Sex-dependent Cytoskeletal Changes of the Human Hypothalamus Develop Independently of Alzheimer's Disease

This study examines a sex-dependent variant of neurofibrillary pathology recently identified in the hypothalamus of elderly human males. Here we focus upon the relationship between the sex-dependent hypothalamic changes and Alzheimer's disease (AD)-related neurofibrillary pathology. To this end, autopsy brains of 31 males (mean age 84.1 years) and 26 age-matched females (mean age 86.7 years) were examined. Both the male and the female subjects exhibited either particularly mild (stage I) or fully developed (stage V) AD-related neurofibrillary brain pathology. Serial 100-micron hypothalamic sections were cut in the frontal plane and stained for hyperphosphorylated tau protein using the monoclonal antibody AT8. Argyrophilic neurofibrillary pathology was demonstrated using a modified Gallyas silver-iodide technique. A conspicuous pathology, characterized by neurofibrillary tangles, a network of dystrophic neurites, and terminal-like vessel-associated processes, was identified in the infundibular nucleus which is located in the mediobasal tuber cinereum. This pathology was noted in 20 males (64.5%), but did not occur in the female group. No statistically significant correlation was noted between the degree of sex-dependent pathology and the presence of AD-related cortical pathology. In particular, the expression of the sex-dependent changes did not differ between males with AD stage I and males with AD stage V. In summary, the existence of a sex-dependent variant of neurofibrillary pathology was confirmed. In addition, our findings strongly suggest that the sex-dependent changes develop independently of the neurofibrillary changes associated with senile dementia of the Alzheimer type. Instead, the sex-dependent hypothalamic pathology probably corresponds to a distinct neurodegenerative entity preferentially affecting elderly males.