Affiliations: [a] Department of Neurology, University of Kansas School of Medicine, Kansas City, KS, USA
| [b] Department of Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City, KS, USA
| [c] Department of Endocrinology, University of Kansas School of Medicine, Kansas City, KS, USA
Correspondence:
[*]
Correspondence to: Jill K. Morris, PhD, KU Alzheimer’sDisease Center, Mail Stop 6002, 4350 Shawnee mission Parkway, Fairway, KS, 66205, USA. Tel.: +1 913 945 7675; Fax: +1 913 945 5035; E-mail: jmorris2@kumc.edu.
Abstract: Alzheimer’s disease (AD) may have heterogeneous pathophysiological underpinnings, with risk factors including apolipoprotein rmvarep4 (APOE4) genotype and insulin resistance. We hypothesized that distinct phenotypes exist within AD. We examined APOE4 and metabolic biomarkers in 338 subjects (n = 213 nondemented (ND), n = 125 AD). We further characterized steady state free fatty acid (FFA) levels in a subset of 45 participants who had also participated in a hyperinsulinemic-euglycemic clamp. Insulin resistance (HOMA-IR) was elevated in AD versus ND (p = 0.04) and in APOE4 noncarriers versus carriers (p < 0.01). This was driven by increased fasting insulin in AD versus ND (p < 0.01) and in APOE4 non-carriers versus carriers (p = 0.01). Fasting glucose was not different. In subjects who underwent a clamp, there was a group x genotype interaction on FFA levels during hyperinsulinemia (p = 0.03). APOE4 non-carriers with AD had higher FFA levels, while APOE4 carriers with AD exhibited lower FFA levels. Metabolic dysfunction is overrepresented in individuals with AD dementia who do not carry the APOE4 allele. This suggests that important subsets of AD phenotypes may exist that diverge metabolically.
Keywords: Alzheimer’s disease, apolipoprotein E, hyperinsulinemia, insulin, insulin resistance
