Energy Metabolism and Cognitive Aging

Obesity and metabolic disturbance are recognized as important risks for disorders such as
cardiovascular disease, stroke, and cancer. However, these conditions also contribute to
age-related cognitive decline and dementia. In particular, insulin resistance and
hyperinsulinemia promote neurocognitive dysfunction and neurodegenerative changes during the
extended pre-clinical phase of Alzheimer's disease (AD). The prevalence of both metabolic
disturbance and dementia are increasing dramatically, and in the absence of effective
treatment, preventive approaches are essential to address the ominous public health concern
represented by Alzheimer's disease and other forms of dementia. Dietary intervention is a
promising and under-investigated preventive option. Regimens involving restricted
carbohydrate consumption designed to induce ketone metabolism have been shown to improve
metabolic parameters. In addition, ketone metabolism is associated with a host of benefits
for neural function, among them enhanced mitochondrial energy production and reduction of
neuropathological factors. Ketone feeding studies have demonstrated acute functional
improvement in older adults with neurocognitive decline.

This research is designed to assess the efficacy of strict carbohydrate restriction in
correcting hyperinsulinemia and improving neurocognitive function in older adults with early
memory decline. Recently, we have shown that relatively brief intervention involving a low
carbohydrate, ketogenic diet can improve memory in subjects with Mild Cognitive Impairment.
We would like to extend these initial findings by adding new study arms involving older
adult subjects with Parkinson's disease and Mild Cognitive Impairment. We also will increase
the intervention period from six weeks to eight weeks.

Aim 1: To evaluate the effect of adaptation to ketosis on cognitive function in older adults
with Age-Associated Memory Impairment (AAMI) and Mild Cognitive Impairment (MCI).

Hypothesis 1. Subjects with AAMI and MCI will show improved working memory and long-term
memory ability after practicing a low carbohydrate, ketogenic diet for six weeks relative to
comparison subjects who maintain a typical, high carbohydrate, nonketogenic diet.

Aim 2: To assess the effect of ketone metabolism on memory and motor function in subjects
with Parkinson's disease and Mild Cognitive Impairment after eight (8) weeks of dietary
intervention.

Hypothesis 2. Subjects with Parkinson's disease and MCI will show improved working memory
and long-term memory function after practicing a low carbohydrate, ketogenic diet for eight
weeks relative to comparison subjects who consume a typical, high carbohydrate nonketogenic
diet.

Hypothesis 3. Subjects with Parkinson's disease and MCI will show improved motor function
after practicing a low carbohydrate, ketogenic diet for eight weeks relative to comparison
subjects who consume a typical, high carbohydrate nonketogenic diet.

We also will evaluate changes in mood, ketone body levels, serum lipids, inflammatory
markers, and fasting glucose and insulin and assess relationships of these factors with the
primary outcome measures. We will obtain diet records during the intervention to assess
adherence to the protocol.

Inclusion Criteria:

- Age 60 years or older

- Mild cognitive impairment

Exclusion Criteria:

- Diabetes

- Medications that have effect on memory

- Memory problems due to medical issues (ie head injury, stroke, untreated sleep apnea
etc.)

- Unable to complete an MRI scan