Early Alzheimer’s Disease - Elderly woman laughing

Early Alzheimer’s Disease

Alzheimer’s disease is a complex condition that can affect people in different ways. The earliest symptom of Alzheimer’s disease is usually short term memory loss. Later symptoms can typically include difficulty with planning and problem solving, and sometimes problems with low mood.1

The connections in the brain, called synapses, are continuously re-formed throughout life. This means that existing synapses are replaced every 3-6 months with new ones. In a healthy brain the amount of new synapses that are formed matches the amount that are lost.

In early Alzheimer’s disease however, the loss of synapses becomes accelerated. It is not yet understood why this is the case, however research suggests that synaptic loss occurs very early in the disease progression. The loss of synapses is one of the key features of early Alzheimer’s disease2.

 

64,000 people in Ireland are living with dementia. Every year 11,000 people are diagnosed3

People living with early Alzheimer’s disease have been shown to have relatively low levels of certain nutrients in their bodies, despite eating a normal diet4-11. These nutrients are important for making new synapses. Omega 3 fatty acids, uridine monophosphate and choline, together with several key vitamins, all work together to help this process. 

Research suggests that taking a carefully formulated nutritional supplement for special medical purposes may be beneficial where the levels of vitamins, omega-3-fatty acids, and the other nutrients (including uridine monophosphate and choline) are above those that can be achieved in a normal diet12-14.

Finding the missing nutrients

There is a strong consensus internationally that there is an urgent need to address the burden of cognitive decline in our aging population1. The safety and efficacy of Souvenaid has been assessed across 20+ years of clinical research, including high quality international clinical trials of > 2000 participants at different 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))12-20.

Disclaimer

Souvenaid is a food for special medical purposes for the dietary management of early Alzheimer’s disease, including Mild Cognitive Impairment (MCI), and must be used under medical supervision.

Key messages on clinical research

Results from clinical trials on Souvenaid builds on the findings from pre-clinical studies21 that demonstrated an effect of administering the specific nutrients in Souvenaid (Fortasyn Connect) on synapse function and formation. Figure 1 provides an overview of the key proof of concept, intervention and observational studies undertaken or ongoing.

The main findings of this research are:

Most of the 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 AD6.  Rijpma et al, 201716 reported evidence from brain scans which showed that Souvenaid improved formation of neuronal phospholipid, supporting the suggested 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 delay decline in cognitive abilities and positively impact memory12,14 in MCI and mild AD, respectively. A similar effect on cognition was not observed in moderate AD17, however Souvenaid was well tolerated in combination with AD medication. 

  • All studies12-19 have found excellent compliance and acceptance of Souvenaid and confirmed that it is safe and well tolerated. ‘Real-life’ observational studies18,22 also reported positive benefits (slower decline) on use of Souvenaid on behavioural, daily living activities/function and on memory.

  • Many of the researchers and expert guidance16,18,23 conclude that use of Souvenaid is more beneficial when started early in the disease process and that its continuous long-term use is required for ongoing synapse formation to potentially impact on cognitive ability2

  • International studies to determine the impact of multimodal lifestyle interventions including the use of Souvenaid (FINGER-NL and MIND-AD24) on cognitive decline and memory are ongoing. 

Patient focused, cognitive decline outcome measures e.g., memory tests, function brain scans, compliance and safety

