In vivo PET imaging and postmortem studies suggest potentially reversible and irreversible stages of brain metabolic failure in Alzheimer's disease.

In vivo brain imaging of patients with Alzheimer's disease (AD) using positron emission tomography (PET) demonstrates progressive reductions in resting-state brain glucose metabolism and blood flow (markers of synaptic activity) in relation to dementia severity, more so in association than primary cortical regions. During cognitive or psychophysical stimulation, however, blood flow and metabolism in the affected brain regions can increase to the same extent in mildly demented AD patients as in age-matched controls, despite reduced resting state values. The extent of activation declines with dementia severity and is markedly reduced in severely demented patients. Thus, there appears to be an initial functionally-responsive stage in AD, which direct brain analysis suggests is accompanied by reversible down-regulation because of reduced synaptic energy demand of enzymes mediating mitochondrial oxidative-phosphorylation. A later irreversible stage of AD is accompanied by marked synaptic loss, accumulation of intracellular neurofibrillary tangles, reduced general transcriptional capacity, and death of neurons.