ALA-enriched Nutrition for Prevention of Cognitive Decline in APOE4 Older Adults

Alpha Linolenic Acid-enriched Nutrition for Prevention of Cognitive Decline in APOE4 Older Adults With Mild Cognitive Impairment: Targeting Cerebrovascular and Blood-brain Barrier Health

This randomized, double-blind, placebo-controlled pilot trial will evaluate the effects of alpha-linolenic acid (ALA) supplementation on cognitive function, blood-brain barrier integrity, and brain vascular health in older adults with mild cognitive impairment and APOE4 genotype. By targeting the endogenous synthesis of docosahexaenoic acid (DHA) through ALA supplementation, the investigators aim to overcome the limitations of direct DHA supplementation, particularly in APOE4 carriers who exhibit low brain DHA levels and impaired blood-brain barrier function. This innovative approach offers a safe, cost-effective, and easily implementable therapeutic strategy for older adults at high risk for Alzheimer's dementia, especially APOE4 carriers, addressing a critical need given the limited cognitive benefits and significant adverse events of current amyloid-clearing drugs in this population.

This randomized, double-blind, placebo-controlled pilot study will evaluate the effects of alpha-linolenic acid (ALA)-enriched nutrition on cognitive function, blood-brain barrier (BBB) integrity, and brain vascular health in a high-risk population of older adults with MCI and APOE4 genotype. Docosahexaenoic acid (DHA), a critical fatty acid for brain health, is synthesized from ALA. Despite previous research showing limited cognitive benefits from DHA supplementation, APOE4 carriers have low brain DHA levels. This deficiency may stem from impaired transport across the BBB and compromised BBB integrity. The investigators hypothesize that ALA supplementation will enhance endogenous DHA synthesis, leading to improved cognitive outcomes through increased brain levels of DHA and its metabolites, including eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA), and improved BBB and brain vascular integrity. The study will include 60 older adults with MCI who carry at least one APOE4 allele. Participants will be randomized to either daily supplementation of 2.6 grams of ALA or a placebo (corn oil) for six months. The specific aims will compare ALA and placebo on: 1) Cognition: The investigators hypothesize improvement in global cognition at 6 months in the ALA-treated group. Secondary outcomes will be episodic memory and executive functions. 2) Cerebral vasculature: The primary neurobiological outcome will be BBB integrity, assessed via MRI. The investigators hypothesize that the ALA group will exhibit reduced BBB leakage compared to placebo. Secondary measures will include cerebral blood flow, brain vascular reactivity, and white matter hyperintensities. 3) Blood Biomarkers: The investigators will measure blood biomarkers indicative of BBB integrity (including mfsd2a, s100B, and GFAP). The investigators expect lower levels of these markers in the ALA group at six months, reflecting improved BBB function. Additionally, the investigators will analyze in plasma ALA and its downstream pathway (DHA, EPA). Finally, to distinguish the specific effects of ALA on cerebral vascular integrity from ADRD processes, the investigators will also explore its effects on plasma p-tau 217 and Neurofilament Light. This pilot study will lay the groundwork for a larger multi-site RCT testing the cognitive, BBB, and cerebrovascular benefits of ALA supplementation in APOE4 carriers at risk for Alzheimer's dementia. With current amyloid-clearing drugs showing limited success in preventing or reversing dementia symptoms-especially among APOE4 carriers-this research has potential for high public health impact by offering a promising new, low cost, safe therapeutic avenue for older adults at high dementia risk.

Inclusion Criteria:

• Age 60 years or older
• Have amnestic Mild Cognitive Impairment (MCI) - memory problems that do not interfere with daily life.
• Carry at least one APOE4 gene allele (determined by a blood test).
• Be fluent in English or Spanish.
• Have a study partner (family member or friend) who can provide information about daily function.
• Have the ability to give informed consent and comply with study visits and procedures.

Exclusion Criteria:

• A diagnosis of dementia or any other brain disease that significantly affects thinking or memory (e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, epilepsy, traumatic brain injury).
• History of stroke or other major neurological condition.
• Short life expectancy due to end-stage disease or other serious medical condition.
• Active cancer treatment that could interfere with study participation.
• Allergy or sensitivity to flaxseed oil or corn oil.
• Current use of flaxseed, flax oil, or fish oil supplements more than once per week.
• MRI contraindications, such as pacemakers, metallic implants, or severe claustrophobia.
• Current or past history of prostate cancer, regardless of remission status, OR a prostate-specific antigen (PSA) level > 20 ng/mL at screening.
• Use of experimental Alzheimer's treatments (e.g., amyloid monoclonal antibodies) unless on a stable regimen as confirmed by the treating physician.