Alzheimer’s disease (AD) is the most common form of dementia worldwide and is defined biologically as the pathologic deposition of folded β-amyloid (Aβ) plaques, and hyperphosphorylated neurofibrillary tau tangles in the brain leading to neurodegeneration.
Clinical trials focusing on therapeutic candidates that modify β-amyloid (Aβ) have repeatedly failed to treat Alzheimer’s disease (AD), suggesting that Aβ may not be the optimal target for treating AD.
Glucose Metabolism as a Marker for AD
In a research study, Hammond et al. reported that diminished uptake of glucose in the brain is a better marker for classifying AD than beta-amyloid or phosphorylated tau deposition.
The team used an advanced statistical learning machine learning method, random forest, on data provided by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to measure the ability of beta-amyloid measured by positron emission tomography (Aβ-PET), phosphorylated tau measured in the cerebral spinal fluid (CSF-pTau).
Their results demonstrated that amyloid, tau, and neurodegeneration have a phase-dependent impact on the development of AD. According to their study, beta-amyloid and pTau are better predictors of early dementia status, also defined as mild cognitive impairment, and neurodegeneration, especially low glucose uptake is a better predictor of later dementia status or clinical AD.
The results suggest that glucose metabolism should be investigated as a potential target for treating AD disease in the later stages of the disease. Also, targeting glucose metabolism and insulin resistance could be an important step in decreasing metabolism failures due to aging and restoring cognitive resilience.
The decreased glucose uptake in important areas of the brain can’t sustain the support necessary for neuronal activity and lead to reduced cognitive function. Reduced glucose metabolism in the brain is also associated with insulin resistance, which has been associated with an exacerbation of Aβ deposition.
According to the researchers, the maintenance of healthy blood glucose metabolism in the brain should be a priority focus for AD treatment as a strategy for preserving cognitive function.
Tyler C. Hammond, et al. β-amyloid and tau drive early Alzheimer’s disease decline while glucose hypometabolism drives late decline. 2020. Commun Biol. doi: 10.1038/s42003-020-1079-x
Tyler C. Hammond, Ai-Ling Lin. Glucose Metabolism is a Better Marker for Predicting Clinical Alzheimer’s Disease than Amyloid or Tau. 2022. J Cell Immunol. Author manuscript.