Effect of choline supplementation in presymptomatic APOE ε4 carriers: a pilot study

With the advent of early detection biomarkers, it is possible to envision testing preventive strategies that delay the onset of Alzheimer's disease (AD). The ε4 allele of apolipoprotein E (APOE ε4) is the strongest genetic risk factor for late-onset AD; approximately 50% of all patients are APOE ε4-positive.¹ APOE is the major central nervous system (CNS) lipoprotein, and studies have linked APOE4-dependent deficits in lipid metabolism to disease-relevant processes.^2-6 Choline, the precursor for phosphatidylcholine (PC), normalizes APOE ε4-mediated lipid dysfunction in human model systems,⁶ and low dietary choline intake correlates with increased disease risk or progression in mouse models and humans.^7-17 We therefore tested whether biomarkers and omics provided early evidence of choline CNS target engagement in an at-risk population.

In a 6-month open-label phase 1 study (NCT05880849), asymptomatic APOE ε4 carriers (n = 13; age 70 ± 5.5 years) received 2200 mg/day oral choline, with plasma and cerebrospinal fluid (CSF) collected before and after treatment.

Choline was well tolerated with no serious adverse events. Treatment increased plasma and CSF choline and betaine, indicating systemic and CNS exposure. Exploratory lipidomics identified changes in plasma PC species and, in CSF, increases in ceramides and cholesterol esters. Although this study was not powered to assess biomarker efficacy, CSF neurofilament light (NfL) was lower at the end of treatment, and CSF phosphoserine-181 tau (pTau181)/amyloid beta (Aβ)42 and plasma pTau217 showed directionally similar trends.

These findings support randomized placebo-controlled trials of choline in at-risk populations and illustrate how fluid biomarkers and omics can de-risk AD prevention studies.