment trial were evaluated. During the 36‐month study period, neurocognitive and functional measures were collected. These measures were assessed over time for change and association with APOE ɛ4 status. Generalized Estimating Equations were performed to model each outcome measure over the study period.ResultsAPOE ɛ4 status had a significant impact on cognitive and functional decline on multiple measures; those who were APOE ɛ4 positive had significantly more rapid decline in performance on all cognitive and functional measures except Number Cancellation and Maze tracing (P < .05). The greatest decline was seen in global measures of cognition and function including the Clinical Diagnostic Rating scale, followed by the Mini‐Mental State Examination, Global Deterioration scale, and the Alzheimer's Disease Assessment Scale‐Cognitive Subscale.ConclusionsThese findings demonstrate that APOE ɛ4 genotype is predictive of increased general rates of decline with global measures of cognition and function most affected. With accelerated declines in common clinical trial primary efficacy measures, APOE ɛ4 status needs to be accounted for in treatment trials of MCI.

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.