Intranasal insulin improves cognition and modulates beta-amyloid in early AD.
BACKGROUND
Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes.


OBJECTIVE
We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, beta-amyloid, and cortisol.


METHODS
Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment.


RESULTS
Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the beta-amyloid peptide (A beta 40; p = 0.0471) without affecting the longer isoform (A beta 42), resulting in an increased A beta 40/42 ratio (p = 0.0207).


CONCLUSIONS
The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.
Reger
M A
MA
Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, WA, USA.
Watson
G S
GS
Green
P S
PS
Wilkinson
C W
CW
Baker
L D
LD
Cholerton
B
B
Fishel
M A
MA
Plymate
S R
SR
Breitner
J C S
JC
DeGroodt
W
W
Mehta
P
P
Craft
S
S
D000281:Administration, Intranasal; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000097:blood / Q000187:drug effects*; D001288:Attention / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018450:Disease Progression; D006801:Humans; D007328:Insulin / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000097:blood / Q000187:drug effects; D010865:Pilot Projects; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000378:metabolism; D016896:Treatment Outcome; D014705:Verbal Behavior / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D007328:Insulin; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)