A Nutritional and Pharmacological Intervention for Body, Brain, and Longevity Effects (NIBBLE)

Participants assigned to the FMD arm will adhere to the diet for 5 days over three cycles for a period of 8 weeks. The FMD diet is produced by L-Nutra and provides 1100 kcals on day 1 and 800 kcals on days 2-5. The diet consists of ingredients which are Generally Regarded As Safe (GRAS) selected for their fasting mimicking properties. Participants randomized to the rapamycin group will receive 1 mg rapamycin daily for 8 weeks and those in the placebo arm will take one matched placebo pill daily for 8 weeks.

Inclusion criteria

• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or female, aged 45-65 years at screening
• Carrier of at least one copy of the APOE e4 allele
• BMI 20-39kg/m2 (inclusive) at screening
• On a stable medication regimen for at least 3 months.
• For females: Post-menopausal status or use of highly effective contraception.

Exclusion criteria

• Has any medical disease or condition that, in the opinion of the principal investigator (PI) or appropriate study personnel, precludes study participation* (*Including acute, subacute, intermittent or chronic medical disease or condition that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of this trial);
• Significant depression (PHQ-9>9) or generalized anxiety (GAD-7>9)
• Diagnosis of a significant neurological condition such as multiple sclerosis, epilepsy, Parkinson's disease, major stroke
• Contraindications to MRI such as claustrophobia, cardiac pacemaker, etc.
• Current adherence or adherence within the past 3 months to a specialized diet (e.g. ketogenic, paleo, intermittent fasting, raw food, vegan)
• Food allergies (e.g. dairy, eggs, fish/shellfish, peanuts, tree nuts, soy, wheat, sesame, corn)
• Diagnosis of mild cognitive impairment or dementia; use of an FDA-approved medication for Alzheimer's disease; MoCA<23
• Diabetes (hbA1c >6.5%) or anti-diabetic medications
• History of gastric bypass;
• Inflammatory bowel disease
• Small or large bowel resection
• Subjects with recent weight loss (>5%), use of weight loss medication, participated in a weight loss program in the past 3 months
• Use of immune suppression drugs;
• Contraindication for study foods (special food needs and allergy);
• Women who are pregnant, lactating, or trying to conceive
• Women who are on hormone replacement therapy
• Alcohol dependency (alcohol intake greater than two drinks per day for women and three drinks per day for men)
• Current smoker or tobacco use within 3 months.
• Active malignant cancer or history of malignancy within the last 1 yea1s (except non-melanoma skin cancer)
• Serious psychiatric disorders such as schizophrenia, bipolar disorder, eating disorders
• Persons with allergy to animal dander or animal-instigated asthma
• Required use of drugs that affect cytochrome P450 3A4 or alter cerebral blood flow (see Appendix 1 for tables of excluded medications)
• Current or chronic liver, kidney, cardiac, or pulmonary diseases
• Untreated hypertriglyceridemia (fasting triglycerides > 300 mg/dl)
• Poorly controlled blood pressure (systolic BP > 160 or diastolic BP > 100 mmHg