Nutritional Interventions in Prodromal Alzheimer’s Disease: The 36-Month LipiDiDiet Multinutrient Clinical Trial
December 1, 2020
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By Lisa Mosconi, PhD
Associate Professor of Neuroscience in Neurology and Radiology, Weill Cornell Medicine
Dr. Mosconi reports no financial relationships relevant to this field of study.
SYNOPSIS: In a randomized, double-blind, placebo-controlled trial of Fortasyn Connect (Souvenaid), a nutraceutical drink, patients with prodromal Alzheimer’s disease demonstrated, over a 36-month period, a slower decline in cognitive functions compared to the control group.
SOURCE: Soininen H, Solomon A, Visser PJ, et al. 36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer’s disease. Alzheimers Dement 2020; Sept. 13. doi: 10.1002/alz.12172. [Online ahead of print].
Late-onset Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, affecting 5.7 million patients in the United States alone. The general consensus is that AD progresses on a spectrum with three stages: an early, preclinical stage with no symptoms; a middle stage of mild cognitive impairment (MCI); and a final stage marked by symptoms of dementia.
Although MCI is heterogeneous, in approximately 50% of cases it represents a transitional state between normal aging and dementia. Early diagnosis of AD in the MCI prodromal stage represents an opportunity for interventions to improve brain health or cognitive functioning and to manage modifiable risk factors implicated in disease progression.
Expert consensus opinions on AD prevention suggest that progression from MCI to dementia could be reduced by attention to modifiable risk factors related to lifestyle.1 Diet and nutritional status now are recognized as important factors for healthy brain aging and dementia, which has provided a rationale for the investigation of nutritional supplements to improve cognitive function in patients with MCI or AD. Although several observational studies reported positive associations between the intake of several single-agent nutrient supplements — mainly vitamin E, vitamin C, some B vitamins, carotenoids, and omega-3 fatty acids — clinical trial evidence for the effectiveness of single nutritional interventions in MCI and AD remains limited. However, it is possible that a combination of nutrients might have greater beneficial effects than any single nutrient taken in isolation, a concept known as “nutritional synergy.”
Fortasyn Connect (Souvenaid) is a once-daily drink containing a mixture of nutrients associated with a lower risk of age-related cognitive decline. Chiefly, these include precursors and cofactors necessary for the formation and function of neuronal membranes and synapses, such as long-chain omega-3 fatty acids, uridine, choline, B vitamins, vitamin C, vitamin E, and selenium, an antioxidant mineral. Preclinical research has shown that the specific combination of nutrients included in Fortasyn Connect reduces AD brain pathology. Previous clinical studies in humans reported some benefits on memory tests in patients with mild AD, but not in patients with moderate to severe AD.1-3 Based on available clinical trial results, an expert consensus opinion stated that Fortasyn Connect should be considered as an option for patients with mild AD dementia or MCI caused by AD pathology (e.g., prodromal AD).
The European LipiDiDiet trial is a randomized, double-blind, placebo-controlled trial designed to investigate the effects of Fortasyn Connect on cognition in a cohort of patients with a diagnosis of prodromal AD. Previous analysis of the first 24-month intervention period showed favorable effects on secondary endpoints, including Clinical Dementia Rating-Sum of Boxes (CDR-SB) and hippocampal atrophy on magnetic resonance imaging (MRI) scans, but not on the primary endpoint (Neuropsychological Test Battery [NTB] five-item composite).4 In this study, the authors extended the time to follow-up to 36 months to test whether a longer intervention duration might lead to improvement on the primary endpoint.
In this randomized, double-blind, placebo-controlled trial, 311 patients with prodromal AD were recruited using the International Working Group-1 criteria and assigned to active product (125 mL once-a-day drink) or an isocaloric, same-tasting, placebo control drink. The main outcome was a change in cognition (NTB five-item composite) over 36 months. Analyses were by modified intention-to-treat, excluding (i.e., censoring) data collected after the start of open-label active product and/or AD medication.
Of the 311 randomized patients, 162 participants completed the 36-month study, including 81 with 36-month data eligible for efficacy analysis. Over 36 months, significant reductions in decline were observed for the NTB five-item composite (-60%; between-group difference, 0.212 [95% confidence interval, 0.044-0.380]; P = 0.014), CDR-SB (-45%; P = 0.014), memory scores (-76%; P = 0.008), and brain atrophy measures, with small to medium Cohen’s d effect size (0.25-0.31) similar to established clinically relevant AD treatment.
Currently, this is the first randomized clinical trial of a nutritional intervention in prodromal AD over a period of 36 months. The authors offered that positive results on the CDR-SB, along with other measures of cognition and function, including some that appeared only after long-term intervention, suggest disease-modifying potential. However, the effects of Souvenaid became statistically significant only after 36 months of intervention, highlighting the need for a long treatment duration.
