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.

Study Overview

• Status: Recruiting
• Conditions: Cognitive Dysfunction; Alzheimer Disease; Fatty Acids, Omega-3; Brain Aging; Apolipoprotein E, Deficiency or Defect of; Blood-Brain Barrier
• Intervention / Treatment: Drug: Alpha-Linolenic Acid (2.6 g/day); Dietary supplement: Placebo Control Group

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Claudio Mendes, MS; Phone Number: 8489328412; Email: alastudy@njms.rutgers.edu
• Study Contact Backup: Name: Rebecca West-Mortimer, PHD; Phone Number: 8489328415; Email: alastudy@njms.rutgers.edu

Study Locations

• United States
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Recruiting
      • Rutgers - Institute for Health
      • Contact: Claudio Mendes; Email: claudio.mendes@rutgers.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ALA Group; Participants receive flaxseed oil in 5 mL oral syringes containing 2.6g of ALA, taken daily for six months.	Drug: Alpha-Linolenic Acid (2.6 g/day); Participants 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.; Other Names: Flaxseed Oil, ALA
Placebo Comparator: Placebo Control Group; Participants receive corn oil without ALA (iso-caloric placebo) in 5 mL oral syringes that are identical in appearance to those containing ALA, taken daily for six months.	Dietary supplement: Placebo Control Group; Participants 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.; Other Names: Corn Oil, Placebo Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and 6 months
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.	Baseline and 6 months
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.	baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and 6 months
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.	Baseline and 6 months
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.	Baseline and 6 months
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.	Baseline and 6 months
White Matter Hyperintensity (WMH)	Changes in WMH volume will be assessed using 3D T2-FLAIR MRI. Changes from baseline to 6 months will be compared between ALA and placebo groups.	Baseline and 6 months
Alzheimer's Disease and Related Dementia (ADRD) Blood Biomarkers - Phosphorylated tau 217 (p-tau217) and Neurofilament Light (NfL)	Changes in plasma levels of Phosphorylated tau 217 (p-tau217) and Neurofilament Light (NfL) will be assessed. Changes from baseline to 6 months will be compared between ALA and placebo groups.	Baseline and 6 months
Blood fatty acids markers	Changes in plasma levels of fatty acids including ALA, DHA, and EPA will be analyzed by TLC-GC-MS. Changes from baseline to 6 months will be compared between ALA and placebo groups.	Baseline and 6 months

Collaborators and Investigators

• Sponsor: Michal Schnaider Beeri, Ph.D.
• Investigators: Principal Investigator: Michal Beeri, PHD, Rutgers University

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: October 20, 2025
• First Submitted That Met QC Criteria: January 30, 2026
• First Posted (Actual): February 6, 2026

Study Record Updates

• Last Update Posted (Actual): February 6, 2026
• Last Update Submitted That Met QC Criteria: January 30, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Neurodegeneration; Biomarkers; Older adults; Vascular Integrity; Brain MRI; Cognitive Function; Magnetic resonance imaging (MRI); Blood-brain barrier; Apolipoprotein E4; Blood Biomarkers; Nutritional Intervention; Dementia prevention; Flaxseed Oil; Alpha-Linolenic Acid; APOE4 Dysfunction; Aging Brain; Memory Loss Prevention; AD Prevention Trial; Cognitive decline prevention
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathologic Processes; Neurocognitive Disorders; Cognition Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Pathological Conditions, Signs and Symptoms; Cognitive Dysfunction; Alzheimer Disease; Nerve Degeneration; Apolipoprotein E, Deficiency or Defect of; Fatty Acids; Lipids; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Plant Preparations; Biological Products; Complex Mixtures; Fatty Acids, Unsaturated; Plant Oils; Oils; Dietary Fats; Fats; Fatty Acids, Omega-3; Dietary Fats, Unsaturated; Fats, Unsaturated; Linolenic Acids; Fatty Acids, Essential; Linseed Oil; Corn Oil; alpha-Linolenic Acid
• Other Study ID Numbers: Pro2025000006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share non-identifiable (no PHI) data with other investigators upon participants' approval.
• IPD Sharing Time Frame: IPD will be made available after the main results of the study are published. This is anticipated to occur in June 2028.
• IPD Sharing Access Criteria: Qualified researchers will be able to access de-identified individual participant data and supporting documents (such as the study protocol and statistical analysis plan) upon reasonable request. Access will be provided after publication of the main results, following approval by the study sponsor and completion of a data use agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes