Glucose Metabolism is a Better Marker for Predicting Clinical Alzheimer’s Disease than Amyloid or Tau

Alzheimer’s disease (AD) research has long been dominated with communications regarding the amyloid hypothesis and targeting amyloid clearance through pharmacological therapies from the brain [1]. Unfortunately, this research strategy has yielded only one new FDA-accelerated approved therapeutic for early AD, and its clinical benefit still needs to be verified [2]. It may be time to employ a new strategy in AD therapeutics research. Hammond et al. reported that diminished uptake of glucose in the brain is a better marker for classifying AD than beta-amyloid (A β ) or phosphorylated tau deposition [3]. The National Institute on Aging and the Alzheimer’s Association published revised guidelines for the diagnosis of AD to include the measurement of amyloid (A), tau (T), and neurodegeneration (N), when diagnosing and treating AD [4]. It is highly relevant to AD therapeutic research whether amyloid, tau, and neurodegeneration contribute equally to the progression of AD at all phases of the disease or in a matter dependent on disease phase. To be able to successfully treat or prevent AD, there is a pressing need to identify precision biomarkers that are sensitive to disease progression and able to predict onset of cognitive impairment [5]. Hammond et al. 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 (A β -PET), phosphorylated tau measured in the cerebral spinal fluid (CSF-pTau), fluorodeoxyglucose measured by positron emission tomography (FDG-PET) and structural imaging measured by magnetic resonance imaging (MRI) to classify AD diagnosis. Their results demonstrated that amyloid, tau, and neurodegeneration have a phase-dependent impact on the development of AD. A β and pTau are better predictors of the early dementia status that is often defined as mild cognitive impairment (MCI), and neurodegeneration, especially low glucose uptake, is a better predictor of later dementia status, or clinical AD. A