title: Insulin Resistance is Associated with Higher Cerebrospinal Fluid Tau Levels in Asymptomatic APOEɛ4 Carriers.
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.
  
  
  METHODS
  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: Aβ₄₂, 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 APOEɛ4, on tau and amyloid pathology. We hypothesized that greater IR would be associated with higher CSF P-Tau181 and T-Tau, and lower CSF Aβ₄₂.
  
  
  RESULTS
  No significant main effects of HOMA-IR on P-Tau181, T-Tau, or Aβ₄₂ were observed; however, significant interactions were observed between HOMA-IR and APOEɛ4 on CSF markers related to tau. Among APOEɛ4 carriers, higher HOMA-IR was associated with higher P-Tau181 and T-Tau. Among APOEɛ4 non-carriers, HOMA-IR was negatively associated with P-Tau181 and T-Tau. We found no effects of IR on Aβ₄₂ levels in CSF.
  
  
  CONCLUSIONS
  IR among asymptomatic APOEɛ4 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.
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Erika J
authors: EJ
authors: Starks
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: J
authors: J
authors: Patrick O'Grady
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Siobhan M
authors: SM
authors: Hoscheidt
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Annie M
authors: AM
authors: Racine
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors: Cynthia M
authors: CM
authors: Carlsson
authors: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.|UCL Institute of Neurology, Queen Square, London, UK.
authors: Henrik
authors: H
authors: Zetterberg
authors: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.|The Torsten Söderberg Professorship at the Royal Swedish Academy of Sciences, Sweden.
authors: Kaj
authors: K
authors: Blennow
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Wisconsin Alzheimer's Institute, Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Ozioma C
authors: OC
authors: Okonkwo
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors: Luigi
authors: L
authors: Puglielli
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors: Sanjay
authors: S
authors: Asthana
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: N Maritza
authors: NM
authors: Dowling
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors: Carey E
authors: CE
authors: Gleason
authors: Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors: Rozalyn M
authors: RM
authors: Anderson
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Nancy J
authors: NJ
authors: Davenport-Sis
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: LeAnn M
authors: LM
authors: DeRungs
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Wisconsin Alzheimer's Institute, Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Mark A
authors: MA
authors: Sager
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA.|Wisconsin Alzheimer's Institute, Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Sterling C
authors: SC
authors: Johnson
authors: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Wisconsin Alzheimer's Institute, Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Barbara B
authors: BB
authors: Bendlin
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D053327:Apolipoprotein E4 / Q000235:genetics*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology; D058225:Plaque, Amyloid; D012044:Regression Analysis; D014922:Wisconsin; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D016875:tau Proteins
keywords: Alzheimer’s disease; apolipoprotein ɛ4; cerebrospinal fluid; glucose; insulin; insulin resistance; tau protein