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Alzheimer’s Disease (AD) is the leading cause of dementia. Epidemiological studies suggest that AD is linked with poor status of nutrients including DHA, B-vitamins and the vitamins E and C. Ongoing neurodegeneration, particularly synaptic loss, leads to the classical clinical features of AD namely, memory impairment, language deterioration, and executive and visuospatial dysfunction. The main constituents of neural and synaptic membranes are phospholipids. Supplemenation of animals with three dietary precursors of phospholipids namely, DHA, uridine monophosphate and choline, results in increased levels of brain phospholipids, synaptic proteins, neurite outgrowth, dendritic spines formation (i.e. the anatomical precursors of new synapses) and an improvement in learning and memory. Other nutrients act as co-factors in the synthesis pathway of neuronal membranes. For example B-vitamins are involved in methylation processes, thereby enhancing the availability of choline as a synaptic membrane precursor. A multi-nutrient concept that includes these nutrients may improve membrane integrity, thereby influencing membrane-dependent processes such as receptor function and amyloid precursor protein (APP) processing, as shown by reduced amyloid production and amyloid β plaque burden, as well as toxicity. Together, these insights provided the basis for the development of a medical food for patients with AD, Souvenaid®, containing a specific combination of nutrients (Fortasyn™ Connect) and designed to enhance synapse formation in AD. The effect of Souvenaid on memory and cognitive performance was recently assessed in a proof-of-concept study, SOUVENIR I, with 212 drug-naïve mild AD patients (MMSE 20-26). This proof-of-concept study demonstrated that oral nutritional supplementation with Souvenaid® for 12 weeks improves memory in patients with mild AD. To confirm and extend these findings, we have designed and initiated three additional studies. Two of these studies will be completed in 2011; Souvenir II, a 24-week European study, with 259 drug-naïve mild AD patients (MMSE≥20) and S-Connect, another 24-week study, with 527 mild-tomoderate AD patients (MMSE 14-24) using AD medication conducted in the US. The third is the EU-funded LipiDiDiet study, a 24-month study, which will enrol 300 people with prodromal AD to assess the effect on memory performance.

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. [ABSTRACT FROM AUTHOR]

Diet is an important lifestyle factor implicated in the etiology of Alzheimer's disease (AD), but so far it is not fully elucidated to which nutrients the suggested protective effect of diet can be attributed. Recent evidence obtained in the amyloid-β 1-42 (Aβ42) infusion model in rats has shown that a multi-nutrient intervention known as Fortasyn™ Connect (FC) may protect the central cholinergic system against Aβ42-induced toxicity. FC comprises the nutritional precursors and cofactors for membrane synthesis, viz. docosahexaenoic acid (DHA), eicosapentaenoic acid, uridine-mono-phosphate (UMP), choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium. In order to investigate whether the combined administration of these nutrients may also affect AD-like pathology, we now evaluated the effects of the FC diet intervention in the transgenic AβPPswe/PS1dE9 mouse model with endogenous Aβ production. In addition we evaluated the effects of diets containing the individual nutrients DHA and UMP and their combination in this model. Between the age of 3 and 6 months, FC diet decreased brain Aβ levels and amyloid plaque burden in the hippocampus of AβPP/PS1 mice. The FC diet also reduced ongoing disintegrative degeneration in the neocortex, as indicated by Amino Cupric Silver staining. Although all three DHA-containing diets were equally effective in changing brain fatty acid profiles, diets differentially affected amyloid-related measures, indicating that effects of DHA may depend on its dietary context. The current data, showing that dietary enrichment with FC reduces AD-like pathology in AβPP/PS1 mice, confirm and extend our previous findings in the Aβ42 infusion model and favor the combined administration of relevant nutrients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Substantial evidence suggests a role for nutrition in the management of AD and especially suggests that interventions with combinations of nutrients are more effective than single-nutrient interventions. The specific multi-nutrient combination Fortasyn™Connect (FC), shown to improve memory in AD, provides phosphatide precursors and cofactors and is designed to stimulate the formation of phospholipids, neuronal membranes, and synapses. The composition comprises nucleotides, omega-3 polyunsaturated fatty acids (n3 PUFA), choline, B-vitamins, phospholipids, and antioxidants. The current study explored the protective properties of FC in a membrane toxicity model of AD, the amyloid-β 1-42 (Aβ42) infused rat, which shows reduced exploratory behavior in an Open Field and impaired cholinergic functioning. To this end, rats were fed an FC enriched diet or a control diet and five weeks later infused with vehicle or Aβ42 into the lateral ventricle. Ten weeks post-infusion Aβ42-rats fed the FC diet showed increased membrane n3 PUFA and phosphatidylcholine content while they did not show the reductions in exploratory behavior or in choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) immunoreactivity that were seen in Aβ42-rats fed the control diet. We conclude that FC protects the cholinergic system against Aβ42-induced toxicity and speculate that the effects of FC on membrane formation and composition might be supportive for this protective effect. Based on these data a long-term intervention study was started in the prodromal stages of AD (NTR1705, LipiDiDiet, EU FP7). [ABSTRACT FROM AUTHOR]

The effect of supplementation with the omega 3 polyunsaturated fatty acid (n-3 PUFA) docosahexaenoic acid (DHA) on membrane composition and amyloid-β1-42 (Aβ42) secretion was studied in human amyloid-β protein precursor-transfected Chinese Hamster Ovary (CHO) cells. Twenty-four hour incubation with a range of DHA concentrations resulted in a dose-dependent increase in membrane DHA and eicosapentaenoic acid content and a decrease in arachidonic acid content. In addition, DHA supplementation caused a dose-dependent reduction in the secreted Aβ42 levels and resulted in a 4-8 fold decrease in extracellular prostaglandin E2 (PGE2) levels. Tocopherol, which was added to DHA to prevent oxidation, may have contributed to the effect of DHA, since it slightly decreased extracellular Aβ42 and PGE2 levels when given alone. The addition of selective COX-2 inhibitors Celebrex and curcumin to the culture medium resulted in a significant and comparable inhibition of PGE2 release, but did not inhibit Aβ42 secretion, and even significantly increased Aβ42 production in this cell system. Together, the present data show that, whereas both DHA and COX-2 inhibitors may reduce PGE2 production, only DHA in the presence of tocopherol significantly reduced Aβ42 production and concurrently changed membrane lipid composition in CHO cells. It is concluded that in this in vitro setting DHA reduced Aβ42 secretion through membrane-related, but not PGE2-related mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer''s disease (AD) is a multi-factorial neurodegenerative disorder and the leading cause of dementia, wherein synapse loss is the strongest structural correlate with cognitive impairment. Basic research has shown that dietary supply of precursors and co-factors for synthesis of neuronal membranes enhances the formation of synapses. Daily intake of a medical food containing a mix of these nutrients for 12weeks in humans improved memory, measured as immediate and delayed verbal recall by the Wechsler Memory Scale-revised, in patients with very mild AD (MMSE 24–26). An improvement of immediate verbal recall was noted following 24weeks of intervention in an exploratory extension of the study. These data suggest that the intervention may improve synaptic formation and function in early AD. Here we review emerging technologies that help identify changes in pathological hallmarks in AD, including synaptic function and loss of connectivity in the early stages of AD, before cognitive and behavioural symptoms are observable. These techniques include the detection of specific biomarkers in the cerebrospinal fluid, as well as imaging procedures such as fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid PET, structural/functional magnetic resonance imaging, diffusion tensor imaging, magnetoencephalography (MEG) and electroencephalography (EEG). Such techniques can provide new insights into the functional and structural changes in the brain over time, and may therefore help to develop more effective AD therapies. In particular, nutritional intervention studies that target synapse formation and function may benefit from these techniques, especially FDG-PET and EEG/MEG employed in the preclinical or early stages of the disease. [Copyright &y& Elsevier]

• Diet is a promising approach for the prevention of age-related neurodegeneration. • Focus has shifted from individual nutrients to whole diets for improving brain health. • Shift in microbiome diversity may affect brain ageing. • Dietary manipulation of the gut microbiota may improve brain functions in ageing. • Brain imaging, modelling and new biomarkers are improving diet and ageing research. The global increases in life expectancy and population have resulted in a growing ageing population and with it a growing number of people living with age-related neurodegenerative conditions and dementia, shifting focus towards methods of prevention, with lifestyle approaches such as nutrition representing a promising avenue for further development. This overview summarises the main themes discussed during the 3rd Symposium on "Nutrition for the Ageing Brain: Moving Towards Clinical Applications" held in Madrid in August 2018, enlarged with the current state of knowledge on how nutrition influences healthy ageing and gives recommendations regarding how the critical field of nutrition and neurodegeneration research should move forward into the future. Specific nutrients are discussed as well as the impact of multi-nutrient and whole diet approaches, showing particular promise to combatting the growing burden of age-related cognitive decline. The emergence of new avenues for exploring the role of diet in healthy ageing, such as the impact of the gut microbiome and development of new techniques (imaging measures of brain metabolism, metabolomics, biomarkers) are enabling researchers to approach finding answers to these questions. But the translation of these findings into clinical and public health contexts remains an obstacle due to significant shortcomings in nutrition research or pressure on the scientific community to communicate recommendations to the general public in a convincing and accessible way. Some promising programs exist but further investigation to improve our understanding of the mechanisms by which nutrition can improve brain health across the human lifespan is still required. [ABSTRACT FROM AUTHOR]