Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults

Article type: Research Article

Authors: Hoscheidt, Siobhan M.^a | Starks, Erika J.^a | Oh, Jennifer M.^a | Zetterberg, Henrik^{b; c} | Blennow, Kaj^b | Krause, Rachel A.^a | Gleason, Carey E.^{d; a} | Puglielli, Luigi^{a; d} | Atwood, Craig S.^{d; a} | Carlsson, Cynthia M.^{d; a; e} | Asthana, Sanjay^{d; a; e} | Johnson, Sterling C.^{d; a; e} | Bendlin, Barbara B.^{a; e; *}

Affiliations: [a] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [b] Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden | [c] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK | [d] Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI, USA | [e] Wisconsin Alzheimer’s Institute, 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; Fax: +1 608 265 3091; E-mail: [email protected].

Abstract: Background: Type 2 diabetes is associated with an increased risk for Alzheimer’s disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline. Objective: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOE ɛ4 carriage would be associated with greater CSF AD pathology and poor memory performance. Methods: Cognitively asymptomatic middle-aged adults (N = 70, mean age = 57.7 years) from the Wisconsin Alzheimer’s Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-β protein precursor β (sAβPPβ), amyloid-β42 (Aβ42), and phosphorylated tau (P-tau181) were examined with respect to HOMA-IR and APOE ɛ4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOE ɛ4 status. Results: Higher HOMA-IR was associated with higher sAβPPβ and Aβ42 .  APOE ɛ4 carriers had significantly higher levels of sAβPPα, sAβPPβ, and P-tau181/Aβ42 compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance. Conclusion: Overall, the findings suggest that IR and APOE ɛ4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD.

Keywords: APOE ɛ4, CSF AD biomarkers, insulin resistance, memory function

DOI: 10.3233/JAD-160110

Journal: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1373-1383, 2016