SKELETAL MUSCLE MITOCHONDRIAL FUNCTION IN COGNITIVELY HEALTHY ELDERLY AND MCI SUBJECTS

Over 60% of Americans are overweight or obese according to body mass index (BMI), and elevated BMI is a risk factor for chronic diseases including Alzheimer's Disease (AD). Both cognitively normal overweight and AD subjects exhibit impaired cardiorespiratory fitness (CRF), potentially due in part to reduced mitochondrial respiratory function in skeletal muscle. However, no studies have characterized the impact of cognitive impairment and BMI on skeletal muscle mitochondrial function in older adults. We enrolled elderly individuals (65+) with no cognitive complaints (n=23), or clinically diagnosed Mild Cognitive Impairment (MCI, n=19). Subjects were divided based upon WHO classifications for normal (18.5-24.9) or overweight/obese BMI (25+). Analyses were controlled for age and sex. We obtained skeletal muscle biopsies (vastus lateralis) to assess high-resolution mitochondrial respiratory capacity in permeabilized muscle fibers. Individuals also underwent CRF testing and a fasting blood draw. We assessed 4 groups: normal cognition and BMI (CN, n=9); normal cognition, high BMI (NO, n=14); MCI, normal BMI (MCI-N, n=10); and MCI, high BMI (MCI-O, n=9). MCI subjects had a mean MMSE of 26. 41.5% of CN subjects (22% of CN and 53% of NO) and 54.5% of MCI subjects (80% of MCI-N and 44% of MCI-O) were APOE ε4 carriers. ADP-stimulated mitochondrial respiration supported by palmitoyl-carnitine in the presence of succinate (State 3S) was significantly different between groups (p=0.01). LSD post-hoc analyses revealed that CN subjects exhibited higher mitochondrial respiration compared to all other groups (p=0.01 vs NO, p=0.02 vs MCI-N and MCI-O). Both high BMI groups exhibited higher HDL levels and lower physical activity compared to both normal BMI groups (p<0.01). CRF was different between groups, with MCI-O subjects exhibiting lower VO2peak compared to CN (p<0.01) and MCI-N (p=0.02) groups. Cognitively normal elderly with overweight BMI status exhibit a similar degree of mitochondrial respiratory impairment as MCI subjects. This may represent a modifiable MCI risk factor. MCI subjects with normal BMI had impaired mitochondrial function despite having similar fitness and activity levels as cognitively healthy subjects. The high percentage of APOE ε4 carriers in this group (80%) may contribute to the observed effect on bioenergetics.