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. 2023;10(4):800-809.
doi: 10.14283/jpad.2023.55.

Protocol of a Phase II Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial of S-Adenosyl Methionine in Participants with Mild Cognitive Impairment or Dementia Due to Alzheimer's Disease

S Holper  1 , R Watson, L Churilov, P Yates, Y Y Lim, K J Barnham, N Yassi
Affiliations

Protocol of a Phase II Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial of S-Adenosyl Methionine in Participants with Mild Cognitive Impairment or Dementia Due to Alzheimer's Disease

S Holper et al. J Prev Alzheimers Dis. 2023.

Abstract

Background: S-adenosyl methionine (SAMe) is a pivotal metabolite in multiple pathways required for neuronal homeostasis, several of which are compromised in Alzheimer's disease (AD). Correction of the SAMe deficiency that is characteristic of the AD brain may attenuate or prevent pathological processes driving AD-associated neurodegeneration including aberrant tau hyperphosphorylation and DNA hypomethylation.

Objectives: The primary aim is to test the hypothesis that daily treatment with 400 mg oral SAMe for 180 days will lead to a greater reduction from baseline in plasma levels of p-tau181 compared to placebo in patients with mild cognitive impairment or dementia due to AD.

Design, setting, participants: This is a phase II, randomized, multi-center, double-blind, placebo-controlled trial among 60 participants with mild cognitive impairment or dementia due to AD. Participants will be randomized in a 1:1 ratio to receive either SAMe or matching placebo, to be taken as an adjunct to their AD standard of care.

Measurements and results: The primary outcome is change in plasma p-tau181 concentration between baseline and following 180 days of treatment, which will be compared between the active and placebo group. Secondary outcomes are the safety of SAMe administration (incidence of serious adverse events), change from baseline in cognitive performance (as measured by the Repeatable Battery for the Assessment of Neuropsychological Status), and epigenetic changes in DNA methylation.

Conclusion: Demonstration of effective and safe lowering of plasma p-tau181 with SAMe in this phase II trial would pave the way for an exciting field of translational research and a larger phase III trial.

Keywords: Alzheimer’s disease; DNA methylation; S-adenosyl methionine; dementia; tau hyperphosphorylation.

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Conflict of interest statement

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Figures

Figure 1
Figure 1
Causes and consequences of S-adenosyl methionine (SAMe) deficiency in AD
Figure 2
Figure 2
A) The methionine cycle. Methionine is activated by adenosine triphosphate (ATP) to form S-adenosyl methionine (SAMe). In the process of methylation, SAMe donates a methyl group to a substrate in a reaction catalyzed by a methyltransferase. The remaining product, S-adenosyl homocysteine (SAH) is converted to homocysteine. From here, homocysteine has two possible fates: transsulfuration to glutathione (a B6-dependent reaction) or remethylation to methionine (a vitamin B12-dependent reaction, using methyl tetrahydrofolate as a substrate). The latter produces much of the methionine required to generate new SAMe. B) Aberrations in the methionine cycle leading to quantitative and functional SAMe deficiency
Figure 3
Figure 3
Summary of SAMe Study design. Participants will complete 6 study visits
See this image and copyright information in PMC

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