Alzheimer Disease, Mild Cognitive Impairment
Conditions
Keywords
Memory, Diet, ketogenic
Brief summary
The Brain Energy for Amyloid Transformation in AD (Alzheimer's disease) or BEAT-AD study will compare the effects of a ketogenic low-carbohydrate diet and a low-fat diet in adults with mild cognitive impairment. The data collected will help determine whether diet interventions induce changes in cognitive function, cerebral blood flow, and levels of certain proteins and hormones in body fluids. The study will include volunteers who have mild cognitive impairment, who will be randomly assigned to receive either a ketogenic low-carbohydrate diet or a low-fat diet for 16-weeks, with follow-up assessment 8 weeks after diet completion. Study measures, clinic visits and phone sessions will occur at baseline and throughout the 24-week study. Participant will follow either a low-carbohydrate or low-fat diet that will be individually planned with help from a study dietitian. After completing the study diet for 16 weeks, participants will resume their normal diet. The final visits will occur at week 24 (8 weeks after the completing the diet). At the end of the 24-week study, participants will be given the opportunity to meet with the study dietitian for education and assistance with planning a healthy diet.
Detailed description
This study will examine the effects of a 4-month Modified Mediterranean-Ketogenic Diet compared with an American Heart Association Diet (AHAD - a regimen that has been shown to reduce the risk for cardiovascular disease). We will investigate diet effects on AD biomarkers, on cognition, and on neuroimaging measures of blood flow. Our study will extend previous findings in several important ways by: 1) using a Modified Mediterranean-Ketogenic Diet rather than a traditional Ketogenic Diet, which has the potential for greater long-term compliance and health benefits; 2) increasing the sample size and duration of the diet intervention; 3) examining potential mechanisms of diet effects that may result in new biomarkers and therapeutic targets; and 4) examining key treatment response variables such as Apolipoprotein E (ApoE) genotype, amyloid positivity and metabolic status that could inform precision medicine approaches to dietary prescription. Adults with amnestic mild cognitive impairment (MCI) will be randomized on a 1:1 schedule to receive either a 4-month Modified Mediterranean-Ketogenic Diet (MMKD) or American Heart Association Diet (AHAD) intervention. Diet interventions will be equicaloric with participants' normal diets. Personalized nutritional guidance and menus will be provided, and compliance will be assessed by a registered dietitian. The principal investigator will be responsible for the overall monitoring of the data and safety of study participants, with assistance by members of the study staff, and the Data and Safety Monitoring Board (DSMB), which will be responsible for monitoring the safety of research participants.
Interventions
OTHERlow carbohydrate/high fat diet
Modified Mediterranean-Ketogenic Diet is a low carbohydrate/high fat diet.
OTHERlow fat/high carbohydrate diet
American Heart Association Diet is a low fat/high carbohydrate diet.
Sponsors
Wake Forest University Health Sciences
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Masking description
It is not possible for participants and the dietitian to be blinded to the study diet. Study personnel involved in performing cognitive testing or other outcome procedures or data analysis will be blinded.
Intervention model description
Adults with amnestic mild cognitive impairment will be randomized on a 1:1 schedule to receive either a 4-month Modified Mediterranean Ketogenic Diet or American Heart Association Diet intervention. Diet interventions will be equicaloric with participants' normal diets. Personalized nutritional guidance and menus will be provided, and compliance will be assessed by a registered dietitian. Amyloid positron emission tomography (PET) will be conducted at baseline. Blood collection and cognitive assessment will be conducted at baseline and after 2 and 4 months of diet. Lumbar puncture (LP) and MRI will be conducted at baseline and following the intervention for all participants.
