An interventional study of LCHF and HCLF in Prodromal Alzheimer's Disease, Alzheimer Disease and Mild Cognitive Impairment, sponsored by Karolinska University Hospital. Recruiting at 1 site in Sweden. Open to participants aged 50 Years to 85 Years. Per ClinicalTrials.gov, last updated 2023-10-27.
Sponsored by Karolinska University Hospital · Not applicable, Interventional, and Prevention
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.
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:
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.
3,678 studies on the registry are indexed under Alzheimer Disease; 869 are open to participants now.
This study's planned enrollment of 40 is below the median of 70 across 2,805 interventional studies indexed under Alzheimer Disease.
Browse Alzheimer Disease studies →Karolinska University Hospital is the lead sponsor of 275 studies on the registry; 54 are open to participants now.
Counted across the registry records on this site, refreshed daily.
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:
(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.)
Exclusion Criteria:
LCHF (12 weeks) followed by HCLF (12 weeks) with immediate contrast (no "wash-out" period)
Other: LCHF · Other: HCLF
HCLF (12 weeks) followed by LCHF (12 weeks) with immediate contrast (no "wash-out" period)
Other: LCHF · Other: HCLF
A diet intervention with the following macronutrient targets: Carbohydrates: 10-25 E%; Fat 50-70 E%; Protein: 20-25 E%; Alcohol 0-5 E%
Also known as: Non-ketogenic carbohydrate restriction
A diet intervention with the following macronutrient targets: Carbohydrates: 50-60 E%; Fat 25-30 E%; Protein: 15-20 E%; Alcohol 0-5 E%
Also known as: A fat-restricted diet compatible with official dietary guidelines
Recruitment Rate
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.
Time frame: 1 year from recruitment start
Adherence
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.
Time frame: Week 0, 6, 12, 18, 24
Retention Rate
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
Time frame: Until the end of data collection
Global Cognition
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
Time frame: Week 0, 12, 24
Amyloid β-42/40
Ratio between β-Amyloid concentrations in blood.
Time frame: Week 0, 6, 12, 18, 24; Primary comparison: ∆0-12 weeks (w) vs. ∆0-24 w, reversed by arm.
Phospho-Tau (pTau) 181/231/217
pTau concentrations in blood.
Time frame: Week 0, 6, 12, 18, 24; Primary comparison: ∆0-12 w vs. ∆0-24 w, reversed by arm.
Neurofilament Light (NFL)
NFL concentrations in blood.
Time frame: Week 0, 6, 12, 18, 24; Primary comparison: ∆0-12 w vs. ∆0-24 w, reversed by arm.
Glial Fibrillary Acidic Protein (GFAP)
GFAP concentrations in blood.
Time frame: Week 0, 6, 12, 18, 24; Primary comparison: ∆0-12 w vs. ∆0-24 w, reversed by arm.
Continuous Glucose Monitoring (CGM)
Concentrations of blood glucose measured in blinded mode for participants every 5th minute.
Time frame: Week 0, 6, 12, 18, 24; Seven days at each timepoint.
Food Record
Nutrient intake from self-reported 7-day food record.
Time frame: Week 0, 6, 12, 18, 24
Body-Mass Index (BMI)
Calculated from measures of weight and height (kg/m\^2).
Time frame: Week 0, 6, 12, 18, 24
Waist
(cm)
Time frame: Week 0, 6, 12, 18, 24
Blood Pressure
Systolic and diastolic blood pressure.
Time frame: Week 0, 6, 12, 18, 24
Ketone Bodies in Blood
Capillary concentrations of β-hydroxybutyrate (BHB) measured with a handheld meter after an overnight fasting.
Time frame: Week 0, 6, 12, 18, 24
Glucose
Blood concentrations of glucose after an overnight fasting.
Time frame: Week 0, 6, 12, 18, 24
Glucose in Oral Glucose Tolerance Test (OGTT)
Blood concentrations of glucose after 75 g glucose load.
Time frame: Week 0, 12, 24; (Minutes 0, 30, & 120)
Insulin (OGTT)
Blood concentrations of insulin after 75 g glucose load.
Time frame: Week 0, 12, 24; (Minutes 0, 30, & 120)
C-Peptide (OGTT)
Blood concentrations of C-Peptide after 75 g glucose load.
Time frame: Week 0, 12, 24; (Minutes 0, 30, & 120)
Lactate (OGTT)
Blood concentrations of Lactate after 75 g glucose load.
Time frame: Week 0, 12, 24; (Minutes 0, 30, & 120)
Hemoglobin 1Ac (HbA1c)
Blood concentrations of glycated hemoglobin
Time frame: Week 0, 12, 24
Apolipoprotein B (ApoB)
Blood concentrations of ApoB
Time frame: Week 0, 12, 24
High-Density Lipoprotein Cholesterol (HDL-C)
Blood concentrations of HDL-C
Time frame: Week 0, 12, 24
Triglycerides
Blood concentrations of Triglycerides
Time frame: Week 0, 12, 24
Lipoprotein(a)
Blood concentrations of Lipoprotein(a)
Time frame: Week 0, 12, 24
The Montreal Cognitive Assessment (MoCa)
(Score 0-30; higher=better)
Time frame: Week 0, 12, 24
Cognitive Sub-domain: Memory
Mean z-scores of cognitive sub-tests 1-5, 7, 9-10, as defined above.
Time frame: Week 0, 12, 24
Cognitive Sub-domain: Non-Memory (Executive function / Processing speed)
Mean z-scores of cognitive sub-tests 6, 8, 11-13, as defined above.
Time frame: Week 0, 12, 24
Geriatric Depression Scale (GDS-15)
Scale 0-15; higher score indicate more depressive symptoms.
Time frame: Week 0, 12, 24
RAND-36
Health-related quality of life (HRQoL) questionnaire from RAND Corporation; higher score=better.
Time frame: Week 0, 12, 24
Subjective Experiences of Diets
Questionnaires specific for this study, assessing subjective experiences by the participant and the study partner respectively.
Time frame: Week 12, 24
Adverse Events
According to International Council for Harmonisation and (ICH) - Good Clinical Practice (GCP) standards.
Time frame: Through study completion (typically 24 weeks)
Plan to share: No — Since this is a feasibility study with limited statistical power for analyses on health outcomes, there is no prospective plan to share individual participant data (IPD). This may be reconsidered if feasibility can be established and data sharing can be scientifically, ethically, and legally justified.
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
Contact study teamGet an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Karolinska University Hospital