As people around the world are living longer, the number of individuals with dementia, particularly Alzheimer's disease (AD), is expected to triple by 2050. There's growing evidence suggesting that our gut health might play a role in the prevention of dementia. The connection between our gut and brain, known as the gut-brain axis, is becoming an important area of study. Research in animals has shown that different types of dietary fibre can improve gut health, brain function, mood, blood sugar level and the immune system and may even prevent certain harmful brain changes seen in Alzheimer's disease. Subjective Cognitive Decline (SCD) is a condition where individuals notice a decline in their mental abilities, and it can be an early sign of Alzheimer's disease.

The goal of this clinical trial is to learn if dietary fibres can improve gut and brain health in older individuals, between the ages of 60 and 79 years, who notice problems in their mental abilities, and meet the criteria of SCD. Three different dietary fibres will be given, and researchers will compare three different fibres to a placebo product to see if there is a difference between the fibres and the placebo.

The main questions it aims to answer are:

1. Does dietary fibre improve working memory?
2. Does dietary fibre improve other markers of brain function?
3. Does dietary fibre improve gut health?
4. Does dietary fibre improve the immune system and blood glucose levels?
5. Does dietary fibre improve mood?

Participants will:

• Consume dietary fibres twice a day, mixed in water, tea or coffee, for a period of 26 weeks
• Have two functional MRI scans, and three additional study visits, where blood, urine and feces will be collected
• Undergo a number of neuropsychological tests, aimed at evaluating brain function
• Fill out questionnaires on their general health, mood, dietary habits, gut health
• Wear smartwatches for one week, at the beginning and the end of the study

Rationale: Due to the greying of society, a triplication of the number of people with dementia worldwide, with Alzheimer's disease (AD) as the commonest form, is expected by 2050. Compelling evidence points towards a crucial role of intestinal health as one potential etiological modifier of dementia, with the (microbiota) gut-brain axis (MGBA) receiving increasing attention. A number of preclinical studies have demonstrated benefit of various sources of dietary fibre for their capacity to improve gut health, cognitive functioning, general mood, glycaemia, immunogenicity, and, to inhibit tau phosphorylation, the latter which is a hallmark in AD brain. Subjective cognitive decline (SCD) lies on the continuum of AD, and subjects with this condition are at increased risk of further conversion to mild cognitive impairment (MCI) or AD. Currently, no cure is available for AD. Various symptomatic and a few disease-modifying treatments are available, but these treatments only have very limited or mild clinical effects and are often accompanied by severe side effects. Clinical follow-up studies to evaluate the effect of dietary fibre in older adults with suspected cognitive decline are required, but are still lacking to date.

Objective: The primary objective of this study is to investigate the effect of 26 weeks of supplementation with three different dietary fibres (chicory inulin, resistant dextrin, and seaweed polysaccharide) compared to a placebo (maltodextrin) on microbiota gut-brain health effects in older adults (aged 60-79) with Subjective Cognitive Decline Plus (SCD+) by assessing changes in brain function and working memory by blood oxygen level dependant (BOLD) signal activity and task accuracy during n-back task functional magnetic resonance imaging (fMRI) assessment.

The secondary objectives are to investigate the effects of 26 weeks of supplementation with dietary fibre (chicory inulin, resistant dextrin, and, seaweed polysaccharide) compared to placebo (maltodextrin) in older adults on the following parameters related to potential gut-brain pathways:

1. neuropsychological test battery scoring,
2. other relevant brain health parameters,
3. relevant intestinal health parameters, and
4. immune and metabolic parameters.

Study population: 164 older adults (60-79 years) with SCD+.

Study design implementation:

Participants will undergo assessments at baseline (T0), mid-study (T1/2, after 13 weeks) and at study end (T1, after 26 weeks. Each participant will have five study visits in total: two at T0, one at T1/2 and two at T1.

At each of the timepoints the following will be collected/performed at WUR: Sample collection (blood, urine (omitted in week 13), faeces); general cognitive assessments (see NTB; Cognitive Failure Questionnaire (CFQ) (baseline and end only), GDS-15, GAD-7); general physiological measures (blood pressure, BMI, grip-strength); dietary assessment (MIND-adjusted Eetscore, FFQ). At ZGV working memory will be evaluated using BOLD fMRI signalling and task accuracy using an n-back task paradigm. Additionally, high-resolution T1- and T2-weighted anatomical images of main regions of interest (hippocampi, (pre)frontal-, and temporal cortices) will be acquired.

For two periods of one week, corresponding with the baseline and week 26 visits, participants will wear smartwatches. These watches will be worn continuously and data will be gathered regarding cardiovascular functioning (heart rate), physical activity and mood (push messages).

Inclusion Criteria:

1. Written informed consent
2. Fluency in Dutch (speaking, reading, writing)
3. Age between 60-79 years (at screening)
4. Subjective cognitive decline plus (SCD+), (criteria of Jessen et al.):

4.1 Self-reported worsening of memory; 4.2 Indication of repetitive concerns (worries) associated with SCD; 4.3 With at least one of the following two features present: (i) onset of SCD within the last 5 years; (ii) age at onset ≥60 years of age;

5. Presence of at least 2 self-reported risk factors for cognitive decline (based on LIBRA criteria): (i) Diabetes mellitus type II (ii) High cholesterol (iii) Hypertension (iv) High BMI (v) Heart disease (vi) Unhealthy diet (lower regular adherence to Mediterranean diet components such as fish, vegetables, olive oil, pasta and red wine)

Exclusion Criteria:

1. Current participation in other intervention trials

2. Technologically illiterate (complete incompetence in working with computers, apps, online questionnaires, smartwatches etc.)

3. No internet access from home

4. Clinical diagnosis of ≥1 of the following:

   • Neurological pathology (e.g. MCI, dementia, multiple sclerosis, Parkinson's disease, epilepsy);
   • Current malignant disease(s), with or without treatment;
   • Current psychiatric disorder(s) (e.g. major depressive disorder, bipolar disorder, schizophrenia, anxiety, psychosis, PTSD);
   • Symptomatic/decompensated cardiovascular disease (e.g. stroke, angina pectoris, heart failure, recent myocardial infarction);
   • Severe visual impairment or blindness
   • Hearing or communicative impairment.
   • Gastrointestinal tract disorder such as irritable bowel syndrome or inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis).

5. Current or recent (<6 weeks) use of prebiotic, probiotic, or dietary fibre supplement that may modulate the microbiota, or unwilling to stop the use of supplements during the study

6. Current or recent (<6 weeks) of algae/phytoplankton supplements such as spirulina or chlorella, or unwilling to stop the use of supplements during the study

7. Use of psychotropic medication (anti-depressants, anti-psychotics)

8. Use of antibiotics in the 3 months before starting the study or planned use during the study

9. Being an employee of the Human Nutrition and Health Division of Wageningen University.

10. Significant cognitive impairment assessed using the Modified Telephone Interview for Cognitive Status battery (TICS-m score <23)

11. Request to have Apo-E genotype result disclosed

12. Allergies to fish or shellfish

13. Having a contra-indication to MRI scanning including:

    • Ferromagnetic implants:

      • Active implantable medical devices such as: insulin pump / medicine pump / neurostimulator; pacemaker / defibrillator;
      • Other passive implants such as: punctured port-a-cath; synthetic heart valve

    • Intra-orbital or intra-ocular metallic fragments

    • Claustrophobia