APOE Genotype and Diet Influences on Alzheimer's Biomarkers

The purpose of this study is to examine how the risk gene for Alzheimer's disease APOE
epsilon 4 (E4) influences acute cognitive responses to different types of meals. The
rationale for this study is that we know that a diet high in saturated fat and high glycemic
index foods (HIGH diet) is a risk factor for Alzheimer's disease (AD). However we have found
paradoxically that a Western style HIGH diet acutely improved cognition in APOE E4 carriers,
but worsened cognition in E4 non-carriers. This experiment will examine mechanisms that
underlie this differential response between E4 carriers and non-carriers.

We will enroll older adults who do not have dementia, half of which will be E4 carriers and
the other half will be non-carriers. Both groups will contain equal numbers of men and women.
These individuals will undergo two experiments in which they eat either a high or a low fat
meal, and then after the meal will undergo several tests. The outcome measures include blood
measures of metabolic markers, cognitive tests that are known to be sensitive to changes even
after a single meal, and spinal fluid measures of Alzheimer's biomarkers such as
beta-amyloid, as well as spinal fluid levels of lipids, glucose and insulin. This study will
allow us to test whether high and low fat meals acutely affect cognitive and Alzheimer's
biomarkers, and if those changes depend on APOE genotype or gender. It is our hope that this
work will contribute to our broader understanding about the risks of diet and AD, to help us
understand more about how to prevent and treat this devastating neurological disease.

Inclusion Criteria:

1. Written consent is signed and dated by the subject.

2. Subject is at least 55 years of age or older, and if female, must be post-menopausal
for at least one year, or be one year out from a hysterectomy.

3. Able to read and understand English

4. Be free of dementia, and able to cognitively and physically give informed consent.

5. In the opinion of the investigator, the subject will be able to complete the study
procedures.

Exclusion Criteria:

1. Diabetes: Known type 1 or Type 2 diabetes, currently taking diabetic medications or
insulin, and/or fasting blood glucose ≥ 126 as per the 2009 American Diabetes
Association guidelines. Remote use of diabetic agents, or a history of gestational
diabetes, is ok.

2. Liver and kidney disease: Active liver disease will be excluded. Also excluded are
elevations in liver function tests of SGOT (AST) and/or SGPT (ALT) > 1.5 times the
upper limit of normal. Active renal disease (Stage IV or V chronic kidney disease)
will also be excluded.

3. Lipid abnormalities: Diagnosis of hyperlipidemia or hypertriglyceridemia requiring
statin, bile acid resins, fibrate medications, and/or high dose niacin will be
excluded, as these medications may interfere with the study outcomes. If subjects are
on omega-3 fatty acids, low dose niacin, or other alternative/herbal remedies such as
red yeast rice, they can be enrolled if they agree to stop the medication during the
study period. Also excluded are significant cholesterol abnormalities as defined by
the Adult Treatment Panel III classification: LDL cholesterol ≥190 mg/dL, total
cholesterol ≥240 mg/dL, or triglycerides > 200. HDL levels outside of the typical
range are ok.

4. Dementia and cognitive impairment: Known diagnosis of dementia, use of dementia
medications, or identification of dementia during the baseline visit, will be
excluded. Also excluded are other significant neurologic diseases which affect
cognition, such as recent stroke, recent severe head injury, or advanced Parkinson's
disease. Mild cognitive impairment with no functional deficits is ok.

5. Contraindications to lumbar puncture: Those with medical conditions that preclude a
lumbar puncture such as an intracranial tumor, lower spinal hardware, or use of
anticoagulation, will be excluded. Daily aspirin for prevention is ok. Use of NSAIDS
is ok as long as participant uses them as needed rather than daily, and is able to
discontinue these agents two days prior to the LP procedures.

6. Significant medical illnesses: Illnesses which would cause a hardship on the
participant to attend study visits and undergo a lumbar puncture. This includes
uncontrolled severe hypertension, unstable angina or cardiovascular disease, moderate
pulmonary disease (COPD), and Class III-IV congestive heart failure (CHF).

7. Active malignancy undergoing treatment with chemotherapeutic or radiation treatments.
Remote history of treated cancer is ok, as long as current cognition and digestion are
not affected

8. Treatment with hormones: Use of estrogen, testosterone, and continuous corticosteroid
replacements will be excluded, as these may have effects on study outcomes. Women must
be post-menopausal for at least 1 year before enrolling in the study, or be one year
out from a hysterectomy. Women who use hormone replacement therapy for symptomatic
menopause can be enrolled, if they agree to discontinue the medication four weeks
before the first meal and then throughout the study. Transgendered subjects can be
included in the study, provided that they are not taking sex steroids.

9. Psychiatric disorders: Subjects who report active untreated major depression,
psychosis, or mania, or who present with those symptoms at the baseline visit, will be
excluded. Psychiatric conditions such as post-traumatic stress disorder (PTSD),
depression, and anxiety which are stable and treated with medication or therapy are
ok.

10. Major digestive disorders including inflammatory bowel diseases, irritable bowel
syndrome, and celiac disease. History of surgical procedures which may affect the
absorption of meals, such as any weight loss surgery such as gastric bypass or
banding, or small intestine resection. Acid reflux is allowed if participant is on a
stable medication regimen.

11. Food allergies and intolerances: Those subjects allergic to the ingredients of the
meals will be excluded. Also excluded are medical conditions requiring strict
adherence to a particular diet, such as celiac disease or phenylketonuria.

12. Alcohol use: While they are in the study, subjects will be asked to limit their
alcohol intake to two drinks per day or less for men, or one drink per day or less for
women, due to alcohol's effects on lipid biochemistry and the study outcomes. Subjects
who are unable or unwilling to meet these criteria will not be enrolled.