Estrogen and other
sex hormones have received a great deal of attention for their speculative role in
Alzheimer's disease (AD), but at present a direct connection between
estrogen and the pathogenesis of AD remains elusive and somewhat contradictory. For example, on one hand there is a large body of evidence suggesting that
estrogen is neuroprotective and improves cognition, and that
hormone replacement therapy (HRT) at the onset of menopause reduces the risk of developing AD decades later. However, on the other hand, studies such as the Women's Health Initiative demonstrate that HRT initiated in elderly women increases the risk of
dementia. While
estrogen continues to be investigated, the disparity of findings involving HRT has led many researchers to examine other
hormones of the hypothalamic-pituitary-gonadal axis such as luteinising
hormone (LH) and
follicle-stimulating hormone. In this review, we propose that LH, rather than
estrogen, is the paramount player in the pathogenesis of AD. Notably, both men and women experience a 3- to 4-fold increase in LH with aging, and
LH receptors are found throughout the brain following a regional pattern remarkably similar to those neuron populations affected in AD. With respect to disease, serum LH level is increased in women with AD relative to non-diseased controls, and levels of LH in the brain are also elevated in AD. Mechanistically, we propose that elevated levels of LH may be a fundamental instigator responsible for the aberrant reactivation of the cell cycle that is seen in AD. Based on these aforementioned aspects, clinical trials underway with
leuprolide acetate, a
gonadotropin-releasing hormone agonist that ablates serum LH levels, hold great promise as a ready means of treatment in individuals afflicted with AD.