COGNIFOOD-Changing the Carbohydrate/Fat-ratio to Prevent Cognitive Decline and Alzheimer Pathology: A Pilot Study

NCT ID: NCT06105320

Last Updated: 2023-10-27

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-31
• Study Completion Date: 2026-04-30

Brief Summary

A 2-arm (sequence), 2-period, 2-treatments, single blinded (outcome assessor), randomized crossover-trial (12+12 weeks with immediate contrast) comparing a low-carbohydrate-high-fat diet (LCHF) with a high-carbohydrate-low-fat diet (HCLF) among individuals with prodromal Alzheimer's disease.

Detailed Description

The impact of macronutritional composition on cognitive health is not fully understood. On one hand, the World Health Organization (WHO) guidelines propose a limit of total fat intake at 30% of total energy intake (E%), implying that carbohydrates provide at least 50 E%. On the other hand, some pilot studies on ketogenic diets (strict carbohydrate restriction, ≤10 E%) have shown promising results-while liberal carbohydrate restriction has not been investigated in a clinical trial among individuals with Alzheimer's disease or mild cognitive impairment (MCI). It is unclear how important the metabolic state ketosis is for driving potential effects of ketogenic diets on cognitive health outcomes, and our previous observational analyses suggest that even macronutritional changes in the non-ketogenic range might impact cognitive function-although estimated effects differed between sub-samples. This pilot study evaluates the potential of liberal carbohydrate restriction, alternatively fat restriction, as targets for future large scale trials. Participants must be diagnosed with prodromal Alzheimer's disease, which means MCI in combination with biologically validated Alzheimer-pathology-but absence of dementia.

The aim of this trial is to generate a contrast within participants regarding a diet parameter of special interest: the carbohydrate/fat-ratio (CFr). In a randomized order, participants will be exposed to 12 weeks with a low CFr diet (LCHF) and 12 weeks with a high CFr diet (HCLF). In LCHF, sustained ketosis is not an aim but transient mild ketosis may appear in some participants. The following strategies will be used to enhance adherence:

• A mandatory supportive study partner.
• Delivery of one daily meal.
• Delivery of some key ingredients for self-prepared meals.
• Individualized guidance by a dietitian, with consideration of preferred protein sources and complexity of cooking.

Beyond a dichotomized comparison between the diet phases, the study is expected to generate data for a substantial number of observational panel analyses where individual continuous CFr-levels assessed at 5 timepoints may be used as the predictor variable. Those CFr-data will be assessed in parallel with health outcomes including neurodegenerative biomarkers in blood, metabolic biomarkers, and Continous Glucose Monitoring (CGM). Cognitive performance is measured only at 3 timepoints to minimize learning effects. The sample size is adapted to assess feasibility and trends in health outcomes. Due to the limited statistical power there is a considerable risk for type-II errors; therefore, p-values >0.05 should not be interpreted as absence of a clinically meaningful effect in this pilot. Effect modification will be explored by one pre-specified stratification: 1. Apolipoprotein E (APOE) genotypes epsilon-3/4 and 4/4; 2. All other APOE-genotypes.

A cross-over design with immediate contrast (no "wash-out" period) is applied, since it is not possible to define a wash-out value of CFr or reliably keep all participants on a particular CFr between the diet periods. Period 1 (and 2) may have a carry-over effect from pre-study CFr and period 2 may have a carry-over effect from period 1. Primary comparisons against baseline are at the end of each period (weeks 12 & 24) when carry-over effects are assumed to be relatively low.

Conditions

Prodromal Alzheimer's Disease; Alzheimer Disease; Mild Cognitive Impairment; Neurocognitive Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

1: LCHF-HCLF

LCHF (12 weeks) followed by HCLF (12 weeks) with immediate contrast (no "wash-out" period)

Group Type: ACTIVE_COMPARATOR

LCHF

Intervention Type: OTHER

A diet intervention with the following macronutrient targets:

Carbohydrates: 10-25 E%; Fat 50-70 E%; Protein: 20-25 E%; Alcohol 0-5 E%

HCLF

Intervention Type: OTHER

A diet intervention with the following macronutrient targets:

Carbohydrates: 50-60 E%; Fat 25-30 E%; Protein: 15-20 E%; Alcohol 0-5 E%

2: HCLF-LCHF

HCLF (12 weeks) followed by LCHF (12 weeks) with immediate contrast (no "wash-out" period)

Group Type: ACTIVE_COMPARATOR

LCHF

Intervention Type: OTHER

A diet intervention with the following macronutrient targets:

Carbohydrates: 10-25 E%; Fat 50-70 E%; Protein: 20-25 E%; Alcohol 0-5 E%

HCLF

Intervention Type: OTHER

A diet intervention with the following macronutrient targets:

Carbohydrates: 50-60 E%; Fat 25-30 E%; Protein: 15-20 E%; Alcohol 0-5 E%

Interventions

LCHF

A diet intervention with the following macronutrient targets:

Carbohydrates: 10-25 E%; Fat 50-70 E%; Protein: 20-25 E%; Alcohol 0-5 E%

Intervention Type: OTHER

HCLF

A diet intervention with the following macronutrient targets:

Carbohydrates: 50-60 E%; Fat 25-30 E%; Protein: 15-20 E%; Alcohol 0-5 E%

Intervention Type: OTHER

Other Intervention Names

Non-ketogenic carbohydrate restriction; A fat-restricted diet compatible with official dietary guidelines

