Calorie Restriction and Brain Function in Mild Cognitive Impairment

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.

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.