Brain Energy for Amyloid Transformation in Alzheimer's Disease Study (BEAT-AD)

Brain Energy for Amyloid Transformation in AD (BEAT-AD) Study

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease; Mild Cognitive Impairment
• Intervention / Treatment: Other: low carbohydrate/high fat diet; Other: low fat/high carbohydrate 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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Modified Mediterranean Ketogenic Diet; The MMKD is a low carbohydrate/high fat diet aimed at inducing ketosis, as the experimental diet in the proposed study. Participants on the MMKD will keep their daily carbohydrate consumption below 20 grams per day throughout the 4 month intervention.The MMKD group will be supplied with extra virgin olive oil during their in person visits to use as a source of fat in their diet, and will be encouraged to eat plentiful fish, lean meats, and nutrient rich foods that meet the requirement of <20 grams total carbohydrates per day. Participants will receive a daily multivitamin (Centrum Silver) over the course of the study and instructed to take 1 tablet each day while on the diet.	Other: low carbohydrate/high fat diet; Modified Mediterranean-Ketogenic Diet is a low carbohydrate/high fat diet.
Experimental: American Heart Association Diet; The American Heart Association Diet (AHAD), is a low fat/high carbohydrate diet (<40 grams/day) will be used as the control diet. Participants on the AHAD will be encouraged to limit their amount of fat intake to <40 grams/day, while eating plentiful fruits, vegetables, and carbohydrates containing adequate fiber. Participants will receive the same daily multivitamin supplement (Centrum Silver) over the course of the study and instructed to take 1 tablet each day while on the diet.	Other: low fat/high carbohydrate diet; American Heart Association Diet is a low fat/high carbohydrate diet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebrospinal Fluid Abeta42	Aβ42 is a a key Alzheimer's disease biomarker that reflects pathological aggregation of amyloid in the brain.	baseline
Cerebrospinal Fluid Abeta42	Aβ42 is a a key Alzheimer's disease biomarker that reflects pathological aggregation of amyloid in the brain.	week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebrospinal Fluid Aβ40	Aβ40 is a peptide biomarker primarily used in the evaluation and diagnosis of Alzheimer's disease and other neurodegenerative conditions	baseline, week 16
Cerebrospinal Fluid Total Tau	total tau is a general indicator of neuronal degeneration and injury	baseline, week 16
Cerebrospinal Fluid ptau181	ptau181 (phosphorylated tau 181) biomarker is a specialized protein used as a primary diagnostic indicator for Alzheimer's disease	baseline, week 16
Cerebrospinal Fluid NfL	NfL (Neurofilament Light Chain) biomarker is a tool for diagnosing, monitoring, and predicting the progression of various neurodegenerative and neurological diseases	baseline, week 16
Plasma Aβ42	Aβ42 is a a key Alzheimer's disease biomarker that reflects pathological aggregation of amyloid in the brain.	baseline, week 16
Plasma Aβ40	Aβ40 is a peptide biomarker primarily used in the evaluation and diagnosis of Alzheimer's disease and other neurodegenerative conditions	baseline, week 16
Plasma p-tau217	p-tau217 (phosphorylated tau at threonine 217) is a biomarker used to detect and predict the brain changes associated with Alzheimer's disease	baseline, week 16
Plasma Phosphorylated Tau 181	pTau181 (phosphorylated tau 181) is a biomarker that serves as a primary diagnostic indicator for Alzheimer's disease	baseline, week 16
Plasma NfL	NfL (Neurofilament Light Chain) biomarker is a tool for diagnosing, monitoring, and predicting the progression of various neurodegenerative and neurological diseases	baseline, week 16
Hemoglobin A1c	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.	baseline, week 16
Triglyceride Level	The level of triglycerides (a type of fat) in blood with less than 150 mg/dL being normal.	baseline, week 16
LDL Level	LDL (low-density lipoprotein) is the amount of "bad" cholesterol in the blood. The optimal level is less than 100 mg/dL.	baseline, week 16
HDL Level	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.	baseline, week 16
Total Cholesterol Level	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.	baseline, week 16
Ketones Level	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.	baseline, week 16
Glucose Level	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.	baseline, week 16
MRI Pseudo Continuous Arterial Spin Labeling Hippocampal Uptake	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.	baseline, week 16
MRI Pseudo Continuous Arterial Spin Labeling Meta-Region of Interest Uptake	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.	baseline, week 16
MRI Neurite Orientation Dispersion and Density Imaging-Neurite Density Index (NODDI-NDI) Hippocampal Uptake	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.	baseline, week 16
MRI Neurite Orientation Dispersion and Density Imaging-Neurite Density Index (NODDI-NDI) Meta-Region of Interest Uptake	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.	baseline, week 16
MRI Neurite Orientation Dispersion and Density Imaging-Isotropic Volume Fraction (NODDI-ISOVF) Hippocampal Uptake	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.	baseline, week 16
MRI Neurite Orientation Dispersion and Density Imaging-Isotropic Volume Fraction (NODDI-ISOVF) Meta-Region of Interest (ROI) Uptake	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.	baseline, week 16
MRI Neurite Orientation Dispersion and Density Imaging Orientation Dispersion Index (NODDI-ODI) Hippocampal Uptake	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).	baseline, week 16
MRI Neurite Orientation Dispersion and Density Imaging Orientation Dispersion Index (NODDI-ODI) Meta-Region of Interest (ROI) Uptake	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).	baseline, week 16
Modified Preclinical Alzheimer Cognitive Composite 5 (mPACC5) Score	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.	Week 16
Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog 12) Score	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.	baseline, week 16
Neuropsychiatric Inventory Questionnaire (NPI-Q) Score	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.	baseline, week 16
Geriatric Depression Scale Score	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.	baseline, week 16

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pittsburgh Sleep Quality Index	Pittsburgh Sleep Quality Index was inadvertently listed as a secondary outcome in the protocol but was actually an exploratory outcome.	baseline, week 16
Epworth Sleepiness Scale	Epworth Sleepiness Scale was inadvertently listed as a secondary outcome in the protocol but was actually an exploratory outcome.	baseline, week 16
WatchPAT Sleep Stage Time	WatchPAT sleep stage time was inadvertently listed as a secondary outcome in the protocol but was actually an exploratory outcome	baseline, week 16

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Suzanne Craft, PhD, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2018
• Primary Completion (Actual): July 19, 2024
• Study Completion (Actual): September 13, 2024

Study Registration Dates

• First Submitted: March 12, 2018
• First Submitted That Met QC Criteria: March 20, 2018
• First Posted (Actual): March 21, 2018

Study Record Updates

• Last Update Posted (Actual): August 3, 2026
• Last Update Submitted That Met QC Criteria: July 30, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Diet; Memory; ketogenic
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Cognitive Dysfunction; Alzheimer Disease
• Other Study ID Numbers: IRB00049474; 1R01AG055122-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data sharing will follow guidelines and timeline recommended by the National Institute on Aging.
• IPD Sharing Time Frame: The data will become available one year after completion of the study and remain available indefinitely.
• IPD Sharing Access Criteria: Consultation with the study team to verify purpose of data sharing request, and collaborative involvement of study team if appropriate.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No