Eligibility Criteria

Inclusion Criteria

• Ability to fully understand written and verbal information regarding the study and provide signed and dated informed consent
• Prodromal Alzheimer's disease, as defined by Mild Neurocognitive Disorder due to Alzheimer's disease (AD) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, and evidence for underlying AD pathology by either:

• Cerebrospinal fluid (CSF) β-amyloid 1-42/1-40x10 ratio < 1 and/or total tau and/or phospho-tau and/or β-amyloid 42 based on local cut-offs OR
• Magnetic Resonance Imaging (MRI) evidence for medial temporal lobe atrophy (MTA score 1 or higher [mesiotemporal atrophy]) OR
• Abnormal Fludeoxyglucose F18 (FDG) Positron Imaging Tomography (PET) and/or Pittsburgh Compound-B (PiB) PET compatible with AD type changes.

(When the diagnosis prodromal AD is confirmed from medical record, no cognitive testing or renewed assessment of biological AD-pathology is needed for fulfilling this criterion.)

• Montreal Cognitive Assessment (MoCa) ≥20.
• Availability of a study partner with sufficient contact with the participant, willing and able to give follow-up information on the participant as well as supporting the participant throughout the study.
• Self-reported expected motivation and ability to prepare most weakly meals according to given instructions, with support from the study partner.
• Accept plant-based food, plus food from at least one of the following categories: A. Fish; B. Meat; C. Eggs and dairy
• Ability to reliably undergo a cognitive test in Swedish

Exclusion Criteria

• Major Neurocognitive Disorder (dementia) according to DSM-5
• Body-mass Index (BMI) < 18 or BMI > 35
• Diagnosed Diabetes Mellitus.
• Ongoing treatment with Metformin, Glucagon-Like Peptide 1 (GLP-1)-analog, or Sodium-Glucose Transport Protein 2 (SGLT-2)-inhibitors
• Diagnosed Familial Hypercholesterolemia
• Untreated or unstable Hypertension
• Alcohol or Substance abuse (current or within 2 years)
• A concomitant serious disease (e.g., cancer, or major psychiatric disorder or other neurological disorder than AD) as judged by study physician
• Major depression or Suicidal ideations (current or within 2 years)
• History of Stroke or Myocardial infarction during the last 5 years.
• Subjects with brain MRI (or CT) scan clinically significant infarct, intracranial macro bleeding, mass lesion or Normal Pressure Hydrocephalus. Those subjects with an MRI scan demonstrating minimal white matter changes (Fazekas scale for white matter lesions classification of 2 or below) and up to 2 lacunar infarcts which are judged to be clinically insignificant are allowed.
• Severe loss of vision or communicative ability
• Conditions preventing cooperation as judged by the study physician.
• Participation in any other intervention trial within 30 days (or, if applicable, 5 half-lives of the relevant drug if longer) before baseline and along the study period.
• Any planned changes in cognitive enhancers (e.g., ginkgo, cholinesterase inhibitors), statins, antidepressants, sleeping pills, supplements like medium-chain triglycerides, or any medication expected to influence cognitive function. Such medications are accepted if taken on a stable dose ≥3 months prior to baseline assessment and should, if possible, remain on the same dose during the study. Unplanned changes that take place within the study do not imply exclusion but should be registered in the case report form (CRF).
• Deviations from habitual diet within 1 month before study start. A carbohydrate-restricted or fat-restricted diet, as well as any time-restricted eating, is accepted as habitual diet if stable (and the participant is open to change).

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fingers Brain Health Institute

OTHER

Sponsor Role: collaborator

Karolinska Institutet

OTHER

Sponsor Role: collaborator

af Jochnick Foundation

UNKNOWN

Sponsor Role: collaborator

Karolinska University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Anne Börjesson-Hanson

Head of Clinical Trials

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Anne Börjesson-Hanson, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Karolinska University Hospital

Locations

Karolinska University Hospital

Solna, , Sweden

Site Status: RECRUITING

Countries

Sweden

Central Contacts

Anne Börjesson-Hanson, MD, PhD

Role: CONTACT

anne.borjesson-hanson@regionstockholm.se

+46-8-123 858 68

Jakob Norgren, PhD

Role: CONTACT

jakob.norgren@ki.se

Facility Contacts

Clara Arvidsson, RD

Role: primary

clara.arvidsson@regionstockholm.se

References

Norgren J, Sindi S, Sandebring-Matton A, Ngandu T, Kivipelto M, Kareholt I. The Dietary Carbohydrate/Fat-Ratio and Cognitive Performance: Panel Analyses in Older Adults at Risk for Dementia. Curr Dev Nutr. 2023 May 7;7(6):100096. doi: 10.1016/j.cdnut.2023.100096. eCollection 2023 Jun.

Reference Type: BACKGROUND

PMID: 37275847 (View on PubMed)

Norgren J, Sindi S, Matton A, Kivipelto M, Kareholt I. APOE-Genotype and Insulin Modulate Estimated Effect of Dietary Macronutrients on Cognitive Performance: Panel Analyses in Nondiabetic Older Adults at Risk of Dementia. J Nutr. 2023 Dec;153(12):3506-3520. doi: 10.1016/j.tjnut.2023.09.016. Epub 2023 Sep 29.

Reference Type: BACKGROUND

PMID: 37778510 (View on PubMed)

Other Identifiers

COGNIFOOD-Pilot

Identifier Type: -

Identifier Source: org_study_id