Brain scans can help identify changes that appear to increase risk for cognitive decline and dementia. Some of these brain changes are thought to reflect actual damage to the small blood vessels that support normal brain function. This clinical trial will determine whether an omega 3 polyunsaturated fatty acid (PUFA) therapy can promote brain health by supporting the small blood vessels in the brain over 3 years in older adults at high risk for cognitive decline and dementia of Alzheimer's type.

The main objective of this study is to determine if omega 3 PUFA can slow the accumulation of brain MRI derived white matter hyper-intensities (WMH) over 3 years in a population at risk for dementia. This trial is designed to collect preliminary data into the mechanism by which PUFA therapy operates on the brain with special attention to the vascular components.

The randomized, double-blind and controlled trial will rigorously test PUFA effects versus a placebo in non-demented elders over 3 years. This biomarker based trial will enroll 100 elders. Aim 1 will assess PUFA effects on neuroimaging parameter changes. Aim 2 will assess PUFA effects on blood-based biomarkers of endothelial health, and Aim 3 will collect preliminary data on PUFA effects on neuropsychological and functional parameters with special attention to the executive and speed of processing skills and gait speed.

Inclusion Criteria:

1. Non-demented or mild cognitive impairment, defined as Clinical Dementia Rating =0 or 0.5 and MMSE >=24.
2. Age 75 and older, male and female
3. Total WMH volume ≥ 5 cc
4. Plasma PUFA index (EPA + DHA) < 110 ug/ml or < 5.5 weight percent
5. Sufficient English language skills to complete all tests
6. Geriatric Depression Scale - 15 < 6 documenting absence of a significant depressive syndrome
7. Sufficient vision and hearing to complete all tests
8. Informant available with frequent (at least 1 hour/day or 1 day/week) contact with subject to verify functional status and CDR rating
9. General health status that will not interfere with the ability to complete the prospective study (these conditions are listed below in the study exclusion list)

Exclusion Criteria:

1. Any dementing illness (AD, vascular dementia, normal pressure hydrocephalus, or Parkinson's disease); dementia defined by CDR ≥ 1, MMSE < 24

2. Significant disease of the CNS such as brain tumor, seizure disorder, subdural hematoma, cranial arteritis

3. Alcohol or substance abuse according to DSM-IV criteria within the last 2 years

4. Major depression, schizophrenia, or other major psychiatric disorder defined by DSM-IV criteria

5. Abnormal labs indicating vitamin B12 deficiency, thyroid disease, or UTI (documented bacterial colonization is acceptable)

6. Unstable or significantly symptomatic CVD (e.g. CAD with frequent angina, CHF with dyspnea at rest)

7. Hypertension: defined as uncontrolled BP > 150/90

8. Clinical symptomatic orthostatic hypotension

9. Diabetes mellitus that requires insulin injections

10. History of cortical stroke

11. Cancer within the last 5 years, with the exception of localized prostate cancer (Gleason Grade < 3) and non-metastatic skin cancers (melanoma).

12. Illness that requires >1 visit /month to a clinician

13. Contraindications to MRI (i.e., heart pacemaker, metal plates or objects in head, , claustrophobia)

14. Medications:

    1. CNS active meds that have not been on stable doses for at least 2 months (cimetidine, beta-blockers, and SSRIs)
    2. Neuroleptics, antiparkinsonian agents, systemic corticosteroids, and narcotic analgesics; in the case where these were used for a self-limited time they must have been discounted for a period of five half-lives prior to baseline visit
    3. Over the counter supplements are not by themselves exclusionary, however, subjects are asked not to change the dosing regimen over the course of the trial unless medically indicated; the presence and dose of these agents are recorded
    4. A baseline screen plasma PUFA > 5.5 weight percent of total fatty acids for EPA+DHA will confirm supplementation of O3PUFA history. If patient indicates regular supplementation with fish oil on phone screen, can wash out for 4 months prior to study visit one.
    5. Cholinesterase inhibitors (i.e., Aricept)
    6. Investigational drugs within five half-lives prior to baseline
    7. Anticoagulation therapy: Vitamin K antagonist: warfarin (Coumadin, jantoven), Factor Xa inhibitors: rivaroxaban (xarelto), fondaparinux (arixtra), dibigatran (pradaxa), apixaban (eliquis); Low molecular weight heparins: dalteparin (fragmin), enoxaparin (lovenox)(Incident use of anticoagulant therapy will exclude further study drug allocation. However, subjects will be asked to complete all follow-up visits.)