Choline Effects - Pre-symptomatic AD

Study Overview
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Brief Summary
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The purpose of this study is to test the safety, tolerability, and effects of choline in people with increased risk of Alzheimer's Disease (AD), also known as pre-symptomatic AD. Choline is a dietary supplement, but is being investigated to see if it has any effects on the progression to AD.

Detailed Description
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The purpose of this study is to determine the safety and tolerability, as well as the biochemical effects of choline bitartrate over a 6-month treatment period in a moderately sized population harboring at least one copy of the APOE4 gene. APOE is a protein involved in lipid transport. Studies show that the APOE4 variant is strongly associated with an increased risk of Alzheimer's Disease. It is unclear how APOE4 results in an increased risk for AD, but a recent study identified a novel molecular pathway, which showed that APOE4-induced dysfunction of lipid metabolism in neurons by cellular accumulation of unsaturated lipids. The investigators hypothesize that choline supplementation normalizes the APOE4-mediated dysregulation by normalizing the Kennedy pathway in neuronal cells, thus stabilizing the lipid metabolism and concomitantly restoring normal cell function by increasing phosphatidylcholine activity via the Kennedy pathway. To evaluate this, the investigators will test if choline supplementation will decrease the ratio of unsaturated lipids to saturated lipids (the fatty acid desaturation index) in cerebrospinal fluid by 15% and increase phosphatidylcholine by 100%.

Official Title
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Testing Whether Choline Normalizes Lipid Metabolism in APOE4 Carriers

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Choline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has signed an informed consent form before any assessment is performed as part of the study. Be male or female between 55 and 80 years old. Be able to understand the nature of the study and have the opportunity to have all questions answered. Has tested positive for at least one copy of ApoE4. Has an MMSE score of 24 or greater. (can be based on documented result obtained within the previous 3 months). Is in the opinion of the Investigator, in good general medical health based upon medical history, physical examination, laboratory tests, vital signs and EKG. Has normal levels of Homocysteine in blood tests. A normal blood level is between 5 to 15 micromoles (mcmol/L) Completes the dietary interview with dietician. Females must be considered post-menopausal or not of child bearing potential. Exclusion Criteria: Current medical or neurological condition that might impact cognition or performance on cognitive assessments. (e.g. TBI, Parkinson's disease, multiple sclerosis, etc.) Inability or unwillingness of patient to undergo neuropsychological testing. Advanced, severe progressive or unstable disease that may interfere with the safety, tolerability and study assessments, or put the participant at special risk. (e.g. significant cardiac disease, severe renal impairment, severe hepatic impairment etc.) History of malignancy of any organ system, treated or untreated, within the past 60 months. Inability or unwillingness to undergo Lumbar Punctures. High dietary choline intake (more than 450mg) as determined by dietician Any condition, which in the opinion of the investigator, would put the subject at undue risk or would interfere with evaluation of the investigational product or interpretation of subject safety or study results.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Choline<br>2.2 g of choline, given as choline bitartrate, for a total of 180 days. | Drug: Choline<br>* Eight 275mg capsules taken orally twice daily (4 capsules with breakfast & 4 capsules with dinner) x 180 days<br>* Other names: VitaCholine(R);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the fatty acid desaturation index (FADI) in the CSF following choline supplementation | FADI will be utilized to determine whether unsaturated to saturated lipids decreases by 15% | baseline, 6 months | 
| Changes in phosphatidylcholine (PC) in the CSF following choline supplementation | FADI ( fatty acid desaturation index) will be utilized to determine whether saturated PC increases by 100% | baseline, 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events | Safety endpoints will be monitored throughout the study and number of incidents reported at end of study. Aggregate values and percentages will be reported | 9 months | 
| Changes in phospholipids in CSF following choline supplementation | Will compare scaled intensity between baseline and 6 months. | Baseline and 6 months | 
| Changes in phosphatidylcholine in blood following choline supplementation | Aggregate values and percentages will be reported. | Baseline and 6 months | 
| Changes in choline in blood following choline supplementation | Aggregate values and percentages will be reported | Baseline and 6 months | 
| Changes in proinflammatory cytokines in blood plasma following choline supplementation | Proinflammatory cytokine panel in plasma will be measured using commercially available immunosorbent assays to determine potential treatment effects. Aggregate values and percentages will be reported. Each sample will be tested in triplicate. | Baseline and 6 months | 
| Changes in neurofilament light chain (Nf-L) in CSF following choline supplementation | Levels of NfL in CSF will be measured using commercially available immunosorbent assays to determine potential treatment effects. Aggregate values and percentages will be reported. Each sample will be tested in triplicate. | Baseline and 6 months | 
| Changes in amyloid-β 42/40 ratio CSF following choline supplementation | Levels of amyloid-β 42/40 ratio in CSF will be measured by LC/MS/MS assays. Aggregate values and percentages will be reported. | Baseline and 6 months | 
| Changes in p-Tau/Total Tau ratio in CSF following choline supplementation | Levels of p-Tau/Total Tau will be measured by LC/MS/MS assays. Aggregate values and percentages will be reported. | Baseline and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pre-symptomatic AD