Androgen receptor gene and sex-specific Alzheimer's disease

Abstract

Women are at a twofold risk of developing late onset Alzheimer’s disease (LOAD) (onset ≥65 years of age) compared to men. During perimenopausal years, women undergo hormonal changes that are accompanied by metabolic, cardiovascular and inflammatory changes. These all together have been suggested as risk factors for LOAD. However, not all perimenopausal women develop AD; we hypothesize that certain genetic factors might underlie the increased susceptibility for developing AD in postmenopausal women. We investigated the androgen receptor (AR) gene in a clinical cohort of male and female AD patients and normal controls by sequencing all coding exons and evaluating the length and distribution of the CAG repeat in exon 1. We could not establish a correlation between the repeat length, gender and the disease status, nor did we identify possible pathogenic variants. AR is located on the X chromosome; in order to assess its role in AD, X-inactivation patterns will need to be studied to directly correlate the actual expressed repeat length to a possible sex specific phenotypic effect.

Sex-specific patterns and differences in dementia and Alzheimer’s disease using informatics approaches

“…Several models for AD and dementia have investigated the impact of sex along with a variety of other factors (Bateman et al, 2012; Ferrari et al, 2013; Petersen, 2010; Spies et al, 2013). Consistent with prior studies, our regression analysis found several factors associated with higher odds of documented probable AD including increasing age, positive family history, abnormal MMSE, and positive APOE ε4 results (“2013 Alzheimer’s disease facts and figures,” 2013; Ballard et al, 2011; Bateman et al, 2012; Beydoun et al, 2013).…”

Estrogen: A master regulator of bioenergetic systems in the brain and body

“…After menopause, estradiol levels no longer fluctuate as they did during perimenopause; instead, the ovaries gradually produce declining levels of estradiol and estrone becomes the predominant circulating estrogen (Nejat and Chervenak, 2010). The dysregulation of ovarian hormone secretion characteristic of the menopausal transition is in contrast to the male andropause, in which testosterone levels decrease steadily over a number of years (Ferrari et al, 2013). …”

When Mars Versus Venus is Not a Cliché: Gender Differences in the Neurobiology of Alzheimer’s Disease

“…Significantly, the AD brain demonstrates a twofold increase of X-chromosome aneuploidy rates in neural cells of the hippocampus and cerebrum, which are the brain areas most affected by neurodegeneration ( 18 ). At the epigenetic level, X-inactivation patterns affecting both coding and non-coding regions may cause a female individual to face both a large gene dosage and sex-specific effects ( 19 ), which could disproportionately increase female vulnerability to AD. Mean X-chromosome expression has also shown to be associated with neuronal density ( 20 ).…”