Alzheimer's disease (AD) prevalence varies by sex, suggesting that sex chromosomes,
sex hormones and/or their signaling could potentially modulate AD risk and progression. Low
testosterone levels are reported in men with AD. Further, variation in the
androgen receptor (AR) gene has been associated with AD risk and
cognitive impairment. We assessed measures of plasma
testosterone levels as a
biomarker of AD in male participants from the
Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Baseline
testosterone levels were significantly different between clinical diagnosis groups [cognitively normal controls,
mild cognitive impairment (MCI), or AD], with the lowest
testosterone levels in men with AD. Lower baseline
testosterone levels were associated with higher baseline clinical severity. Change in
testosterone levels between baseline and 1-year follow-up varied by diagnosis; MCI had the greatest decreases in
testosterone levels between baseline and 1-year follow-up. Despite differences by clinical diagnosis, there was no association between plasma
testosterone and CSF
biomarkers of AD pathology. We also tested single nucleotide polymorphisms (SNPs) in AR for association with AD risk in a separate cohort from ADNI and found 26 SNPs associated with risk for AD. The top associated SNP is predicted to be an expression quantitative trait locus for AR in multiple tissues, including brain, with the AD-associated risk allele predicted to confer lower AR expression. Our findings suggest a link between the
androgen pathway and AD through Aβ/tau independent pathways. These effects may be most pronounced during conversion from MCI to
dementia.