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of amnestic mild cognitive impairment * An informant (study partner) able to provide collateral information on the participant * Stable medical condition (generally 3 months prior to screening visit) at the discretion of study physician * Stable on medications (generally 4 weeks prior to screening visit) at the discretion of study physician * Able to complete baseline assessments
Exclusion criteria
* Diagnosis of neurodegenerative illness (except for MCI); * History of a clinically significant stroke * Current evidence or history in past year of focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse * Sensory impairment (i.e.: visual or auditory) that would preclude the participant from participating in the protocol * Diabetes that requires current use of diabetes medications * Clinically significant elevations in liver function tests * Active neoplastic disease (stable prostate cancer and non-melanoma skin cancer is permissible) * History of epilepsy or seizure within past year * Contraindications for MRI (claustrophobia, craniofacial metal implants, pacemakers) * Significant medical illness or organ failure, such as uncontrolled hypertension or cardiovascular disease, chronic obstructive pulmonary disease, liver disease, or kidney disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebrospinal Fluid Abeta42 | baseline | Aβ42 is a a key Alzheimer's disease biomarker that reflects pathological aggregation of amyloid in the brain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cerebrospinal Fluid Aβ40 | baseline, week 16 | Aβ40 is a peptide biomarker primarily used in the evaluation and diagnosis of Alzheimer's disease and other neurodegenerative conditions |
| Cerebrospinal Fluid Total Tau | baseline, week 16 | total tau is a general indicator of neuronal degeneration and injury |
| Cerebrospinal Fluid ptau181 | baseline, week 16 | ptau181 (phosphorylated tau 181) biomarker is a specialized protein used as a primary diagnostic indicator for Alzheimer's disease |
| Cerebrospinal Fluid NfL | baseline, week 16 | NfL (Neurofilament Light Chain) biomarker is a tool for diagnosing, monitoring, and predicting the progression of various neurodegenerative and neurological diseases |
| Plasma Aβ42 | baseline, week 16 | Aβ42 is a a key Alzheimer's disease biomarker that reflects pathological aggregation of amyloid in the brain. |
| Plasma Aβ40 | baseline, week 16 | Aβ40 is a peptide biomarker primarily used in the evaluation and diagnosis of Alzheimer's disease and other neurodegenerative conditions |
| Plasma p-tau217 | baseline, week 16 | p-tau217 (phosphorylated tau at threonine 217) is a biomarker used to detect and predict the brain changes associated with Alzheimer's disease |
| Plasma Phosphorylated Tau 181 | baseline, week 16 | pTau181 (phosphorylated tau 181) is a biomarker that serves as a primary diagnostic indicator for Alzheimer's disease |
| Plasma NfL | baseline, week 16 | NfL (Neurofilament Light Chain) biomarker is a tool for diagnosing, monitoring, and predicting the progression of various neurodegenerative and neurological diseases |
| Hemoglobin A1c | baseline, week 16 | Hemoglobin A1c measures your average blood sugar levels over the past 2 to 3 months. Below 5.7% is normal, 5.7-6.4% indicates prediabetes, 6.5% or higher indicates diabetes. |
| Triglyceride Level | baseline, week 16 | The level of triglycerides (a type of fat) in blood with less than 150 mg/dL being normal. |
| LDL Level | baseline, week 16 | LDL (low-density lipoprotein) is the amount of "bad" cholesterol in the blood. The optimal level is less than 100 mg/dL. |
| HDL Level | baseline, week 16 | HDL (High-Density Lipoprotein) blood test measures the amount of "good" cholesterol in the blood. Optimal level is ≥ 60 mg/dL. Low HDL (\<40 mg/dL for men, \<50 mg/dL for women) indicates a higher risk for cardiovascular disease. |
| Total Cholesterol Level | baseline, week 16 | Measure of overall amount of cholesterol in the blood, which includes both "bad" (LDL) and "good" (HDL) cholesterol. Desirable level is less than 200 mg/dL with higher levels indicating greater risk for heart attack and stroke. |
| Ketones Level | baseline, week 16 | A blood ketone test specifically measures beta-hydroxybutyrate, the primary ketone in your blood. Under 0.6 mmol/L normal or negative. 0.6 to 1.5 mmol/L slightly elevated, body is in ketosis (burning fat for fuel). 1.6 to 3.0 mmol/L elevated, risk for diabetic ketoacidosis. Over 3.0 mmol/L high, indicates potentially dangerous levels that require emergency medical attention. |
| Glucose Level | baseline, week 16 | Level of blood glucose with normal being less than 100 mg/dL while fasting. Fasting levels of 100 to 125 mg/dL indicate prediabetes. Fasting levels of 126 mg/dL or higher (on more than one occasion) indicate diabetes. |
| MRI Pseudo Continuous Arterial Spin Labeling Hippocampal Uptake | baseline, week 16 | Cerebral blood flow will be measured with pseudo continuous arterial spin labeling MRI and voxel based analyses will be conducted to determine diet-induced changes and their relationship to cognitive and biomarker outcomes. Healthy adult gray matter typically ranges between 50 to 70 ml/100g/min. Lower than typical range indicates reduced cerebral blood flow. |
| MRI Pseudo Continuous Arterial Spin Labeling Meta-Region of Interest Uptake | baseline, week 16 | Pseudo Continuous Arterial Spin Labeling measures regional cerebral blood flow. Meta-Region of Interest combines data from multiple predefined brain regions into a single composite uptake score. Higher values in mL/100g/min indicate greater tissue perfusion, while lower values reflect reduced blood flow. Normal gray matter perfusion in a healthy adult typically ranges between 50 and 60 mL/100g/min, while white matter generally measures around 20 mL/100g/min. |