At-risk elderly
Subjective Cognitive Decline
Mild Cognitive Impairment
Mild Alzheimer's Disease
Moderate Alzheimer's Disease
FINGER‍-‍NL
REACTION
LipiDiDiet
MIND‍-‍AD
MEMENTO
Souvenir II
S‍-‍Connect
AWARE
Souvenir I
MRS
AWARE
Souvenir I
MRS
Observational studies
FINGER-like randomized controlled trials
Randomized controlled trials
Trial and type Population # of Subjects / Duration Key outcomes investigated Links to key publications
LipiDiDiet (RCT) Prodromal AD (Mild Cognitive Impairment stage) N=311 / 6 years Cognition, function, memory, brain volumes Soininen et al. 2021 Alzheimer’s and Dementia Soininen et al. 2017 Lancet Neurology
Souvenir I (RCT) Mild AD N=225 / 3 months Memory, cognition Scheltens et al. 2010 Alzheimer’s and Dementia
Souvenir II (RCT) Mild AD N=259 / 6 months Memory Scheltens et al. 2012 Journal of Alzheimer’s Disease
MRS (RCT) Mild AD N=33 / 1 month Phospholipid metabolism Rijpma et al. 2017 Alzheimer’s Research and Therapy
S-Connect (RCT) Mild & Moderate AD N=527 / 6 months Cognition Shah et al. 2013 Alzheimer’s Research and Therapy
REACTION (RCT) Subjective Cognitive Decline N=60 / 6 months Feasibility, memory, cognition Coming soon
AWARE (RWE) Mild AD N=73 / 6-12 months Activities of daily life Coming soon
MEMENTO (RWE) MCI and Mild AD N=500 / 3-6 months Cognition, bahavior, function Bianchetti et al. 2018 Journal of Gerontology and Geriatrics
MIND-AD (FINGER) MCI due to AD N=103 / 6 months Feasibility Thunborg et al. 2024 Alzheimer’s Research and Therapy
FINGER-NL (FINGER) At-risk elderly N=1200* / 2 years Cognition, function, memory Study ongoing

LipiDiDiet multinutrient clinical trial in Mild Cognitive Impairment - figure 1 graph

The LipiDiDiet12,15 study is a randomised 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. 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-months15 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. 

Results from 36 months of the intervention were published in 2021 showing significant positive benefits on cognition, function, and rates of brain atrophy in the active group (Souvenaid) specifically12

  • Significant reductions in decline on the primary outcome of NTB measuring cognition (60% reduction in decline) as illustrated in figure 1. 

  • Statistically significant differences between groups in favour of the active group were observed for the CDR-SB (45% less worsening;), memory (76% less worsening;). Such a sustained benefit over 3 years has not been reported before in early AD. The CDR-SB benefits occurred in conjunction with several NTB items supporting the positive impact of the active intervention on cognition and function. 

  • The rates of deterioration for hippocampal, whole brain and ventricular volume (brain atrophy) were significantly less in the active than the control group, showing potential effect on disease pathology. The effect on hippocampal atrophy may be the basis for the memory benefit reported for the active group. The decline rates in hippocampal atrophy in the control group were typical of those for MCI/mild AD reported. 

  • A small to medium Cohen’s d effect size (0.25–0.31) similar to that of established clinically relevant AD treatment was found. 

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. 

Early Alzheimer’s Disease

This RCT13, 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 randomised 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.

This study demonstrated that:

  • Patients with mild AD who consumed Souvenaid experienced a significant improvement in WMS-r–delayed verbal recall score (one of the co-primary outcomes measures in this study) at 12 weeks compared to controls.

  • There was no difference between the groups for the other co-primary outcome measure (ADAS-cog), which was unchanged in both groups at 12 weeks.

  • Although no significant between group differences in either of the co-primary outcome measures (WMS-r and ADAS-cog) were observed at 24 weeks, a post hoc analysis revealed a significant improvement in WMS-r immediate verbal recall score in the Souvenaid group compared to controls at 24 weeks.

  • Compliance was excellent (95%) and the product was well tolerated. 

The Souvenir I study provided proof-of-concept support for the hypothesis that combinations of defined nutrients have the potential to fulfil 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)14, this RCT aimed to confirm and extend the findings from the Souvenir I study13. 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 randomised to one of two treatment groups: Souvenaid (n = 130) or an iso-caloric control product (n = 129), once daily.

This study demonstrated that:

  • Souvenaid has a beneficial effect on cognitive function in mild AD, as evidenced by the NTB memory domain Z-score which was significantly increased in the Souvenaid versus the control group over the 24-week intervention period. The results from this follow-up study confirm the earlier finding that Souvenaid improved memory performance in individuals with mild AD.

  • EEG measures of functional connectivity were significantly different in trajectory over 24 weeks between study groups in favour of the Souvenaid group. These findings suggest that Souvenaid has an effect on brain functional connectivity, supporting the hypothesis that the intervention enhances synapse formation and function.

