Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial

Abstract

Objective: To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD).

Design: Randomized, double-blind, placebo-controlled trial.

Setting: Clinical research unit of a Veterans Affairs medical center.

Participants: The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington).

Main outcome measures: Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.

Results: Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred.

Conclusions: These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration clinicaltrials.gov Identifier: NCT00438568.

Figure 1

Patient enrollment flowchart for our trial, which examines the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease. ITT indicates intent-to-treat sample; LP, lumbar puncture; PET, positron emission tomographic.

Figure 2

Log mean (A) delayed story recall, (B) Dementia Severity Rating Scale (DSRS), (C) Alzheimer Disease’s Assessment Scale–cognitive subscale (ADAS-cog), and (D) Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) scale change scores (from baseline to month 4) with standard errors of the mean (error bars) for placebo, 20-IU dose insulin, and 40-IU dose insulin groups. All scores are adjusted for age; ADAS-cog scores are further adjusted for the interaction of age with treatment group, and ADCS-ADL scale scores are further adjusted for diagnosis. AD indicates Alzheimer disease; aMCI, amnestic mild cognitive impairment.

Figure 3

A, Areas of hypometabolism at baseline (scan 1) and month 4 (scan 2), along with changes in hypometabolism (Δ time 2 − time 1) within each group, and differences in change between the placebo group and the 20-IU or 40-IU dose insulin group (Δ nasal insulin − Δ placebo). The red and orange colors, compared with the green and blue colors, indicate areas of greater hypometabolism from time 1 to time 2, and from placebo group to insulin groups. B, Change in mean regional z scores with standard errors of mean (error bars) for the right and left frontal regions and the left parietal region for the placebo, 20-IU dose insulin, and 40-IU dose insulin groups. For the right and left frontal volume-of-interest (VOI) values, placebo-assigned participants had reduced activity during the 4-month period, whereas the 20-IU and 40-IU dose insulin groups had preserved or slightly increased activity (treatment group × time interaction: P = .04 for comparison between placebo group and 20-IU dose insulin group; P = .03 for similar comparison between placebo group and 40-IU dose insulin group). Similar analyses for left medial parietal VOI values revealed reduced activity over time for the placebo group compared with the 40-IU dose insulin group (time × treatment group interaction: P = .05).