Blood Sugar

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Evidence exists that high blood sugar levels, as in diabetes and pre-diabetic states, influence the progression of many forms of dementia, including Alzheimer's, regardless of ApoE status. Also see Insulin Resistance.

Epidemiological studies generally show an increase in the risk for AD in people with diabetes or impaired glucose tolerance/insulin resistance.

In the presence of high blood sugar, animal studies show increased Aβ40/Aβ42 in the cortex and hippocampus, and the generation of Aβ-derived assemblies similar to those found in human AD. Recent rat studies showed that the combination of both hyperglycemia and beta amyloid increased the susceptibility of brain microvascular endothelial cells to Aβ toxicity and decreased their viability by 40%. Hyperglycemia or Aβ alone did not affect cell viability.

Why it is important for ApoE4s

1) "Individuals with both type 2 diabetes and the APOE epsilon4 allele had an RR of 5.5 (CI 2.2-13.7) for AD compared with those with neither risk factor. Participants with type 2 diabetes and the epsilon4 allele had a higher number of hippocampal neuritic plaques (IRR 3.0 [CI 1.2-7.3]) and neurofibrillary tangles in the cortex (IRR 3.5 [1.6-7.5]) and hippocampus (IRR 2.5 [1.5-3.7]), and they had a higher risk of cerebral amyloid angiopathy (RR 6.6, 1.5-29.6)." [1]

2) In contrast, the Kungsholmen project ([2]) reported no interaction between diabetes and the APOE ε4 genotype, as described in [3]. These authors stated that “These differences could be due to chance or differences in ethnicity and sex distribution in the populations.”

3) “Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory.” [4]. However, a 2013 study showed that the response might be dose related. [5]

4) "Among AD individuals with DM2, those who are ApoE ε4 carriers had significantly greater neuropathology than those who do not carry an ApoE ε4 allele. Positive DM2 status appears to exacerbate AD neuropathology in the presence of ApoE ε4." [6]

Strategies for controlling blood sugar

Doctors tend to overlook testing for blood glucose levels in Alzheimer's patients. When recruiting people for a resveratrol study to study glucose effects in patients with Alzheimer’s, a Georgetown neurologist was “shocked” by how many had pre-diabetes. [7]

For strategies, check out the Insulin Resistance page.

The Science

- Epidemiological studies.

1) Glucose levels and risk of dementia. (2013) PubMed ID:23924004

2) Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. (2004, full text) PubMed ID:15148141

3) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. (2002, full text) PubMed ID:11916953

4) Risk of Dementia among Persons with Diabetes Mellitus: A Population-based Cohort Study (1997, full text) PubMed ID:9329716

5) Increased Alzheimer's disease neuropathology is associated with type 2 diabetes and ApoE ε.4 carrier status. (2013) PubMed ID:23627755

- Other studies.

1) Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence (2013, full text) PubMed ID:23719722

- Animal studies.

1) Increased Susceptibility to Amyloid-β Toxicity in Rat Brain Microvascular Endothelial Cells under Hyperglycemic Conditions. (2013) PubMed ID:23948922

2) Amyloid-β and tau pathology of Alzheimer's disease induced by diabetes in a rabbit animal model. (2012) PubMed ID:22785400

3) Epigenetic mechanisms linking diabetes and synaptic impairments. (2013) PubMed ID:24154559

Proposed mechanism(s)

1) Insulin plays an important role in the formation of memories. Abnormal insulin and insulin receptor levels and activities are seen in Alzheimer's dementia, whereas administration of insulin significantly improves the cognitive performance of these patients. ([8]) Increased blood glucose increases amyloid beta “oligomer” assemblies in the brain, which bind to hippocampal neurons and cause insulin receptors to be eliminated from the surface membranes, contributing to insulin resistance in the brain. ([9])

2) Diabetes may induce epigenetic modifications in the brain. Elevation of HDAC IIa in the brains of diabetics coincide with altered expression of synaptic proteins. [10]

Related SNPs

SNPs associated with Type II Diabetes: List

SNPs associated with HbA1c levels : Article