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Genetic Variation in the Androgen Receptor and Measures of Plasma Testosterone Levels Suggest Androgen Dysfunction in Alzheimer's Disease.

ABSTRACT: 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 A?/tau independent pathways. These effects may be most pronounced during conversion from MCI to dementia.

SUBMITTER: Carr JS

PROVIDER: S-EPMC6090298 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Genetic Variation in the Androgen Receptor and Measures of Plasma Testosterone Levels Suggest Androgen Dysfunction in Alzheimer's Disease.

Carr Jessie S JS Bonham Luke W LW Morgans Alicia K AK Ryan Charles J CJ Yokoyama Jennifer S JS Geier Ethan G EG

Frontiers in neuroscience 20180807

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. B ...[more]

PMID: 30131669

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Project description:INTRODUCTION:Recently, testosterone (T) has been shown to be associated with premature ejaculation (PE) symptoms in the literature. Furthermore, studies suggest that the etiology of PE is partly under genetic control. AIM:The aim of this study was to reassess findings suggesting an association between testosterone (T) and a key symptom of PE, ejaculation latency time (ELT), as well as exploratively investigating associations between six androgen-related genetic polymorphisms and ELT. MATERIALS AND METHODS:Statistical analyses were performed on a population-based sample of 1,429 Finnish men aged 18-45 years (M = 26.9, SD = 4.7). Genotype information was available for 1,345-1,429 of these (depending on the polymorphism), and salivary T samples were available from 384 men. Two androgen receptor gene-linked, two 5-alpha-reductase type 2-gene-linked, and two sex hormone-binding globuline gene-linked polymorphisms were genotyped. MAIN OUTCOME MEASURES:Ejaculatory function was assessed using self-reported ELT. RESULTS:We found no association between salivary T levels and ELT. We found a nominally significant association between a 5-alpha-reductase type 2-gene-linked polymorphism (rs2208532) and ELT, but this association did not remain significant after correction for multiple testing. One single nucleotide polymorphism in the sex hormone-binding globulin gene (rs1799941) moderated (significantly after correction for multiple testing) the association between salivary T and ELT, so that A:A genotype carriers had significantly lower salivary T levels as a function of increasing ELT compared with other genotype groups. CONCLUSIONS:We were unable to find support for the hypothesis suggesting an association between T levels and ELT, possibly because of the low number of phenotypically extreme cases (the sample used in the present study was population based). Our results concerning genetic associations should be interpreted with caution until replication studies have been conducted. Jern P, Westberg L, Ankarberg-Lindgren C, Johansson A, Gunst A, Sandnabba NK, and Santtila P. Associations between salivary testosterone levels, androgen-related genetic polymorphisms, and self-estimated ejaculation latency time. Sex Med 2014;2:107-114.

Project description:BackgroundLow vitality is a common symptom of testosterone deficiency; however, clinical trial results remain inconclusive regarding the responsiveness of this symptom to hormone replacement.AimThe aim of the present study was to determine if the relationship between circulating testosterone levels and vitality would be moderated by the CAG repeat length in the androgen receptor (AR) gene, which influences the receptor's sensitivity to testosterone.MethodsWe examined 676 men in the Vietnam Era Twin Study of Aging when they were, on average, 55.4 years old (SD = 2.5). Salivary testosterone levels were measured by using 3 samples collected at waking on 3 nonconsecutive days. The average testosterone level was classified as low, normal, or high based on 1-SD cutoffs. Analyses were conducted using multilevel, mixed linear models, which accounted for the nonindependence of the twin data, and adjusted for the effects of age, ethnicity, BMI, chronic health conditions, depressive symptoms, and sleep quality.OutcomesVitality was measured using the 36-item Short Form (SF-36) vitality subscale.ResultsWe observed a significant interaction between salivary testosterone and the AR-CAG repeat length. When the repeat length was short, men with low testosterone had significantly lower vitality. As the AR-CAG repeat length increased, the magnitude of the testosterone effect decreased.Clinical translationThe observed interaction between testosterone and variation in the AR gene suggests that men with more sensitive ARs, as indicated by a shorter AR-CAG repeat, are more likely to experience symptoms of age-related testosterone deficiency.Strengths & limitationsStrengths of the present study include our use of a large community-based sample, the use of multiple testosterone measurements, and the availability of a comprehensive set of covariates that may impact the association of interest. Limitations include the homogeneous nature of the sample with respect to ethnicity, the brevity of the 36-item Short Form vitality subscale, and our inability to establish change in testosterone levels because of the cross-sectional nature of data.ConclusionsThe association between testosterone and vitality appears to be clinically meaningful and is in part dependent on variation in the AR gene. Panizzon MS, Bree K, Hsieh T-C, et al. Genetic Variation in the Androgen Receptor Modifies the Association Between Testosterone and Vitality in Middle-Aged Men. J Sex Med 2020;17:2351-2361.

Project description:BackgroundPlasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer's disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are also known to be present in a majority of Alzheimer or mild cognitive impaired (MCI) subjects with raised β-amyloid load on their positron emission tomography (PET) imaging. It is now considered that the earliest phase of inflammation may be protective to the brain, removing amyloid plaques and remodelling synapses. Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker 11C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects.MethodsTwenty-seven MCI or early AD cases with raised cortical β-amyloid load had 11C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Correlation analyses were performed using surface-based cortical statistics.ResultsStatistical maps localised areas in MCI cases where levels of brain inflammation correlated inversely with plasma NfL levels. These areas were localised in the frontal, parietal, precuneus, occipital, and sensorimotor cortices. Brain inflammation correlated negatively with mean diffusivity (MD) of water with regions overlapping.ConclusionWe conclude that an inverse correlation between levels of inflammation in cortical areas and plasma NfL levels indicates that microglial activation may initially be protective to axons in AD. This is supported by the finding of an inverse association between cortical water diffusivity and microglial activation in the same regions. Our findings suggest a rationale for stimulating microglial activity in early and prodromal Alzheimer cases-possibly using immunotherapy. Plasma NfL levels could be used as a measure of the protective efficacy of immune stimulation and for monitoring efficacy of putative neuroprotective agents.

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Genetic Variation in the Androgen Receptor and Measures of Plasma Testosterone Levels Suggest Androgen Dysfunction in Alzheimer's Disease.

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Genetic Variation in the Androgen Receptor and Measures of Plasma Testosterone Levels Suggest Androgen Dysfunction in Alzheimer's Disease.

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