Abstract
Alzheimer's disease (AD) is the most common form of dementia. Current AD treatments slow the rate of cognitive decline, but do not restore lost function. One reason for the low efficacy of current treatments is that they fail to target neurotrophic processes, which are thought to be essential for functional recovery. Bolstering neurotrophic processes may also be a viable strategy for preventative treatment, since structural losses are thought to underlie cognitive decline in AD. The challenge of identifying presymptomatic patients who might benefit from preventative treatment means that any such treatment must meet a high standard of safety and tolerability. The neurotrophic peptide insulin-like growth factor-2 (IGF2) is a promising candidate for both treating and preventing AD-induced cognitive decline. Brain IGF2 expression declines in AD patients. In rodent models of AD, exogenous IGF2 modulates multiple aspects of AD pathology, resulting in (1) improved cognitive function; (2) stimulation of neurogenesis and synaptogenesis; and, (3) neuroprotection against cholinergic dysfunction and beta amyloid-induced neurotoxicity. Preclinical evidence suggests that IGF2 is likely to be safe and tolerable at therapeutic doses. In the preventative treatment context, the intranasal route of administration is likely to be the preferred method for achieving the therapeutic effect without risking adverse side effects. For patients already experiencing AD dementia, routes of administration that deliver IGF2 directly access the CNS may be necessary. Finally, we discuss several strategies for improving the translational validity of animal models used to study the therapeutic potential of IGF2.