By Lisa Mosconi, PhD

Associate Professor of Neuroscience in Neurology and Radiology, Weill Cornell Medicine

SYNOPSIS: Over a 36-month period, patients with prodromal Alzheimer’s disease who consumed Fortasyn Connect (Souvenaid), a nutraceutical drink, demonstrated a slower decline in cognitive functions vs. 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 consensus is 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 state between regular aging and dementia. Diagnosing AD in the MCI prodromal stage early is a chance to implement interventions to strengthen cognitive functioning or brain health and to handle modifiable risk factors associated with disease progression.

Experts believe more attention on modifying risk factors connected to lifestyle could slow the progression from MCI to dementia.1 Diet and nutritional status 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 be more beneficial than any single nutrient taken in isolation, a concept known as “nutritional synergy.”

Fortasyn Connect (Souvenaid) is a once-daily drink that contains nutrients associated with a lower risk of age-related cognitive decline. Chiefly, these include cofactors and precursors that help the formation and function of neuronal membranes and synapses, such as B vitamins, vitamin C, vitamin E, long-chain omega-3 fatty acids, choline, uridine, and selenium. Research has shown the mixture of nutrients in Fortasyn Connect reduces AD brain pathology. The authors of 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 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 was 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. A 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 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. The authors recruited 311 patients with prodromal AD using the International Working Group-1 criteria and assigned patients 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 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% CI, 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.

This was the first randomized clinical trial of a nutritional intervention in prodromal AD over 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.

COMMENTARY

Experts recently concluded some lifestyle, medical, nutritional, and psychosocial interventions may prevent or slow the progression from MCI to dementia. However, researchers do not recommend pharmacologic interventions with AD drugs for those with MCI. Those drugs could be considered if clinicians see biomarker evidence of AD, although researchers based this on limited clinical trial evidence.5 Generally, researchers have not observed significant benefits with pharmacologic therapies, such as memantine and cholinesterase inhibitors.

Medical and lifestyle interventions are encouraged more consistently. The Lancet Commission on Dementia Prevention suggested 21.7% of dementia cases progressing from MCI may be preventable by eliminating diabetes, poor diets, and neuropsychiatric symptoms. Therefore, pay attention to modifiable risk factors for those diagnosed with MCI. The best evidence indicates managing patients with an MCI diagnosis likely requires a multipronged approach that includes changing lifestyle habits to reduce the effects of modifiable risk factors (hypertension, smoking, hearing loss, obesity, physical inactivity, depression, social isolation, and diabetes mellitus) and to promote healthy diets.

The most compelling data so far concern the role of exercise in reducing the risk of dementia. However, mounting 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 revealed a connection between diets with high antioxidant content (e.g., the Mediterranean diet) and a lower risk of MCI, dementia, and cognitive decline in older patients. The evidence also suggests multipronged modifications of lifestyle risk factors may be better than focusing on individual parameters. Likewise, although single nutritional supplements are not recommended because of a lack of evidence showing clinical benefit, combinations of specific nutrients seem to yield more encouraging results.

Souvenaid is a nutraceutical preparation that includes several nutrients with AD risk-lowering properties. The authors of 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 the benefits are greater when the product is used early in the disease course. In the LipiDiDiet study, the benefits of Souvenaid on memory, hippocampal volume, and cognition were more helpful to individuals with mild AD dementia and prodromal AD, but not in mild-moderate AD dementia. These data, along with high rates of long-term product adherence, indicate Souvenaid is a useful tool in early-stage disease, including AD-induced MCI.

Patient experience programs and real-world data also have indicated benefits for Souvenaid in those with mild AD and MCI, including more social engagement and motivation; mental and physical resilience; higher energy levels; and improvements in memory, cognition, and mood connected to a return to functional hobbies and tasks. Although these data are not as reliable as those 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 exhibited evidence for underlying AD pathology based on positive findings from at least one diagnostic biomarker test (cerebrospinal fluid, MRI, and fluorodeoxyglucose F 18 PET). No studies are available regarding the effects of Souvenaid on MCI patients with a different diagnostic type. These data also speak to the importance of biomarker testing for clinical trials as well as clinical practice. The success of techniques 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.

Identifying individuals at risk of progression from MCI to AD dementia early is vital to facilitate patient management when clinical deficits and pathological changes are not too severe yet. Physicians play an important role in encouraging patients to adopt a healthy diets and lifestyles to support cognitive function, which is a crucial first step in MCI management. In addition, MCI patients with AD pathology should be provided with information about nutritional supplementation, including Souvenaid.

REFERENCES

  1. Scheltens P, Kamphuis PJ, Verhey FRJ, et al. Efficacy of a medical food in mild Alzheimers disease: A randomized, controlled trial. Alzheimers Dement 2010;6:1-10e1.
  2. Scheltens P, Twisk JWR, Blesa R, et al. Efficacy of Souvenaid in mild Alzheimers disease: Results from a randomized, controlled trial. J Alzheimers Dis 2012;31:225-236.
  3. Shah RC, Kamphuis PJ, Leurgans S, et al. The S-Connect study: Results from a randomized, controlled trial of Souvenaid in mild to moderate Alzheimers disease. Alzheimers Res Ther 2013;5:59.
  4. Soininen H, Solomon A, Visser PJ, et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimers disease (LipiDiDiet): A randomised, double-blind, controlled trial. Lancet Neurol 2017;16:965-975.
  5. 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.