30 July 2010. For those who had all but turned their noses up at the dearth of big clinical trial news at the International Conference on Alzheimer’s Disease, held 10-15 July 2010 in Honolulu, Hawaii, a Hot Topics presentation offered a whiff of fresh air. Suzanne Craft of the University of Washington, Seattle, presented data from a four-month Phase 2 study of intranasal insulin, which seemed to improve certain measures of cognition and daily function, as well as biomarker profiles, in patients with mild cognitive impairment (MCI) or early Alzheimer disease.

Known for its role in managing diabetes, insulin also appears important for aging brains, Craft reminded attendees. For starters, the hippocampus, entorhinal cortex, and frontal cortex—brain areas important for cognition and hit hard in AD—all have a fair share of insulin receptors. Furthermore, insulin readily reaches the brain, where it helps neurons manage their glucose usage and maintain synapses. A few studies (e.g., van der Heide et al., 2005) suggest that insulin can modulate long-term potentiation, a change in synaptic strength that underlies learning and memory. More directly relevant to AD, insulin promotes Aβ trafficking out of cells and regulates levels of insulin-degrading enzyme, which also breaks down Aβ, Craft said. And in AD patients, Craft and others have reported reduced levels of cerebrospinal fluid (CSF) insulin and less brain insulin at early stages of disease, i.e., between Braak stages 0-1 and 2-3 (Rivera et al., 2005).

These findings fueled an early pilot study in which insulin, delivered intranasally with a nebulizer, boosted CSF insulin levels within 30 minutes and improved memory in young, healthy adults. Importantly, the treatment did not affect plasma glucose or insulin levels, suggesting that the nasal delivery targeted the brain while averting systemic side effects. Craft and colleagues then took the treatment into disease populations. In a double-blind, placebo-controlled study of 24 amnestic MCI and early AD patients, three weeks of daily treatment with 20 IU (international units) intranasal insulin improved verbal recall without affecting peripheral glucose or insulin in treated participants (Reger et al., 2008 and ARF related news story).

In Honolulu, Craft presented data from a four-month trial of 104 patients with amnestic MCI or early AD. Aptly named SNIFF-120 (Study of Nasal Insulin to Fight Forgetfulness), this double-blind Phase 2 trial was funded by the National Institute on Aging. Participants were randomized into three roughly equal groups that received saline placebo or insulin (20 or 40 IU) through the nose each day, and underwent cognitive testing at baseline, two months, and four months. A small subset got brain scans using fluorodeoxyglucose positron emission tomography (FDG-PET) to measure glucose utilization, and spinal taps to check CSF biomarkers. Primary outcome measures were four-month change on cognitive (ADAS-Cog, delayed story recall) and functional (ADCS-ADL, Dementia Severity Rating Scale) tests. CSF and FDG-PET profiles served as secondary measures.

The placebo group declined by about 1.5 points on the ADAS-Cog, which was within expectation for a four-month timeframe, Craft said. For comparison, a recent meta-analysis of 87 double-blind, placebo-controlled AD trials showed ADAS-cog changes of 1.44 at six months and 4.13 at one year (see ARF ICAD 2008 story). The insulin-treated participants did not decline on the ADAS-Cog and showed net improvement on the functional tests. The low-dose (20 IU) insulin group also improved their scores in the delayed recall test. As for the eight placebo and 18 insulin-treated participants who underwent spinal taps, the pooled low- and high-dose insulin group had lower CSF Aβ40/Aβ42 ratios, which correlate with lower AD risk, compared to participants on placebo. Daily insulin also seemed to protect treated patients (n = 24) from the four-month reduction in glucose utilization seen on FDG-PET in the placebo group (n = 16).

The team is in the process of applying for NIA funding for a longer, larger Phase 3 trial of intranasal insulin, Craft told ARF.

On the basic science front, other studies presented at ICAD added to the emerging connection between insulin and regulation of both Aβ and tau. Ewan McNay, University at Albany, State University of New York, in collaboration with Craft, reported that rat models of type 1 and type 2 diabetes show impaired production, accumulation, and clearance of Aβ. In other studies with wild-type rats, McNay and colleagues reported that small Aβ oligomers known as ADDLs (amyloid-derived diffusible ligands) may mediate these effects. Hippocampal injection with synthetic ADDLs into wild-type rats caused problems on a spatial memory task and with glucose transporter translocation and insulin signaling. Evidence for a potential role for Aβ oligomers also appeared on a poster by Fernanda De Felice, Federal University of Rio de Janeiro, Brazil, and colleagues. In cultures of rat hippocampal neurons, the researchers found that—similar to what occurs in type 2 diabetes—ADDLs trigger abnormal phosphorylation of insulin receptor substrate-1 and that c-Jun N-terminal kinase might be responsible. Cheng-Xin Gong and colleagues at the New York State Institute for Basic Research on Staten Island found depressed insulin-PI3K-AKT signaling in the brains of patients with AD and type 2 diabetes. In quantitative Western analyses of postmortem brain tissue, these researchers correlated the downregulation of insulin-PI3K-AKT signaling components with calpain-1 overactivation and abnormal tau phosphorylation.

All told, the recent intranasal insulin trial data, as well as emerging evidence from in vivo and in vitro studies, suggest that a growing number of scientists are ferreting out ties between insulin signaling and Alzheimer disease.—Esther Landhuis.