International experts agree that there is an urgent need to address the burden of cognitive decline in an aging population, for those with MCI/AD and the wider society. The efficacy and safety of Souvenaid has been assessed in a research programme spanning > 20 years, including high quality international clinical trials of > 2000 participants at varying stages of cognitive decline and impairment (i.e., at risk elderly, those with age related cognitive decline, mild cognitive impairment (MCI) and patients with mild-moderate Alzheimer’s disease (AD)).
International experts agree that there is an urgent need to address the burden of cognitive decline in an aging population, for those with MCI/AD and the wider society. The efficacy and safety of Souvenaid® has been assessed in a research programme spanning > 20 years, including high quality international clinical trials of > 2000 participants at varying stages of cognitive decline and impairment (i.e., at risk elderly, those with age related cognitive decline, mild cognitive impairment (MCI) and patients with mild-moderate Alzheimer’s disease (AD)). The Souvenaid research programme builds on the findings from pre-clinical studies that demonstrated an effect of administering the specific nutrients combination in Souvenaid (Fortasyn Connect™) on synapse function/formation. Figure 1 provides an overview of the key proof of concept, intervention and observational studies undertaken or ongoing.
The majority of key nutrients contained in Fortasyn Connect have been found in a meta-analysis of studies to be significantly lower in the blood of patients with AD1 . Rijpma et al, 20172 reported evidence from brain scans which showed that Souvenaid improved formation of neuronal phospholipid, supporting the proposed mode of action of the product in synapse formation, which may impact on cognitive function.
Souvenaid has been shown in randomised controlled trials (RCTs) to slow down the decline in cognitive abilities and positively impact memory3,4 in MCI and mild AD, respectively. A similar effect on cognition has not been observed in moderate AD5. Finally, Souvenaid was well tolerated in combination with AD medication.
The LipiDiDiet1 study is a randomized double blind, placebo-controlled trial of 311 people with prodromal AD (MCI with underlying AD pathology) assigned to active (Souvenaid once per day) or control (isocaloric placebo drink) groups. The study assessed the effects of Souvenaid on cognition, and brain atrophy at baseline, 6 months, 12 months, and yearly thereafter up to 6 years using a range of established and validated clinical outcomes in this population. The primary outcome was cognition measured by a Neuropsychological Test Battery (NTB) and secondary measures included the NTB memory domain, NTB executive function domain, and NTB total; Clinical Dementia Rating-Sum of Boxes (CDR-SB) – a measure of cognition and function; and hippocampal, ventricular, and whole brain atrophy based on magnetic resonance imaging (MRI) brain scans. The subjects were recruited from four European countries, aged 55-85 at enrolment and did not use AD drugs. Results from 24 months and 36 months of the intervention have now been reported.
Analysis from the first 24-months9 showed favourable effects on some secondary outcomes (e.g., CDR-SB and hippocampal atrophy) but not on the primary NTB endpoint. As some effects were observed at 24 months but cognitive decline was less than anticipated in the control group, it was proposed that the longer intervention may lead to more pronounced effects. A post-hoc analysis was performed using the Alzheimer’s Disease Composite Score (ADCOMS), which identified the cognitive and functional benefits of the specific multi-nutrient intervention, with 36% less decline in the active group16. The most recent analysis on this data applied a Time Component Test (TCT) to the primary NTB endpoint, the CDR-SB and hippocampal volume, and combined the outcomes to show 9 months of time savings relative to placebo over 24 months of treatment (9.0, 10.5, and 7.2 months for NTB, CDR-SB, and hippocampal volume respectively)17.
Results from 36 months of the intervention were published in 2021 showing significant positive benefits on cognition, function, and rates of brain atrophy (brain shrinkage) in the active group (Souvenaid) specifically.
Subsequent post-hoc ADCOMS analysis showed a statistically significant slowing in change from baseline scores over 36 months, with 36% less worsening of disease in the active group compared with the control group. The TCT analyses on the 36-month results of the intervention are currently being prepared.
The active product was found to be safe, very well tolerated, and compliance with the supplement at 36 months was very high (means of 91.4% in the active group and 90.8% in the control group).
Given the observed positive impact on cognition, brain function and atrophy, the study demonstrated that long-term nutritional intervention with Souvenaid has the potential to alter disease trajectories over 3 years. The authors suggest that the duration of the nutritional intervention and early initiation in the disease may be factors that contribute to the observed benefits.
