title: Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial.
abstract: Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.
  
  
  
  The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.
  
  
  
  This randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.
  
  
  
  The regular insulin treated group had better memory after two and four months compared with placebo (p < 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio.
  
  
  
  Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Craft
authors.affiliation: Alkermes, Inc., Waltham, MA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Claxton
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Baker
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Hanson
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA, USA.
authors.forename: Brenna
authors.initials: B
authors.lastname: Cholerton
authors.affiliation: Department of Psychiatry & Behavioral Science, University of Washington School of Medicine, Seattle, WA, USA.|Geriatric Research, Education, & Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Trittschuh
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Dahl
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Caulder
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Neth
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Youngkyoo
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Maldjian
authors.affiliation: Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Whitlow
authors.affiliation: Seattle Children's Hospital, Seattle, WA, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Friedman
mesh_terms: D000203:Activities of Daily Living; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D061385:Insulins / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D018697:Nootropic Agents / Q000627:therapeutic use*; D009929:Organ Size; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016896:Treatment Outcome; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D061385:Insulins; C054369:MAPT protein, human; D018697:Nootropic Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer’s disease; clinical trial; insulin; intranasal; magnetic resonance imaging; memory