Type 2 diabetes, insulin metabolism, and Alzheimer disease
are linked in a variety of ways. Numerous epidemiological
studies have shown that there is an increased risk of
developing AD among type 2 diabetic patients (Arvanitakis
et al., 2004; Leibson et al., 1997). Diet-induced
peripheral insulin resistance in Tg2576 mice has been
shown to increase γ-secretase activity and decrease
insulin-degrading enzyme activity. These combined changes
result in increased Aβ40 and Aβ42 levels and
amyloid plaque burden in the brain, and impaired
performance in a water maze test of learning and memory
(Ho et al., 2004). ApoE4 allele-positive individuals
account for 40-50 percent of sporadic late-onset AD
(Risner et al., 2006). Glucose is the brain’s primary
fuel, and it is metabolized by the tricarboxylic acid
(TCA) cycle. ApoE4 carriers have declines in brain
mitochondrial TCA enzyme activities (Gibson et al., 2000;
Bubber et al., 2005). Rosiglitazone therapy has been shown
to improve cognitive function in both a subset of human AD
patients (Watson et al., 2005; Risner et al., 2006) as
well as in preclinical AD model mice (Pedersen et al.,
2006).
In two small clinical trials, rosiglitazone
treatment for 24 weeks resulted in a modest but
significant improvement in cognition in non-ApoE4
subjects, but no improvement and rather a decline in
cognition in ApoE4 allele carriers (Risner et al., 2006).
Preliminary results from Phase III clinical study
NCT00428090 were reported at ICAD 2009 (Rabiner et al 2009).
This study failed to demonstrate significant efficacy at
any dose, in any test group (by ApoE genotype) assessed by
either ADAS-cog or CIBIC-Plus (Clinician Interview Based
Impression of Change) tests.
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