Correlations of disability and biologic alterations in Alzheimer brain and test of significance by a therapeutic trial in humans

Abstract

Literature values for the correlations between a number of major neurobiological hallmarks of Alzheimer's disease (AD) and the degree of global cognitive impairment among AD patients have been compared, in an attempt to identify biological abnormalities whose treatment might ameliorate the clinical disabilities. High correlations have been described with impairments of cerebral metabolism at both the level of cerebral metabolic rate in vivo and that of mitochondria. The metabolic abnormality develops even before morphological or symptomatic evidence of the illness. Information on such correlations with markers of oxidative stress are not available. Correlations with morphological abnormalities were lower and less consistent than with brain oxidative metabolism; significant correlations have been observed, in descending order, with a synaptic marker (synaptophysin), with tangle count, and with amyloid. Neither a decrease in a synaptic marker nor in a marker for cholinergic neurons have been found in mild, early AD. Preliminary therapeutic trials of manipulations designed to increase cerebral metabolic rate have given encouraging results, including a trial described briefly in this communication. The clinical value of treatments of the cerebrometabolic deficiency in AD warrants further investigation.