24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial

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Summary

Background

Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial.

Methods

LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705.

Findings

Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was −0·028 (SD 0·453) in the active group and −0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI −0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of −0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention.

Interpretation

The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed.

Funding

European Commission 7th Framework Programme.

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Most cited references 19

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Report of the task force on designing clinical trials in early (predementia) AD.

Bernard Schneider, Fábio Sampaio, Z S Khachaturian … (2011)

A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

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Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination.

Nick van Wijk, Laus M. Broersen, Martijn de Wilde … (2013)

Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models.

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Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally.

Ismail H Ulus, Mehmet Cansev, Lei Wang … (2006)

The synthesis of brain phosphatidylcholine may utilize three circulating precursors: choline; a pyrimidine (e.g., uridine, converted via UTP to brain CTP); and a PUFA (e.g., docosahexaenoic acid); phosphatidylethanolamine may utilize two of these, a pyrimidine and a PUFA. We observe that consuming these precursors can substantially increase membrane phosphatide and synaptic protein levels in gerbil brains. (Pyrimidine metabolism in gerbils, but not rats, resembles that in humans.) Animals received, daily for 4 weeks, a diet containing choline chloride and UMP (a uridine source) and/or DHA by gavage. Brain phosphatidylcholine rose by 13-22% with uridine and choline alone, or DHA alone, or by 45% with the combination, phosphatidylethanolamine and the other phosphatides increasing by 39-74%. Smaller elevations occurred after 1-3 weeks. The combination also increased the vesicular protein Synapsin-1 by 41%, the postsynaptic protein PSD-95 by 38% and the neurite neurofibrillar proteins NF-70 and NF-M by up to 102% and 48%, respectively. However, it had no effect on the cytoskeletal protein beta-tubulin. Hence, the quantity of synaptic membrane probably increased. The precursors act by enhancing the substrate saturation of enzymes that initiate their incorporation into phosphatidylcholine and phosphatidylethanolamine and by UTP-mediated activation of P2Y receptors. Alzheimer's disease brains contain fewer and smaller synapses and reduced levels of synaptic proteins, membrane phosphatides, choline and DHA. The three phosphatide precursors might thus be useful in treating this disease.

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Author and article information

Contributors

Hilkka Soininen

Journal

Journal ID (nlm-ta): Lancet Neurol

Journal ID (iso-abbrev): Lancet Neurol

Title: The Lancet. Neurology

Publisher: Lancet Pub. Group

ISSN (Print): 1474-4422

ISSN (Electronic): 1474-4465

Publication date PMC-release: 1 December 2017

Publication date (Print): December 2017

Volume: 16

Issue: 12

Pages: 965-975

Affiliations

[a ]Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland

[b ]Neurocenter, Department of Neurology, Kuopio University Hospital, Kuopio, Finland

[c ]Department of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Huddinge, Sweden

[d ]Clinical Trials Unit, Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden

[e ]Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, University of Maastricht, Maastricht, Netherlands

[f ]Department of Neurology, Alzheimer Center, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands

[g ]Pentara Corporation, Salt Lake City, UT, USA

[h ]Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden

[i ]Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

[j ]German Institute for Dementia Prevention (DIDP), Medical Faculty, and Department of Experimental Neurology, Saarland University, Homburg, Germany

Author notes

[* ]Correspondence to: Prof Hilkka Soininen, Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, 70211 Kuopio, FinlandCorrespondence to: Prof Hilkka Soininen, Department of NeurologyInstitute of Clinical MedicineUniversity of Eastern FinlandKuopio70211Finland hilkka.soininen@ 123456uef.fi

[†]

Study group members listed in the appendix

Article

Publisher ID: S1474-4422(17)30332-0

DOI: 10.1016/S1474-4422(17)30332-0

PMC ID: 5697936

PubMed ID: 29097166

SO-VID: 4caee255-605f-4940-804e-d22b95bd839e

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial

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Karger: Neurology and Neuroscience

Most cited references 19

Report of the task force on designing clinical trials in early (predementia) AD.

Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination.

Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally.

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