Intranasal insulin causes improvement in Alzheimer’s patients

Alzheimer’s disease (AD) proves to be a both diagnostic and therapeutic challenge. The disease strikes unannounced and with progression severely debilitates. Amnestic Mild Cognitive Impairment (aMCI) often seems to precede it. Among some risk factors of developing AD, recently insulin resistance is the one intensely discussed. The current issue of Archives of Neurology journal (1) reports that intranasal administration of insulin may provide AD and aMCI patients with undeniable benefits. The 4-month therapy improved or stabilized memory, cognition and overall functional ability. Authors suggest that their pilot trial serves as a fair basis for future research.

Insulin seems to play a major role in human brain. Its receptors are found mainly in hippocampus and frontal cortex. They are localized in synapses, where they seem to be engaged in synaptogenesis and synaptic remodeling (2). More importantly, in healthy brain insulin stampedes the processes of memory when at optimal levels (3). On the contrary, nervous system of patients suffering from AD is characterized by low insulin activity or even insulin resistance (especially when type 2 diabetes is co-morbid).

Furthermore, β-amyloid peptide (Aβ ) is considered as a main wrongdoer in the pathogenesis of AM. Indeed, the oligomers bind to synapses regions which triggers off oxidative stress and causes loss of synaptic spines. The β-amyloid deposits lead to redistribution of insulin receptors, which are crucial for brain plasticity and memory. Some authors suggest that insulin serves as a natural protection against Aβ induced synapses’ damage (4). Bringing back the normal levels of insulin in the brain would therefore provide treatment for patients with AD.

So far this idea seems to be working. The discussed study was designed as a double-blind, placebo-controlled, randomized trial. It enrolled adults otherwise healthy with aMCI and probable AD who presented moderate dementia (Mini-Mental State Examination scores of >15). On the whole, 104 participants were divided into groups receiving placebo, 20 IU of insulin or 40 IU a day administered with a nasal drug delivery device. This was done to ensure the highest concentration in the central nervous system and to minimize the peripheral effects of insulin. Previous studies showed no cases of any adverse effects after intranasal administration of insulin, including hypoglycemia (5).

Primary measures of the brain function included 2 tests: delayed story recall score and Dementia Severity Rating Scale (DSRS). The delayed story recall representing delayed memory was improved for participants receiving the 20-IU dose, but not for those taking 40-IU of insulin. DRDS was observed superior in both doses of insulin. The scientists explain that in their previous studies they discovered a special relationship between the dose and effects of insulin. Beneficial influence of insulin on memory is found only at optimal levels. When the dose of insulin is too high or too low there are none or negative effects. Perhaps the 40-IU dose of insulin exceeded the optimum for memory but not for other aspects of cognition and daily function, expressed in DRDS test.

Additionally authors investigated the cerebrospinal fluid AD biomarkers and used brain PET scan to assess the glucose metabolism. The results were consistent with previous findings. Changes in CSF biomarkers seemed correlated with cognitive improvement for insulin-treated participants. Brain hypometabolism, characteristic for AD, was reduced in the group receiving insulin. Although the study was limited by a relatively short period of time (caused by precautions due to the scarcity of safety data for internasal insulin treatment) the results provide a solid ground for the future research. So it seems that the field is left clear for anybody wishing to pick up the gauntlet.

Written by: Natalia Neumann

1.Craft S, Baker LD, Montine TJ et al “Intranasal insulin therapy for Alzheimer disease an amnestic mild cognitive impairment: a pilot clinical trial” Arch Neurol 2011; DOI:10.1001/archneurol.2011.233.
2.Chiu SL, Chen CM, Cline HT.” Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo.” Neuron. 2008;58(5):708-719.
3.McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. “Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance.” Neurobiol Learn Mem. 2010;93(4):546-553
4.De Felice FG, Vieira MN, Bomfim TR, et al. “Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers.” Proc Natl Acad Sci U S A. 2009;106(6):1971-1976.
5.Reger MA, Watson GS, Green PS, et al. “Intranasal insulin improves cognition and modulates beta-amyloid in early AD.” Neurology. 2008;70(6):440-448.

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