Phosphate/calcium alterations in the first stages of Alzheimer's disease: Implications for etiology and pathogenesis

The present study tested aspects of a novel etiological/pathogenetic hypothesis of Alzheimer's disease (AD), which proposes that alterations in endocrine regulation of peripheral calcium/phosphate ( Ca PO₄) homeostasis (e.g., by glucocorticoids, vitamin D, etc.) induce and/or reflect altered calcium homeostasis and neurotoxicity in brain neurons. Two key predictions of this hypothesis were tested, namely that: (1) alterations in serum Ca and/or PO₄ regulation should be present before or near the onset of AD and (2) these alterations should be found consistently in subjects with unconfounded AD. Previous studies have sought evidence of changes in Ca regulation primarily late in the disease, and usually in severely demented, thin and immobile inpatients in whom Ca PO₄ measures are likely to be confounded. In the present study, only mobile, relatively healthy, adequately nourished outpatients with probable AD were selected. In comparison to age-matched controls or demented subjects with even mild indications of vascular contributions, the AD subjects were characterized by lower serum PO₄ and, to a lesser degree, lower serum Ca as well as a higher chloride PO₄ ratio. On serum chemistry tests from the first stages of AD (within 1 or 3 years after the onset of cognitive symptoms), these changes in serum PO₄ Ca were as pronounced as they were later in the disease. Moderately low values of either PO₄, Ca, or both (below -1.0 S.D. from the control group mean) identified 74% of all AD subjects and 100% of early onset AD subjects, in comparison to only 46% of mixed/vascular dementia subjects and 31% of normal age-matched controls. Thus, the results were consistent with the predictions and may have significant etiological/pathogenetic implications. If larger tests confirm these frequencies, serum Ca PO₄ indices may also prove useful in differential diagnosis.