Publication Type:Journal Article
Source:European Journal of Neurology (2016)
Many epidemiological studies suggest that metabolic dysfunction increases the risk for Alzheimer's disease (AD) and its prodrome, mild cognitive impairment (MCI) 1, 2. Whilst the exact mechanisms are unclear, conditions such as type 2 diabetes, insulin resistance and metabolic syndrome (MetS) predict AD neuropathology in late‐onset patients 3, 4 and late middle‐aged adults at risk for AD 5. Despite growing interest in metabolic dysfunction and AD, the effects of MetS and related factors on cognition and especially affect are not well studied. A recent meta‐analysis of longitudinal studies, by Siervo et al. 6, found that MetS was related to small effects on overall cognition and Mini Mental State Examination scores in participants at or under 70 years, but not above 70 years. One limitation is the paucity of such studies that examine executive function and memory, because the brain areas that subserve these processes have a relatively high density of insulin receptors. Indeed, brain insulin resistance is clearly manifest in AD and to a lesser extent in MCI, and is directly related to cognitive dysfunction. In normal brain, insulin receptor binding activates downstream effectors including insulin receptor substrate 1 (IRS‐1). In the post‐mortem hippocampal formation of MCI and AD patients, IRS‐1 signaling is severely impaired and strongly corresponds to worse ante‐mortem declarative memory and global cognitive performance 7.