A Single-Dose Pilot Trial of Intranasal Rapid-Acting Insulin in Apolipoprotein E4 Carriers with Mild–Moderate Alzheimer’s Disease

Rosenbloom, Michael; Barclay, Terry R.; Pyle, Maria; Owens, Brian; Cagan, Amanda; Anderson, Christopher P.; Frey, William H.; Hanson, Leah R.

doi:10.1007/s40263-014-0214-y

Cited by 49 publications

(77 citation statements)

References 16 publications

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“…Insulin was effective in improving performance on a verbal memory test in a group of AD and MCI patients; however, within these groups patients who were APOE ε 4 positive or female showed poorer recall following insulin administration compared to patients who did not possess this allele and males [17]. Similar results were found with rapid-acting insulin, which is thought to have superior effects intranasally when compared to regular insulin, in APOE ε4 positive AD patients [18]. …”

Section: Introductionmentioning

confidence: 79%

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Salameh

Bullock

Hujoel

et al. 2015

JAD

108

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Intranasal insulin has shown effficacy in patients with Alzheimer’s disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory defficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects. Uptake into the brain from the cribriform plate was saturable, stimulated by PKC inhibition, and responded differently to cellular pathway inhibitors than did insulin transport at the blood-brain barrier. In summary, these results show intranasal delivery to be an effective way to deliver insulin to the brain.

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Section: Introductionmentioning

confidence: 79%

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Salameh

Bullock

Hujoel

et al. 2015

JAD

108

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“…Other studies have examined the effect of intranasal insulin on memory, particularly in cognitively impaired subjects, and the results have been mixed. For instance, intranasal insulin improved memory performance in some studies (Craft et al, 2012; Reger et al, 2008b) while other studies found insulin’s effects on memory are dependent on ApoE genotype with reports of beneficial effects (Reger et al, 2006; Reger et al, 2008a), no effect (Rosenbloom et al, 2014), or a negative effect (Claxton et al, 2015) in APOE ε4 noncarriers. Another study found effects only when sex and ApoE genotype were considered.…”

Section: Discussionmentioning

confidence: 96%

“…However, not all studies show a beneficial effect of insulin in AD; for instance, Apolipoprotein E (APOE) ε4 carriers generally do not exhibit improved cognition (Rosenbloom et al, 2014). Furthermore, our group has shown that the relationship between circulating insulin, cognition, and brain structure differs between individuals with normal cognition and AD (Burns et al, 2007; Burns et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin

Morris

Vidoni

Mahnken

et al. 2016

Neurobiology of Aging

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Insulin resistance is a risk factor for Alzheimer’s disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n=37) and with cognitive impairment (CI; n=14). CI subjects exhibited either Mild Cognitive Impairment or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass (GDRLM), the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs CI: 2.01 [2.3] p=0.028) and during the hyperinsulinemic clamp (GDRLM; ND: 9.9 (4.5) vs. AD 7.2 (3.2) p=0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs ND: 4.2 [3.8] µU/mL; p=0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p=0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued SRT) in both groups (p<0.0001) and no change in performance on an additional task (delayed logical memory). In this study, although insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and GDR was present only in ND (p=0.0002) but not in cognitively impaired (p=0.884) subjects, indicating potentially important physiological differences between these cohorts.

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“…Conversely, high dose of insulin experienced increased peripheral insulin resistance in APOE negative patients (Claxton et al, 2015). These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration (Reger et al, 2008a; Rosenbloom et al, 2014). Further, it is reported that insulin treated subjects retained more verbal information, improved attention and raised fasting plasma Aβ 40 /Aβ 42 ratio (Reger et al, 2008b).…”

Section: Intranasal Insulin Improves Memory In the Healthy Humans As mentioning

confidence: 99%

Aberrant insulin signaling in Alzheimer's disease: current knowledge

et al. 2015

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Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment.

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A Single-Dose Pilot Trial of Intranasal Rapid-Acting Insulin in Apolipoprotein E4 Carriers with Mild–Moderate Alzheimer’s Disease

Abstract: Larger clinical trials of longer duration are necessary to better understand the relationships between RA insulin, ApoE4 carrier status and cognitive performance in AD.

Cited by 49 publications

References 16 publications

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition

Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin

Aberrant insulin signaling in Alzheimer's disease: current knowledge

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