  • Compliance was very high (96.6% [control] and 97.1% [Souvenaid]).

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 randomised 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). Primary outcome parameters were phospholipid synthesis (PME) and breakdown (PDE) levels and the PME/PDE ratio. 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. Souvenaid was found to be safe and 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 suggested that continuous, prolonged intake of the Souvenaid is required to support long term synapse formation and potentially cognitive function.

Early studies13,14 demonstrated a beneficial effect of Souvenaid on memory performance in patients with mild AD who were not taking any AD medication. The S-connect study17  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 randomised to Souvenaid (n = 265) or an iso-caloric control product (n = 262), taken once daily for the duration 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. 

This study demonstrated that:

  • Souvenaid did not slow cognitive decline in individuals treated for mild – moderate AD. Both the treatment and control groups showed a moderate increase of ADAS-cog scores, with no significant difference between study groups. These findings suggest that there was cognitive deterioration over the 24-week study period, which is consistent with expectations for patients with mild – moderate AD.

  • Souvenaid may be more beneficial for patients if started at an earlier stage of the disease process, when the neurodegenerative damage is still limited and thus there are greater possibilities to delay cognitive decline with a nutritional intervention.

  • Compliance was high (94.1% [Souvenaid] and 94.5% [control]). Souvenaid resulted in the predicted change in peripheral nutritional blood biomarkers and was well tolerated in combination with standard care AD medication.

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 dementias25.  

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 MCI2,26.

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. 

Elderly women laughing

The AWARE observational study22 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 reference population was selected from a historical dataset of individuals attending memory clinics in the Netherlands who had been diagnosed with mild AD27.

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.

Souvenaid Belgium, Early Alzheimer Disease, AMN

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 AD28. Randomised clinical trials have shown that Souvenaid, a multi-nutrient intervention, positively impacts on cognition and memory in MCI and mild AD12,14.

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 vattending 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 randomised 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.

Healthy food

Suboptimal dietary intakes are associated with worsening cognition, and nutritional deficits may increase an individual’s risk of cognitive decline. Based on a Finnish intervention trial29, WW-FINGERS is a worldwide research network that aims to share results 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. 

    1. FINGER-NL is a 2-year randomised controlled multi-domain lifestyle intervention study which includes Souvenaid, aiming to investigate the effects of a FINGER-like intervention battery in 1206 older Dutch adults at risk of cognitive decline. This study will investigate whether these lifestyle changes have an impact on cognitive outcomes, such as memory. The study is ongoing. 

    2. MIND-AD (Mini) tested a multimodal lifestyle intervention alone or combined with Souvenaid in people with MCI in 4 EU countries24. 93 participants with MCI were recruited and randomly allocated to one of the following groups 1) Multimodal lifestyle intervention 2) Multimodal lifestyle intervention + Souvenaid 3) Regular health advice. 

This study determined that a multidomain lifestyle intervention, alone or combined with medical food, had good feasibility and adherence in prodromal AD. Adherence to the lifestyle intervention plus medical food was 87.5% and adherence to lifestyle alone was 78.1%30

The Lifestyle + medical food group showed a decrease in vascular risk burden (p = 0.043) and less cognitive-functional decline (p<0.05, exploratory analysis) compared with control. This was not seen in the lifestyle only group30.