Recent expert reports conclude that some medical, lifestyle, psychosocial, and nutritional interventions may prevent or delay the progression from MCI to dementia. However, pharmacologic interventions with AD drugs are not recommended for patients with MCI, but may be considered if there is biomarker evidence of AD, although this opinion is based on limited clinical trial evidence.5 Generally, no significant benefits have been shown with pharmacologic therapies, such as cholinesterase inhibitors and memantine.
Medical and lifestyle interventions are encouraged more consistently. The Lancet Commission on Dementia Prevention suggested that 21.7% of dementia cases progressing from MCI potentially are preventable by eliminating poor diets, diabetes, and neuropsychiatric symptoms. Therefore, attention to modifiable risk factors is the first step for patients diagnosed with MCI. The best evidence indicates that management of patients with a diagnosis of MCI likely requires a multimodal approach involving lifestyle changes to reduce the effects of modifiable risk factors (hearing loss, obesity, hypertension, smoking, depression, physical inactivity, social isolation, and diabetes mellitus) and to promote healthy nutrition. The most compelling data so far are for the role of exercise in reducing the risk of dementia. However, increasing evidence points to dietary and nutritional interventions as part of broader lifestyle changes that may contribute to improved cognitive performance among individuals at risk of progression to dementia.
Epidemiological studies have shown an association between diets with high antioxidant content, such as the Mediterranean diet, and a decreased risk of dementia, MCI, and cognitive decline in older adults. The evidence also suggests that multimodal interventions of lifestyle risk factors may be more appropriate than focusing on single parameters. Likewise, although single nutritional supplements are not recommended because of insufficient evidence of clinical benefit, combinations of specific nutrients seem to yield more encouraging results.
Souveanid is a nutraceutical preparation that includes several nutrients with AD-risk-lowering properties. Randomized controlled trials investigated Souvenaid across a spectrum of patients with AD, ranging from prodromal AD to mild-moderate AD dementia, and the data showed that the benefits are greater when the product is used early in the course of the disease. In the LipiDiDiet study, the benefits of Souvenaid on cognition, memory, and hippocampal volume were greater among patients with prodromal AD and mild AD dementia, but not in mild-moderate AD dementia. These data, together with high rates of long-term product adherence, indicate that Souvenaid is a viable option for use in early-stage disease, including MCI caused by AD.
Real-world data and patient experience programs also have reported benefits for Souvenaid in patients with MCI and mild AD, including increased motivation and social engagement, improved energy levels, physical and mental resilience, and improvements in mood, cognition, and memory associated with a return to functional tasks and hobbies. Although these data are not as reliable as data from randomized controlled trials, they provide important information on quality of life for the patient and the family.
A major limitation to using Souvenaid is the need for biomarker support of the diagnosis of MCI caused by AD (prodromal AD). In fact, the only randomized controlled trial data showing clinical benefit were obtained in MCI patients who had evidence for underlying AD pathology based on positive findings from at least one diagnostic biomarker test (cerebrospinal fluid, MRI, and flurodeoxyglucose F 18 positron emission tomography). It is important to note that no studies are available on the effects of Souvenaid in MCI patients with a different diagnostic type. These data also speaks to the importance of biomarker testing for clinical trials as well as clinical practice. The success of strategies to delay progression of MCI to dementia depends in large part on early and accurate identification of people at risk of AD.
Finally, it remains unclear whether simply taking multivitamin supplements containing similar doses of the same nutrients included in Souvenaid would yield similar results.
In conclusion, early identification of individuals at risk of progression from MCI to AD dementia is crucial to facilitate patient management at a time when pathological changes and clinical deficits are not yet too severe. Physicians have an important role to play in encouraging patients to adopt a healthy lifestyle and diet to support cognitive function, which is a crucial first step in the management of patients with MCI. In addition, MCI patients with AD pathology should be provided with information about nutritional supplementation, including Souvenaid.
- Scheltens P, Kamphuis PJ, Verhey FRJ, et al. Efficacy of a medical food in mild Alzheimer’s disease: A randomized, controlled trial. Alzheimers Dement 2010;6:1-10e1.
- Scheltens P, Twisk JWR, Blesa R, et al. Efficacy of Souvenaid in mild Alzheimer’s disease: Results from a randomized, controlled trial. J Alzheimers Dis 2012;31:225-236.
- Shah RC, Kamphuis PJ, Leurgans S, et al. The S-Connect study: Results from a randomized, controlled trial of Souvenaid in mild to moderate Alzheimer’s disease. Alzheimers Res Ther 2013;5:59.
- Soininen H, Solomon A, Visser PJ, et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer’s disease (LipiDiDiet): A randomised, double-blind, controlled trial. Lancet Neurol 2017;16:965-975.
- Cummings J, Passmore P, McGuinness B, et al. Souvenaid in the management of mild cognitive impairment: An expert consensus opinion. Alzheimers Res Ther 2019;11:73.
In a randomized, double-blind, placebo-controlled trial of Fortasyn Connect (Souvenaid), a nutraceutical drink, patients with prodromal Alzheimer’s disease demonstrated, over a 36-month period, a slower decline in cognitive functions compared to the control group.
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