Calorie Restriction and Brain Function in Mild Cognitive Impairment

Problems with blood sugar metabolism (i.e., metabolic dysfunction) progressively develop through old age, which is primarily due to obesity and lack of physical activity. Metabolic dysfunction increases the risk for Alzheimer's disease (AD) and negatively impacts memory and related brain function. There is intense interest in developing interventions, particularly non-drug therapies, to combat AD. Recent clinical trials have found that intranasal insulin, which facilitates glucose metabolism in the brain, is able to maintain memory in participants with Mild Cognitive Impairment (MCI), the precursor to AD. While intranasal insulin is a useful, proof-of-concept intervention, it does not affect visceral fat mass and therefore metabolic dysfunction will persist in a given person.

The investigators wish to engage participants with MCI in intermittent calorie restriction (CR), to reduce metabolic dysfunction and improve glucose metabolism. Intermittent calorie restriction in this case refers to eating whatever one wants for 5 days, followed by 2 consecutive days of consuming 530 calories via one protein shake with sufficient nutrients to sustain the person. This results in reliable weight loss, which itself improves glucose metabolism in the body and has a wealth of other benefits. (It should be mentioned here that weight maintenance has been shown in studies when participants restrict to 1 day/week).

AD diagnosis is projected to increase from approximately 5 million to 13.8 million Americans by 2050. The Alzheimer's Association estimates that healthcare costs for AD by 2050 could be 1.2 trillion dollars per year for Americans aged 65 years or older. There is marked focus on treating AD during the MCI phase, which precedes AD.

In the brain, insulin normally facilitates microvascular blood flow, glucose uptake, and glucose oxidation for adenosine triphosphate (ATP) generation. Insulin resistance (IR) is defined as a reduced cellular responsiveness to insulin, characterized by higher insulin levels needed to maintain glucose regulation in the periphery and certain brain areas. IR is found in MCI and AD patient brains. AD-related neuropathology, such as amyloid beta-containing plaques, progressive atrophy, and glucose hypometabolism first occur in brain areas that also have a high density of insulin receptors. Such areas include medial temporal lobe (MTL) and prefrontal cortex (PFC). Furthermore, as illustrated in the literature and previous work of the investigators, peripheral IR is associated with AD-like changes in MTL and PFC, including: 1) brain atrophy; 2) less glucose uptake; 3) accumulation of amyloid-beta, a hallmark of AD; and 4) increased phosphorylation of tau fibrils, another hallmark of AD. Finally, higher IR is related to deficits in memory performance and executive function.

These cognitive deficits can be ameliorated with 40 IU of intranasal insulin, which increases insulin processing in the brain with minimal peripheral effects, where MCI and AD patients show stable visuospatial working memory, as well as declarative learning and memory. One limitation of intranasal insulin is that it does not change obesity, which causes IR, and may therefore be only temporarily effective. As such, the investigators are interested in dietary regimens that can lower IR and may have long-term beneficial effects on AD neuropathology and cognitive output. Critically, intermittent calorie restriction (CR) diets reliably decrease body weight and IR in human adults. Intermittent CR protects neurons against dysfunction and degeneration in AD models. The underlying cellular and molecular mechanisms involve improved cellular bioenergetics and up-regulation of protein chaperones and antioxidant pathways in neurons. For example, 5-2 CR, a diet consisting of 5 days ad libitum followed by 2 consecutive days consuming 500-600 kcal, decreases IR beyond what is achieved with daily CR, and has a compliance rate of 83% versus 55% even by 6 months. It is also important to mention that no serious Adverse Events have occurred during past 5-2 CR studies.

Eligibility Criteria:
Inclusion Criteria:

1. Years of age 70-85;
2. Body Mass Index =\> 28 and \< 40 and weight \< 350 pounds;
3. Mini-Mental State Examination \>= 24;
4. A subjective memory concern from the participant, caregiver/informant, or a clinician;
5. An education-adjusted score for the Logical Memory II, paragraph A Wechsler Scale (16 years: 8-10; 8-15 years: 5-7; \< 0-7 years: 2-3);
6. A Clinical Dementia Rating - sum of boxes = 0.5;
7. No deficits in activities of daily living;
8. Consensus confirmation of MCI by senior investigators;
9. An informant/caregiver that is informed about the study and will be present at study visits.

Exclusion Criteria:

1. A history of a major cardiovascular event(e.g., heart attack);
2. A history of cerebrovascular or other neurological disorders (e.g., stroke, epilepsy, multiple sclerosis, etc.);
3. A history of substance abuse in the past 6 months;
4. A history of eating disorders;
5. A history of clinically significant endocrine disorders (e.g., hypothyroidism);
6. A history of mood and anxiety disorders (e.g., Major Depressive Disorder, Generalized Anxiety Disorder, Bipolar disorder, etc.);
7. Taking insulin;
8. Current use of systemic corticosteroids;
9. Current use of Warfarin;
10. Having smoked tobacco products in the last 3 months;
11. Contraindications for MRI (pacemakers, ferrous metal implants or shrapnel about the face or eyes, etc.);
12. Other medical history that, in the opinion of the investigators, would constitute risk for subject participation;
13. Hypertension, defined by a diastolic/systolic blood pressure of \> 160/110;
14. No current use of memantine or other Alzheimer's disease drugs.