Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype
Introduction
Several mechanisms are now recognized through which insulin may influence central nervous system (CNS) functioning. Insulin-sensitive glucose transporters (GLUT4 and 8) are expressed in brain and are co-localized with insulin and insulin receptors in the hippocampus and hypothalamus [1], [3], [7], [18], [27], [28], [32], [44], [56]. Changes in insulin levels may thus affect physiology in these selective brain regions. Insulin may also modulate long-term potentiation (LTP). For example, insulin influences cell membrane expression of NMDA receptors, which affects the induction of LTP [61]. In addition, insulin modulates CNS concentrations of neurotransmitters, such as acetylcholine and norepinephrine, which influence cognitive function [21], [37].
Converging evidence suggests that insulin abnormalities in the CNS play a significant role in some neurodegenerative diseases, such as AD [15]. We have reported that patients with AD showed lower CSF insulin levels, higher plasma insulin levels, and reduced CSF-to plasma insulin ratios compared to healthy controls [14]. Also, reduced insulin receptor tyrosine kinase activity has been demonstrated in AD brain [23]. Lower levels of brain insulin may occur as a result of the chronic peripheral hyperinsulinemia that has been documented in some patients with AD [12], [14], [40], [48], [55]. Peripheral hyperinsulinemia may down-regulate transport of insulin to the brain. For instance, genetically obese hyperinsulinemic Zucker rats showed reduced insulin binding to brain capillaries [60] and reduced hypothalamic insulin levels [25]. Acute administration of insulin may improve memory by supplementing low brain levels or overcoming insulin resistance. In rats, intracerebroventricular insulin administration enhanced memory [50]. In humans, intravenous insulin administration, while maintaining euglycemia, improved verbal memory [9], [10], [12], [13], [69]. However, peripherally administered insulin is not a viable treatment option due to risks associated with hypoglycemia.
This risk can be circumvented with an intranasal administration technique in which insulin travels through a nasal pathway to the brain and largely bypasses the periphery [6], [22]. A significant number of compounds have been successfully delivered to the brain or CSF following intranasal administration [2], [6], [20], [47], [51], [57], [58], [64], [65]. For example, insulin-like growth factor-I (IGF-I) has been delivered to the brain following intranasal administration, resulting in reduced infarct volume and improved neurological function [41], [42], [43]. In healthy, young adults, intranasal administration of insulin resulted in increased CSF insulin levels within 10 min of administration with peak levels noted within 30 min [6]. CSF insulin levels had not returned to baseline by the end of the 80 min study, while blood glucose and insulin levels did not change. Intranasal insulin administration also induced changes in evoked brain potentials [34] and improved verbal memory in young, healthy adults [4]. The rapid transport of compounds following intranasal administration indicates that the primary pathway is extraneuronal, although an additional olfactory intraneuronal pathway is also possible hours later [65]. Recent evidence supports three extracellular pathways from the nasal cavity to the CNS. Drugs can access the CSF along the olfactory neurons and cribriform plate, or they can enter the CNS parenchyma through channels associated with the olfactory or peripheral trigeminal systems [22], [65], [66]. These findings suggest that intranasal insulin administration may produce the same memory facilitation as IV insulin, but without the risk for hypoglycemia.
The purpose of the present study was to test the hypothesis that intranasal administration of insulin would improve memory in subjects with AD or amnestic mild cognitive impairment (MCI) without raising plasma insulin. Amnestic MCI is widely believed to represent a prodromal stage of AD with approximately 80% of patients receiving an AD diagnosis within 6 years [52]. Prior studies have demonstrated that the dose of insulin required for memory facilitation may differ according to apolipoprotein E (APOE) genotype [9], [11], [12], [14]. Therefore, we predicted that the treatment response would differ between subjects with (ɛ4+) and without (ɛ4−) the APOE-ɛ4 allele, a genetic risk factor for sporadic AD.
Section snippets
Subjects
This study was approved by the Human Subjects Review Committee of the University of Washington. Written informed consent was obtained from all subjects and from the legal representatives of the subjects with AD. Memory-impaired subjects included those diagnosed with probable AD (NINCDS/ADRDA) [45] or amnestic MCI [53].
There were 35 normal adults (ɛ2/3 n = 8, ɛ3/3 n = 19, ɛ3/4 n = 7, ɛ4/4 n = 1) and 26 subjects with either probable AD (ɛ2/3 n = 1, ɛ3/3 n = 5, ɛ3/4 n = 5, ɛ4/4 n = 2) or amnestic mild cognitive
Metabolic data
Intranasal insulin administration had no effect on plasma insulin or glucose levels for any of the diagnostic groups (Table 2). Insulin and glucose levels did not differ when AD and MCI groups were compared directly.
Verbal memory
For story recall, insulin produced significant memory improvement for the MI/ɛ4− group at both 20 and 40 IU doses (Fig. 1; p = .0006 and .0013). Neither the normal nor the MI/ɛ4+ group showed a significant change in story recall with insulin. At the 20 IU dose, improvement was greater
Discussion
Acute intranasal insulin administration improved verbal memory in AD and MCI subjects without the APOE-ɛ4 allele without changing plasma insulin or glucose levels. These results are consistent with previous literature that demonstrated verbal memory facilitation in memory-impaired ɛ4− subjects following peripheral elevations of insulin while maintaining euglycemia [9], [11], [12]. Prior studies have demonstrated that intranasal insulin administration results in acute elevations of CSF insulin
Acknowledgement
This study was supported by the Department of Veterans Affairs and NIA grant P50 AG 05136.
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