Insulin Resistance is Associated with Higher Cerebrospinal Fluid Tau Levels in Asymptomatic APOEɛ4 Carriers

Article type: Research Article

Authors: Starks, Erika J.^a | Patrick O’Grady, J.^a | Hoscheidt, Siobhan M.^a | Racine, Annie M.^a | Carlsson, Cynthia M.^{a; b} | Zetterberg, Henrik^{c; d} | Blennow, Kaj^{c; e} | Okonkwo, Ozioma C.^{a; f} | Puglielli, Luigi^{a; b} | Asthana, Sanjay^{a; b} | Dowling, N. Maritza^{a; g} | Gleason, Carey E.^{a; b} | Anderson, Rozalyn M.^b | Davenport-Sis, Nancy J.^a | DeRungs, LeAnn M.^a | Sager, Mark A.^{a; f} | Johnson, Sterling C.^{a; b; f} | Bendlin, Barbara B.^{a; f; *}

Affiliations: [a] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [b] Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA | [c] Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [d] UCL Institute of Neurology, Queen Square, London, UK | [e] The Torsten Söderberg Professorship at the Royal Swedish Academy of Sciences, Sweden | [f] Wisconsin Alzheimer’s Institute, Wisconsin School of Medicine and Public Health, Madison, WI, USA | [g] Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

Correspondence: [*] Correspondence to: Barbara B. Bendlin, PhD, J5/1M, Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA. Tel.: +1 608 265 2483; [email protected]

Abstract: Background: Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimer’s disease (AD), including neurofibrillary tangles and amyloid plaques. However, the extent to which IR is associated with AD pathology in the cognitively asymptomatic stages of preclinical AD remains unclear. Objective: To determine the extent to which IR is linked with amyloid and tau pathology in late-middle-age. Method: Cerebrospinal fluid (CSF) samples collected from 113 participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention study (mean age = 60.6 years), were assayed for AD-related markers of interest: Aβ 42, P-Tau181, and T-Tau. IR was determined using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Linear regression was used to test the effect of IR, and APOE ɛ4, on tau and amyloid pathology. We hypothesized that greater IR would be associated with higher CSF P-Tau181 and T-Tau, and lower CSF Aβ 42. Results: No significant main effects of HOMA-IR on P-Tau181, T-Tau, or Aβ 42 were observed; however, significant interactions were observed between HOMA-IR and APOE ɛ4 on CSF markers related to tau. Among APOE ɛ4 carriers, higher HOMA-IR was associated with higher P-Tau181 and T-Tau. Among APOE ɛ4 non-carriers, HOMA-IR was negatively associated with P-Tau181 and T-Tau. We found no effects of IR on Aβ 42 levels in CSF. Conclusion: IR among asymptomatic APOE ɛ4 carriers was associated with higher P-Tau181 and T-Tau in late-middle age. The results suggest that IR may contribute to tau-related neurodegeneration in preclinical AD. The findings may have implications for developing prevention strategies aimed at modifying IR in mid-life.

Keywords: Alzheimer’s disease, apolipoprotein ɛ4, cerebrospinal fluid, glucose, insulin, insulin resistance, tau protein

DOI: 10.3233/JAD-150072

Journal: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 525-533, 2015