Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.

Keywords: Alzheimer’s disease; clinical trial; insulin; intranasal; magnetic resonance imaging; memory.

Fig.1

Enrollment data for study participants.

Fig.2

Change from baseline for delayed memory composite Z score for placebo-assigned, regular insulin-treated, and detemir-treated groups. The regular insulin group had improved memory compared with the placebo group after two (p < 0.03) and four (p < 0.05) months of treatment. No differences were observed between placebo and detemir groups.

Fig.3

Change from baseline volume (cm³) for key AD-related ROIs. Increased or preserved volumes were noted in four ROIs for the regular insulin-treated group compared with the placebo group: (A) left superior parietal cortex; (B) right middle cingulum; (C) left cuneus; (D) right parahippocampal gyrus (all ps < 0.05). Decreased volume was observed for the detemir group relative to placebo for (E) right cuneus and (F) right hippocampus (ps < 0.01 and 0.05), whereas preserved volume was observed for (G) left anterior cingulum and (H) left middle cingulum (ps < 0.05).

Fig.4

Representative relationships between changes in MRI volume and cognitive outcomes. For regular insulin-treated participants, improved memory composite Z scores were associated with increased volume for (A) right middle cingulum (r = 0.62, p < 0.05), (B) left cuneus (r = 0.82, p < 0.01), (C) left inferior parietal (r = 0.61, p < 0.04) and (D) right superior frontal (r = 0.67, p < 0.03). For the placebo group, participants who had less volume loss in (C) left inferior parietal or (D) right superior frontal cortex showed less memory decline (rs = 0.65 and 0.64, ps < 0.05). No relationships between ROI volumes and memory were observed for the detemir-treated group.