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.
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.
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.
Parallel
Alpha-Linolenic Acid (2.6 g/day)
DrugParticipants in this group will take flaxseed oil that contains 2.6 grams of alpha-linolenic acid (ALA) each day for six months. The oil will be provided in 5 mL prefilled oral syringes prepared by the Rutgers Clinical Research Pharmacy. Participants will take one syringe daily in the morning with food. They may mix the oil with cold foods such as yogurt or applesauce but should not heat it. The ALA supplement is intended to improve cognitive and brain health by enhancing the body's natural production of DHA that supports blood-brain barrier integrity and brain function.
Placebo Control Group
Dietary supplementParticipants in this group will take corn oil that does not contain ALA. The oil will be provided in the same 5 mL prefilled oral syringes as the active supplement and will look, taste, and smell similar to the ALA oil. Participants will take one syringe daily in the morning with food for six months. The placebo is used to compare effects against the ALA supplement and to maintain blinding for both participants and study staff.
Change in global cognitive (score) function
Change in global cognition score from baseline to 6 months measured by an average of the z-scores across a broad cognitive battery, will be compared between ALA and placebo groups.
Change in Blood-Brain Barrier Integrity - Permeability of the BBB
Blood-brain barrier (BBB) permeability will be assessed using the water exchange rate constant (Kw), derived from a validated motion-corrected diffusion-weighted pseudocontinuous arterial spin labeling (MCDW-pCASL) MRI sequence. Values will be extracted from whole-brain and region-specific areas, including hippocampus, dorsolateral frontal cortex, and parietal cortex. Changes from baseline to 6 months will be compared between ALA and placebo groups.
Levels of blood biomarkers of BBB Integrity
Changes in protein levels in serum of: mfsd2a, s100B, and Glial Fibrillary Acidic Protein (GFAP) indicative of BBB function. Changes from baseline to 6 months will be compared between ALA and placebo groups.
Episodic Memory
Changes in episodic memory scores - the average z-score of the immediate and delayed word recall task, and the word recognition task will be assessed. Changes from baseline to 6 months will be compared between ALA and placebo groups.
Executive Function
Changes in executive function scores - the average z-score of: Trail Making Test Parts A and B, Digit Span Forward and Backward, Animal Fluency, and Vegetable Fluency assessments. Changes from baseline to 6 months will be compared between ALA and placebo groups.
Cerebral Blood Flow
Changes in cerebral blood flow will be assessed by MRI sequence measured by PSeudo Continuous Arterial Spin Labelling Sequence (pCASL). Values will be extracted from whole-brain and region-specific areas: hippocampus, as well as parietal, superior temporal, dorsolateral prefrontal, and precuneus cortex. Changes from baseline to 6 months will be compared between ALA and placebo groups.
Brain Vascular Reactivity
Changes in brain vascular reactivity measured by a EPI BOLD scan tracing a CO2 concentration. Changes from baseline to 6 months will be compared between ALA and placebo groups.
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Michal Schnaider Beeri, Ph.D.
Lead sponsor
Rutgers, The State University of New Jersey
Sponsor institution
