Long-Acting Intranasal Insulin Detemir Improves Cognition for Adults with Mild Cognitive Impairment or Early-Stage Alzheimer's Disease Dementia

Abstract

Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-ε4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of intranasal insulin detemir.

The diabetic brain and cognition

“…These data support possible causal role of IRBS in sAD etiopathogenesis de la Monte et al 2014), confirmed by therapeutic effect of icv insulin in this model (Shingo et al 2013) and intranasal insulin in AD patients (Claxton et al 2015), and contributing role of vascular pathology in progression of cognitive decline as demonstrated in 9-month follow-up studies of this model Salkovic-Petrisic et al 2011).…”

“…Long-term drug testing polygon considering the preliminary data of the therapeutic role of icv insulin in the STZ-icv model (Shingo et al 2013) and of intranasal insulin in AD patients (Claxton et al 2015) should be performed to elucidate the importance of glucose/insulin pathology as risk factor for both, AD and VaD.…”

“…Many studies suggest that adding more insulin to the brain would improve memory and prevent cell damage (Shingo et al 2013;Claxton et al 2015). In individuals without DM, it has been shown amongst cognitively intact and cognitively impaired individuals that a form of insulin that enters the brain selectively has beneficial effects on some cognitive domains (Shemesh et al 2012).…”

Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

“…In rodents, intranasal IGF‐1 has been shown to rapidly and effectively gain entry to the CNS via the olfactory and trigeminal system (Thorne et al ., 2004), and protect against Huntington disease and toxin‐induced brain injury (Cai et al ., 2011; Lopes et al ., 2014). Interestingly, intranasal insulin, which is under investigation in humans to treat metabolic (Heni et al ., 2014; Gancheva et al ., 2015) and cognitive decline (Claxton et al ., 2015), has shown promise in healthy volunteers, but efficacy appears to wane in obese (Heni et al ., 2014) and T2DM (Gancheva et al ., 2015) patients, which may be the direct result of acquired central insulin resistance in these subjects. Thus, it seems plausible that increasing IGF‐1 in the brain may represent an important therapeutic alternative to circumvent central insulin resistance for the treatment of these diseases in older humans, a possibility that should be considered in future clinical trials.…”

Nose-to-Brain delivery of insulin for Alzheimer’s disease

“…A recently published study used the long-acting insulin (Detemir, Levemir®) delivered intranasally via the ViaNase™ device twice daily over 21 days in AD patients [62]. Detemir binds to albumin resulting in a prolonged release and greater parenchymal penetration.…”