 
  1. World Health Organisation. Dementia Fact Sheet. [Online]. March 2023. Available from: http://www.who.int/mediacentre/factsheets/fs362/en/ [Accessed April 2024]
  2. Scheff SW et al. Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 2006 Oct;27(10):1372-84 
  3. The Alzheimer Society of Ireland. Dementia in the Media [Online]. 2024. Available at: https://alzheimer.ie/creating-change/awareness-raising/dementia-in-the-media/ [Accessed August 2024].
  4. de Wilde MC et al. Lower brain and blood nutrient status in Alzheimer's disease: Results from meta-analyses. Alzheimers Dement (N Y) 2017;3(3):416-431. 
  5. van Wijk N et al. Nutrients required for phospholipid synthesis are lower in blood and cerebrospinal fluid in mild cognitive impairment and Alzheimer's disease dementia. Alzheimers Dement (Amst) 2017;8:139-146.
  6. Lopes da Silva S et al. Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis. Alzheimers Dement 2014;10(4):485-502. 
  7. Hosseini, M et al. Blood fatty acids in Alzheimer's disease and mild cognitive impairment: A meta-analysis and systematic review. Ageing Res Rev 2020;60:101043.
  8. Judd J.M et al. Inflammation and the pathological progression of Alzheimer's disease are associated with low circulating choline levels. Acta Neuropathol 2023; Oct;146(4):565-583. 
  9. Mangialasche F et al. Tocopherols and tocotrienols plasma levels are associated with cognitive impairment. Neurobiol Aging 2012;33(10):2282-90.
  10. Socha K et al. Dietary Habits, Selenium, Copper, Zinc and Total Antioxidant Status in Serum in Relation to Cognitive Functions of Patients with Alzheimer's Disease. Nutrients 2021;13(2):287 
  11. Yu J et al. Associations Between Mild Cognitive Impairment and Whole Blood Zinc and Selenium in the Elderly Cohort. Biol Trace Elem Res 2023;201(1):51-64.
  12. Soininen H et al. 36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease. Alzheimers Dement 2021;17(1):29-40. 
  13. Scheltens P et al. Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial. Alzheimers Dement 2010;6(1):1-10.e1.
  14. Scheltens P et al. Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial. J Alzheimers Dis 2012;31(1):225-36. 
  15. Soininen H 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(12):965-975.
  16. Rijpma A et al. The medical food Souvenaid affects brain phospholipid metabolism in mild Alzheimer's disease: results from a randomized controlled trial. Alzheimers Res Ther 2017;9(1):51. 
  17. Shah RC 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(6):59.
  18. Bianchetti A et al. Effectiveness of a specific nutritional supplement on cognitive, behavioral and functional symptoms in mild cognitive impairment and Alzheimer's dementia: caregivers judgments. Results of an observational survey. Journal of Gerontology and Geriatrics 2018;66:68-74. 
  19. Hartmann T et al. 8-year safety and compliance to a multinutrient intervention in mild cognitive impairment/prodromal Alzheimer’s disease: Data from the placebo-controlled LipiDiDiet trial. Alzheimer's & Dementia 2023;19(S8):e064068
  20. Olde Rikkert MG et al. Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study. J Alzheimers Dis 2015;44(2):471-80. 
  21. References available on file. 2002 – 2022. 
  22. Ziere G et al. A prospective observational study in real-world daily clinical practice to evaluate the use of the medical food Souvenaid on instrumental activities of daily living in people with mild Alzheimer’s disease. Unpublished. 
  23. Cummings J et al. Souvenaid in the management of mild cognitive impairment: an expert consensus opinion. Alzheimers Res Ther 2019;11(1):73.
  24. Sindi S et al. Multimodal Preventive Trial for Alzheimer's Disease: MIND-ADmini Pilot Trial Study Design and Progress. J Prev Alzheimers Dis 2022;9(1):30-39. 
  25. NIH National Institute on Aging. What is Mild Cognitive Impariment. [Online]. April 2021. Available from: What Is Mild Cognitive Impairment? | National Institute on Aging (nih.gov) [Accessed April 2024].
  26. Dorostkar M et al. Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities. Acta Neuropathol 2015;130(1):1–19. 
  27. Koster N et al. The sensitivity to change over time of the Amsterdam IADL Questionnaire(©). Alzheimers Dement 2015;11(10):1231-40.
  28. Gu Y et al. Food combination and Alzheimer disease risk: a protective diet. Arch Neurol 2010;67(6):699-706. 
  29. Ngandu T et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 2015;385(9984):2255-63.
  30. Thunborg et al. Integrating a multimodal lifestyle intervention with medical food in prodromal Alzheimer’s disease: the MIND-ADmini randomized controlled trial. Alzheimers res ther 2024;16:118.

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