| MRI Neurite Orientation Dispersion and Density Imaging-Neurite Density Index (NODDI-NDI) Hippocampal Uptake | baseline, week 16 | NODDI-NDI measures the packing and density of neurites (axons and dendrites) in the hippocampal region of the brain. NDI values drop in the hippocampus as neurites degenerate during Alzheimer's disease or normal aging. NDI is expressed as a decimal value typically falling between 0 and 1. A value of 0 represents an area with no neurites (e.g., pure cerebrospinal fluid), while a value closer to 1 indicates a highly dense network of axons or dendrites. |
| MRI Neurite Orientation Dispersion and Density Imaging-Neurite Density Index (NODDI-NDI) Meta-Region of Interest Uptake | baseline, week 16 | NODDI-NDI measures the packing and density of neurites in the region of interest in the brain. NDI values drop as neurites degenerate during Alzheimer's disease or normal aging. NDI is expressed as a decimal value typically falling between 0 and 1. A value of 0 represents an area with no neurites (e.g., pure cerebrospinal fluid), while a value closer to 1 indicates a highly dense network of axons or dendrites. |
| MRI Neurite Orientation Dispersion and Density Imaging-Isotropic Volume Fraction (NODDI-ISOVF) Hippocampal Uptake | baseline, week 16 | ISOVF measures the proportion of water molecules that are diffusing freely and isotropically in the hippocampal region of the brain. Elevated ISOVF is frequently observed in Alzheimer's disease, cognitive decline, aging, and infection burdens, reflecting a breakdown of tissue structure. Expressed as a value between 0 and 1 with a higher number indicating a higher level of free, isotropic water. |
| MRI Neurite Orientation Dispersion and Density Imaging-Isotropic Volume Fraction (NODDI-ISOVF) Meta-Region of Interest (ROI) Uptake | baseline, week 16 | ISOVF Meta-ROI measures the proportion of water molecules that are diffusing freely and isotropically within a region of interests in the brain. Elevated ISOVF is frequently observed in Alzheimer's disease, cognitive decline, aging, and infection burdens, reflecting a breakdown of tissue structure. Expressed as a value between 0 and 1 with a higher number indicating a higher level of free, isotropic water. |
| MRI Neurite Orientation Dispersion and Density Imaging Orientation Dispersion Index (NODDI-ODI) Hippocampal Uptake | baseline, week 16 | NODDI ODI (Orientation Dispersion Index) is used to quantify the spatial configuration and branching of neurites (axons and dendrites) in hippocampal region of the brain. It measures how widely the orientations of neurites spread out in space within a voxel. Low ODI indicates highly aligned or parallel fibers, typical of coherent white matter tracts. High ODI indicates highly dispersed or fanned-out fibers, typical of gray matter or areas with complex fiber crossings. ODI ranges from 0 to 1, where values closer to 0 represent fibers pointing in nearly the same direction (low dispersion). |
| MRI Neurite Orientation Dispersion and Density Imaging Orientation Dispersion Index (NODDI-ODI) Meta-Region of Interest (ROI) Uptake | baseline, week 16 | NODDI ODI (Orientation Dispersion Index) is used to quantify the spatial configuration and branching of neurites (axons and dendrites) in the region of interest in the brain. It measures how widely the orientations of neurites spread out in space within a voxel. Low ODI indicates highly aligned or parallel fibers, typical of coherent white matter tracts. High ODI indicates highly dispersed or fanned-out fibers, typical of gray matter or areas with complex fiber crossings. ODI ranges from 0 to 1, where values closer to 0 represent fibers pointing in nearly the same direction (low dispersion). |
| Modified Preclinical Alzheimer Cognitive Composite 5 (mPACC5) Score | Week 16 | The modified Preclinical Alzheimer Cognitive Composite 5 (mPACC5) measures cognitive changes associated with Alzheimer's-related brain pathology. It aggregates z-scores from five specific cognitive tests across four domains: episodic memory (delayed recall tests), timed executive function (speed and processing tasks), semantic memory (verbal fluency tests), global cognition (overall mental status exams). Total Z-score range: healthy /unimpaired baseline -0.50 to +1.00, mild cognitive impairment -2.50 to -0.50, dementia -3.50 to -2.50. The central value of the mPACC5 is 0. |
| Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog 12) Score | baseline, week 16 | The ADAS-Cog 12 is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment. Scores range from 0-85 with higher scores indicating greater cognitive impairment. |
| Neuropsychiatric Inventory Questionnaire (NPI-Q) Score | baseline, week 16 | The NPI-Q is widely used to assess the presence of mood disorders in geriatric populations. The NPI-Q measures 12 symptom categories and is scored on a scale of 0-36. A higher score indicates a higher burden of neuropsychiatric symptoms. A score of 0 indicates no symptoms are present. |
| Geriatric Depression Scale Score | baseline, week 16 | The Geriatric Depression Scale is a well-validated self-report questionnaire used frequently in clinical and research settings to assess mood in older adults. Total score range is 0-15 with 0-4 normal range (no risk of depression indicated), 5-8 mild depressive symptoms, 9-11 moderate depressive symptoms, 12-15 severe depressive symptoms. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSuzanne Craft, PhD
Wake Forest University Health Sciences
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 69.9 years STANDARD_DEVIATION 7.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 61 Participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 40 |
| other Total, other adverse events | 30 / 44 | 15 / 40 |
| serious Total, serious adverse events | 1 / 44 | 6 / 40 |
Outcome results
None listed