This RCT8, was a proof-of-concept study designed to investigate the impact of Souvenaid on cognitive function in subjects with mild AD who were not taking any AD medication. The trial consisted of a 12-week core study followed by a 12-week exploratory and optional extension, in 5 European countries. Subjects were randomized to one of two nutritional treatment groups: Souvenaid (n = 99) or an iso-caloric control product (n = 100). These study products were taken once-daily over the study period.
Co-primary outcome measures were the delayed verbal recall task of the Wechsler Memory Scale–revised (WMS-r), a sensitive measure of episodic memory, and the 13-item modified Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) subscale at week 12. Secondary outcome measures included 12-item Neuropsychiatric Inventory, Alzheimer’s disease Co-operative Study–Activities of Daily Living, Quality of Life in Alzheimer’s Disease.
The Souvenir I study provided proof-of-concept support for the hypothesis that combinations of defined nutrients have the potential to fulfill a nutritional need and raise the nutritional levels. Subsequently, this may promote the synthesis of synaptic membranes and provide relevant clinical benefits for patients with mild AD.
In the second study in this series (Souvenir II), this RCT aimed to confirm and extend the findings from the Souvenir I study4. Individuals with the same clinical diagnosis as those who took part in the Souvenir I study (mild AD) were recruited in 6 European countries, and a different and potentially more sensitive tool to assess cognitive function (memory function domain Z-score of the Neuropsychological Test Battery [NTB]) was used as the primary outcome. This study also included biomarkers of synaptic activity and connectivity (Electroencephalography [EEG]) to gain an understanding of the potential mechanism of action of Souvenaid. The nutritional treatment (24 weeks) was longer than in the Souvenir I study. Subjects were randomized to one of two treatment groups: Souvenaid (n = 130) or an iso-caloric control product (n = 129), once daily.
Souvenaid contains nutritional precursors and co-factors for phospholipid synthesis aiming to improve neuronal phospholipid metabolism at synapses and so cognitive function. This randomised controlled trial (RCT) explored whether Souvenaid affects brain phospholipid metabolism in 34 patients with mild AD. Patients were randomized to active (Souvenaid n=16) or control (isocaloric placebo n=17) product for 4 weeks and advised to minimize intake of high-choline foods and maintain stable intakes of nutritional supplements and (where possible) medication.
Magnetic resonance spectroscopy (MRS) was performed to assess markers of phospholipid synthesis (phosphomonoesters (PME) and breakdown phosphodiesters (PDE)); neural integrity (N-acetyl aspartate); gliosis (myo-inositol); and choline metabolism (choline-containing compounds). The primary outcome parameters were phospholipid synthesis (PME) and breakdown (PDE) levels and the PME/PDE ratio. In addition, blood samples were taken to assess plasma levels of some of the key nutritional precursors and co- factors in the active product.
Thirty-three patients (aged 60-86 years) completed the study, and it was reported that PME/PDE ratio and choline-containing compounds levels were significantly higher in the Souvenaid than the control group at the end of the intervention. Plasma levels of uridine, choline, and vitamin E, as well as percentages of DHA, EPA, and total long-chain polyunsaturated fatty acids were higher in the active than the control group. The active product was found to be safe and generally well tolerated.
This was the first study in patients with mild AD to show that daily intake of the blend of nutrients in the Souvenaid improved neuronal phospholipid synthesis/formation compared to breakdown. These findings support the proposed mode of action of the nutritional precursors and co-factors in Souvenaid on synapse formation and cognitive function. The authors propose that continuous, prolonged intake of the Souvenaid is required to support long term synapse formation and potentially cognitive function.
Early studies8,4 demonstrated a beneficial effect of Souvenaid on memory performance in patients with mild AD who were not taking any AD medication. The S-connect study5 followed those 2 studies but in a slightly different population: individuals with mild – moderate AD who were also taking medication to manage their AD (cholinesterase inhibitors and/or memantine). In this study, 527 patients from European centres were randomized to Souvenaid (n = 265) or an iso-caloric control product (n = 262), taken once daily over the course of the 24-week trial.
The primary outcome measure was the effect on cognition as measured by the 11-item Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), which assesses memory, language, praxis, attention, and other cognitive abilities. The secondary outcomes assessed the effect on cognition, functional abilities, global clinical impression, safety, and nutritional blood parameters of Souvenaid as compared with the control product.
