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In addition to increasing patients’ risk for cardiovascular disease, stroke, and cancer, obesity and metabolic disturbance contribute to age-related cognitive decline and dementia. In particular, insulin resistance and hyperinsulinemia promote neurocognitive dysfunction and neurodegenerative changes during the extended, preclinical phase of Alzheimer’s disease (AD). However, with dietary modification it may be possible to resensitize insulin receptors, correct hyperinsulinemia, and improve memory function.
Metabolic disturbance and neurodegeneration
In the United States, 5.4 million people have AD, and there will be an estimated 16 million cases by 2050.1 Simultaneously we are experiencing an epidemic of metabolic disturbance and obesity. Approximately, 64% of adults in the United States are overweight (body mass index [BMI]: 25.0 to 29.9 kg/m2) and 34% are obese (BMI: ≥30 kg/m2).2 By 2030, 86% of adults will be overweight and 51% will be obese.3 This confluence of epidemics is not coincidental but instead reflects the fact that metabolic disturbance is a fundamental factor contributing to cognitive decline and neurodegeneration.4
Ninety-six percent of AD cases are classified as late onset, sporadic AD, occurring after age 64.1 Mild cognitive impairment (MCI) is a clinical construct that entails greater than expected memory impairment for the patient’s age and identifies older adults who are at increased risk for dementia. MCI represents the first clinical manifestation of neurodegeneration for a subset of patients who will progress to AD.5,6 MCI is distinguished from age-associated memory impairment (AAMI), which originally was conceptualized as normal or benign memory decline with aging.7,8 Recent data indicate that Alzheimer’s-type neuropathologic changes are the basis for subjective memory complaints and objectively assessed age-related cognitive decline,9 and early neurodegeneration is present in many patients with AAMI or MCI.10 This is consistent with the idea that an extended preclinical phase precedes AD onset. The preclinical phase can persist for a decade or more and precedes MCI and overt functional decline. However, neuropathologic changes accumulate during the preclinical phase of AD11 and during the preclinical phase of type 2 diabetes mellitus (T2DM).
Hyperinsulinemia and dementia
Insulin resistance and hyperinsulinemia occur in >40% of individuals age ≥60 and prevalence increases with age.4,12 Hyperinsulinemia develops to compensate for insulin resistance to overcome receptor insensitivity and maintain glucose homeostasis. Insulin receptors are densely expressed in brain regions vulnerable to neurodegeneration, including the medial temporal lobe and prefrontal cortex, which mediate long-term memory and working memory. However, insulin must be transported into the CNS from the periphery because little is synthesized in the brain. Paradoxically, peripheral compensatory hyperinsulinemia resulting from insulin resistance is associated with central (brain) hypoinsulinemia because of insensitivity and saturation of the receptor-mediated blood-brain barrier transport mechanism.13-15
Hyperinsulinemia is the precursor to T2DM. However, hyperinsulinemia is not well recognized in clinical contexts and generally is not a treatment target. Nonetheless, it contributes to several health problems, and insulin resistance in middle age is associated with age-related diseases such as hypertension, coronary artery disease, stroke, and cancer, while insulin sensitivity protects against such disorders.16
Chronic insulin resistance may contribute more to dementia development than T2DM because of the extended period of hyperinsulinemia that precedes T2DM onset. In population studies,17 insulin resistance syndrome increases risk for developing AD independent of apolipoprotein E (APOE e4) allele status, and in a longitudinal study,18 the risk for AD solely attributable to peripheral hyperinsulinemia was up to 39%. Being overweight in midlife increases risk for dementia in late life, and APOE e4 allele status does not contribute additional risk after accounting for BMI.19 Middle-aged individuals with hyperinsulinemia show memory decline, and obesity in middle age was associated with greater cognitive impairment after 6-year follow-up.20 Even in older adults who seem cognitively unimpaired, BMI and fasting insulin are positively correlated with atrophy in frontal, temporal, and subcortical brain regions, and obesity is an independent risk for atrophy in several brain regions, including the hippocampus.21
Compared with healthy older adults, individuals with AD have lower ratios of cerebrospinal fluid to plasma insulin.22 This lower ratio reflects the peripheral-to-central gradient of insulin levels in AD and suggests an etiological role for such metabolic disturbance. Insulin resistance has downstream effects that potentiate neurodegenerative factors, and central hypoinsulinemia can accelerate neurodegenerative processes and cognitive decline.4,23 Brain insulin plays a direct role in regulating proinflammatory cytokines and neurotrophic and neuroplastic factors essential for memory function. Insulin degrading enzyme, which varies with insulin levels,24 regulates the generation and clearance of amyloid β (Aβ) from the brain.25