Prodromal Alzheimer's Disease, Alzheimer Disease, Mild Cognitive Impairment, Neurocognitive Disorders
Conditions
Keywords
Cognitive health, Cognition, Dementia prevention, Macronutrients
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.
Interventions
Sponsors
Fingers Brain Health Institute
Karolinska Institutet
af Jochnick Foundation
Karolinska University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
Assessors of disease monitoring outcomes (defined as Secondary outcomes below) are blinded. One of the primary outcomes (Adherence) assessed by dietitian which cannot be blinded.
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recruitment Rate | 1 year from recruitment start | Number of participants that are randomized within 1 year from start of recruitment, or time to reach 40 randomized participants if reached within \<1 year. |
| Adherence | Week 0, 6, 12, 18, 24 | Self-reported carbohydrate/fat-ratio (CFr) from 7-day food record: Intra-individual difference in CFr (log-transformed) between the diet treatments (mean Period 1 \[week 6 &12\] vs. mean Period 2 \[week 18 & 24\], reversed by arm) expressed as standard deviations of the baseline distribution. |
| Retention Rate | Until the end of data collection | The proportion of those randomized who complete the 12-week and 24-week follow-up with data on both a. Self-reported carbohydrate/fat-ratio; b. Secondary outcomes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neurofilament Light (NFL) | Week 0, 6, 12, 18, 24; Primary comparison: ∆0-12 w vs. ∆0-24 w, reversed by arm. | NFL concentrations in blood. |
| Global Cognition | Week 0, 12, 24 | Mean of z-scores (higher=better) from 13 sub-tests of a modified Neuropsychological Test Battery (NTB), subsequently z-transformed. Sources of sub-tests include Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery and Wechsler Memory Scale (WMS). 1. CERAD 10-word List Learning 2. CERAD 10-word Delayed Recall 3. CERAD 10-word Recognition 4. WMS-Verbal Immediate (story) 5. WMS-Verbal Delayed (story) 6. WMS-Digit Span 7. WMS-Visual Paired Associates 8. Category Fluency 9. CERAD Constructional Praxis 10. CERAD Constructional Praxis Recall 11. Letter Digit Substitution Test 12. Trail Making Test A 13. Trail Making Test B |
| Glial Fibrillary Acidic Protein (GFAP) | Week 0, 6, 12, 18, 24; Primary comparison: ∆0-12 w vs. ∆0-24 w, reversed by arm. | GFAP concentrations in blood. |
| Amyloid β-42/40 | Week 0, 6, 12, 18, 24; Primary comparison: ∆0-12 weeks (w) vs. ∆0-24 w, reversed by arm. | Ratio between β-Amyloid concentrations in blood. |
| Phospho-Tau (pTau) 181/231/217 | Week 0, 6, 12, 18, 24; Primary comparison: ∆0-12 w vs. ∆0-24 w, reversed by arm. | pTau concentrations in blood. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Blood Pressure | Week 0, 6, 12, 18, 24 | Systolic and diastolic blood pressure. |
| Ketone Bodies in Blood | Week 0, 6, 12, 18, 24 | Capillary concentrations of β-hydroxybutyrate (BHB) measured with a handheld meter after an overnight fasting. |
| Glucose | Week 0, 6, 12, 18, 24 | Blood concentrations of glucose after an overnight fasting. |
| Glucose in Oral Glucose Tolerance Test (OGTT) | Week 0, 12, 24; (Minutes 0, 30, & 120) | Blood concentrations of glucose after 75 g glucose load. |
| Insulin (OGTT) | Week 0, 12, 24; (Minutes 0, 30, & 120) | Blood concentrations of insulin after 75 g glucose load. |
| C-Peptide (OGTT) | Week 0, 12, 24; (Minutes 0, 30, & 120) | Blood concentrations of C-Peptide after 75 g glucose load. |
| Lactate (OGTT) | Week 0, 12, 24; (Minutes 0, 30, & 120) | Blood concentrations of Lactate after 75 g glucose load. |
| Geriatric Depression Scale (GDS-15) | Week 0, 12, 24 | Scale 0-15; higher score indicate more depressive symptoms. |
| Apolipoprotein B (ApoB) | Week 0, 12, 24 | Blood concentrations of ApoB |
| High-Density Lipoprotein Cholesterol (HDL-C) | Week 0, 12, 24 | Blood concentrations of HDL-C |
| Triglycerides | Week 0, 12, 24 | Blood concentrations of Triglycerides |
| Lipoprotein(a) | Week 0, 12, 24 | Blood concentrations of Lipoprotein(a) |
| The Montreal Cognitive Assessment (MoCa) | Week 0, 12, 24 | (Score 0-30; higher=better) |
| Cognitive Sub-domain: Memory | Week 0, 12, 24 | Mean z-scores of cognitive sub-tests 1-5, 7, 9-10, as defined above. |
| Cognitive Sub-domain: Non-Memory (Executive function / Processing speed) | Week 0, 12, 24 | Mean z-scores of cognitive sub-tests 6, 8, 11-13, as defined above. |
| Hemoglobin 1Ac (HbA1c) | Week 0, 12, 24 | Blood concentrations of glycated hemoglobin |
| RAND-36 | Week 0, 12, 24 | Health-related quality of life (HRQoL) questionnaire from RAND Corporation; higher score=better. |
| Subjective Experiences of Diets | Week 12, 24 | Questionnaires specific for this study, assessing subjective experiences by the participant and the study partner respectively. |
| Adverse Events | Through study completion (typically 24 weeks) | According to International Council for Harmonisation and (ICH) - Good Clinical Practice (GCP) standards. |
| Continuous Glucose Monitoring (CGM) | Week 0, 6, 12, 18, 24; Seven days at each timepoint. | Concentrations of blood glucose measured in blinded mode for participants every 5th minute. |
| Food Record | Week 0, 6, 12, 18, 24 | Nutrient intake from self-reported 7-day food record. |
| Body-Mass Index (BMI) | Week 0, 6, 12, 18, 24 | Calculated from measures of weight and height (kg/m\^2). |
| Waist | Week 0, 6, 12, 18, 24 | (cm) |
Countries
Sweden
Contacts
Primary ContactAnne Börjesson-Hanson, MD, PhD
Backup ContactJakob Norgren, PhD
Outcome results
None listed