Age-related cognitive decline (ARCD) are the cognitive changes that can occur in individuals because of aging. This may progress to MCI when an older adult has more learning or memory problems than other adults of the same age. Some adults with MCI may go on to develop AD or other dementias What Is Mild Cognitive Impairment? | National Institute on Aging (nih.gov).
The structure (morphology) of the spines of neuronal dendrites and their ability to change shape (plasticity) is involved in learning and memory. It is thought that altered dendritic spine morphology and loss of synaptic plasticity, as well as loss of entire synapses, can lead to cognitive changes seen in ARCD and MCI.
This pilot study being undertaken at the University of Miami, Florida (USA) aims to examine the feasibility of recruiting people with Subjective Cognitive Decline and the impact of nutritional intervention with Souvenaid on memory, cognition and quality of life in the early stages of cognitive changes in healthy older adults.
This study is ongoing with results due in 2024..
The AWARE observational study10 evaluated the impact of Souvenaid on daily living in individuals with mild AD. This study was an open-label, prospective, observational, 12-month study that recruited 116 patients with mild AD who were already taking Souvenaid before their recruitment to the study. The primary outcome was 6-month change from baseline in activities of daily living measured by the validated Amsterdam instrumental activities of daily living (A-IADL) questionnaire. Some of the subjects also provided valid A-IADL scores at 12 months.
A historical dataset of individuals attending memory clinics in the Netherlands who had been diagnosed with mild AD was used for comparison (reference population)7.
The subjects in this study had less decline in A-IADL scores over 6 and 12 months than a broadly similar reference population who were not taking Souvenaid. These findings suggest that Souvenaid may slow clinical deterioration in individuals with mild AD. There was a high rate of self-reported adherence with study product (96%). Souvenaid was well accepted and tolerated.
Caregivers input and judgement on patient’s symptoms and the effectiveness of pharmacological interventions play a key role in the clinical management of patients with MCI and dementia. Observational studies report that dietary patterns influence the risk of developing MCI and AD12. Randomized clinical trials have shown that the multi-nutrient intervention, Souvenaid, positively impacts on cognition and memory in MCI and mild AD3,4.
To determine patient and caregiver judgements about changes in cognitive, behavioural, and functional areas after intervention with Souvenaid, the MEMENTO study was undertaken in 500 patients attending Alzheimer’s Evaluation Units in 30 Italian centres. This observational study recorded responses to standardised questions on cognitive (e.g., memory of appointments/dates, orientation in new places), behavioural (e.g., apathy/loss of interest, sleep disturbances), and functional (e.g., household activities, reading) areas of ‘real life’.
Patients took Souvenaid for an average of 4 months and depending on the cognitive/functional or behavioural domain area being assessed, 28.6-49.6% of caregivers provided a positive judgement on the product’s effectiveness particularly for ‘memory of appointments, apathy and domestic activities’. Depending on the domain area, 36.2-46.2% of patients provided a positive judgement of supplement use particularly for ‘memory and mood’. Overall, caregivers of patients with MCI and higher Mini Mental State Examination (MMSE) scores reported statistically significant positive judgements of effectiveness compared to caregivers of AD patients in several areas questioned (see table 3 in publication). Furthermore, patients with higher duration of use of the supplement reported a higher benefit for its use.
This study confirms the findings of randomized clinical trials on use of Souvenaid but by caregivers and patients in ‘real life’ behavioural and functional areas as well as cognition. It also supports the idea that use of the supplement should be early in the disease progression, and it should be taken for a prolonged period of time.
A suboptimal diet is associated with worsening cognition and a poorer nutritional status may increase an individual’s risk of cognitive decline. Based on a Finnish intervention trial13, WW-FINGERS is a worldwide research network that aims to share outcomes and experience of lifestyle intervention trials for dementia prevention and risk reduction. Studies carried out by the network aim to target multimodal lifestyle interventions (e.g., diet, cognitive training, physical exercise, vascular and metabolic monitoring, and social activity) to prevent cognitive impairment and disability.
There are many studies underway around the world studying the effects of lifestyle interventions, 2 of which (FINGER-NL and MIND-AD) use Souvenaid as part of the dietary modification for the active group.
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