Androgen receptor CAG repeat length as a moderator of the relationship between free testosterone levels and cognition

https://doi.org/10.1016/j.yhbeh.2021.104966Get rights and content

Highlights

  • Differences in CAG repeat length moderate the relationship between baseline FT, change in FT and cognition in older men.

  • Low and decreasing FT levels are a risk factor for poorer attention and processing speed

  • Shorter CAG repeats exacerbate detrimental effects of low and decreasing FT levels on attention and processing speed

  • Individual differences in CAG repeats is an important consideration for future research in testosterone and cognition.

Abstract

Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition.

Introduction

Progressive, age-related decrease in testosterone levels has been implicated as a potential risk factor for neuropathological cognitive decline in older men (Lv et al., 2016; Pike, 2006; Rosario et al., 2004). However, findings from observational studies and clinical trials alike have been inconsistent, suggesting that the relationship between testosterone and cognition is complex and requires further exploration (Boss et al., 2014; Holland et al., 2011). The relationship between testosterone and cognition can further be elucidated by examining the role of genetic variability in the androgen receptor (AR) gene in the relationship between endogenous calculated free testosterone (cFT) levels and cognitive performance.

A gradual decrease in testosterone levels is a normal consequence of ageing in men and testosterone levels may decrease by up to 50% by the time a male reaches the age of 80. In particular, free testosterone (testosterone that is not bound to sex hormone binding globulin and albumin) decreases at a higher rate, compared to total testosterone levels, and is proposed to be a more accurate measure of androgen status in the brain (Pike, 2006; Yeap et al., 2008). Androgens have a range of neuroprotective properties, such as maintaining neuronal viability and encouraging regeneration (see Pike, 2006 for review). The hippocampus and frontal lobes have a high concentration of androgen receptors, and decrease in androgenic activity as a result of decreasing testosterone levels, may increase susceptibility to degeneration and pathology (Janowsky, 2006). In turn, this plausibly impacts cognitive processes associated with the hippocampus and frontal lobes, such as memory and executive functioning, respectively. Androgens are also posited to have vital roles in the regulation and clearance of Aβ-amyloid (Aβ) protein, one of the pathological hallmarks of Alzheimer's disease (AD) (Braak and Braak, 1991; Pike et al., 2009).

Research has examined the association between endogenous testosterone levels and cognitive performance across both cognitively normal populations and those diagnosed with AD. Compared to controls, individuals in the preclinical and clinical stages of AD were found to have lower testosterone levels (Hogervorst et al., 2001; Moffat et al., 2004; Verdile et al., 2014a). Low plasma testosterone levels have also been associated with an increased risk of AD in older men (Lv et al., 2016). Cross-sectional studies report an association between lower testosterone levels and poorer performance on some cognitive domains but not others (see Holland et al. (2011) for review). Lower levels of testosterone have been associated with poorer performance on tasks assessing verbal memory, visuospatial memory and attention, but not in executive function or verbal fluency. Longitudinal studies examining the relationship between testosterone levels and cognition in cognitively normal healthy older males, indicate that a greater decline in free testosterone levels is associated with increased dementia risk, suggesting that decreasing free testosterone levels is a risk factor for cognitive impairment (Carcaillon et al., 2014; Ford et al., 2018; Hogervorst et al., 2004; Hsu et al., 2015).Collectively, these findings suggest that low testosterone levels are a risk factor for cognitive decline in older men and can have differential effects on cognitive domains.

Findings from clinical trials examining the efficacy of testosterone supplementation on cognition have also returned a similar pattern of results. In some studies, testosterone supplementation appears to improve performance on tasks of global cognition, spatial and verbal memory, while it appears to confer no cognitive benefit in other domains (Gray et al., 2005; Haren et al., 2005; Resnick et al., 2017; Wahjoepramono et al., 2015).

While animal and cell culture studies have provided evidence for the neuroprotective properties of testosterone, findings in human studies have been inconsistent and there is consensus that more research is needed to understand the relationship between testosterone and cognition. Beyond heterogeneous methodology between studies, null findings could be attributed to other factors that can impact the relationship between testosterone and cognition but have yet to be accounted for. For example, Holland et al. (2011) proposed that the modifying role of genetic factors should be considered in the relationship between testosterone and cognition: specifically, a polyglutamine (CAG) repeat site in the X-linked AR gene (Holland et al., 2011). Testosterone exerts its effects via the AR that directly regulates gene transcription. The polymorphic CAG repeat, residing in exon 1 of the AR gene, modulates the first step of AR gene expression, allowing it to interact with specific androgen responsive elements and initiate transcription of target genes (Casella et al., 2001). As such, the length of AR CAG repeats could impact cognitive functioning by influencing androgen action across different brain regions.

CAG repeat lengths in ‘healthy’ individuals vary from 7 to 38, while pathological expansions have been associated with several conditions including spinal-bulbar muscular atrophy (SBMA) and Kennedy's disease (Casella et al., 2001). AR gene CAG repeat lengths within the normal range have been examined in the context of male infertility, prostate cancer risk, symptoms of depression, and reactivity to threat (Van Golde et al., 2002; Van Pottelbergh et al., 2001; Zitzmann et al., 2001). However, research on the impact of CAG repeat length on cognition is limited and the results are inconsistent. Yaffe et al. (2003) found that older males with CAG base pairs in the highest tertile had poorer test scores on measures of general cognition, cognitive flexibility and psychomotor speed. By contrast, Lee et al. (2010) reported no significant interactions between CAG repeat length, total testosterone or free testosterone levels and a composite of vision-based cognitive measures after age, education, depression and other health factors were controlled for. The above study by Lee et al. (2010) was the first to examine the interactions between AR CAG repeat lengths, testosterone levels and cognition. However, it is limited in its cross-sectional design and reliance on only visually-based measures of cognition. Therefore, more studies are needed to elucidate this relationship, across a broader range of cognitive domains using visual and auditory testing modalities.

Collectively, current literature suggests that low testosterone levels, as well as testosterone levels that are decreasing over time, are risk factors for cognitive decline. These relationships may be further altered by a modification of AR activity due to individual variations in CAG repeat length. The differential effects that testosterone has on different cognitive domains, suggest that the interaction between CAG repeat length and testosterone may differ across individual cognitive domains. The primary aim of this study is to evaluate whether AR CAG repeat length moderates the relationship between baseline cFT levels, change in cFT levels and individual cognitive domains, over and above other established risk factors of cognitive decline such as age, cognitive reserve and genetic risk for AD, i.e., apolipoprotein E (APOE) ɛ4 carriage.

Given that the literature on the effects of AR CAG repeat length on cognitive function is limited and inconsistent, we adopted an exploratory approach. Specifically, we wanted to explore if longer or shorter CAG repeat lengths altered the relationship between low, decreasing testosterone levels and performance in individual cognitive domains.

The following hypotheses were proposed:

  • 1)

    Lower baseline cFT levels will be associated with poorer performance at 18-months across individual cognitive domains (recall memory, language, executive function, attention and processing speed) after controlling for age, cognitive reserve, baseline cognitive performance and genetic risk for AD.

  • 2)

    A decrease in cFT levels at 18- month follow up, that is greater than expected, will be associated with poorer 18-months follow-up performance across individual cognitive domains after controlling for age, cognitive reserve, baseline cognitive performance and genetic risk for AD.

  • 3)

    Lower cFT levels at baseline that are also lower than expected at 18-month follow-up will be associated with poorer performance at 18-months across individual cognitive domains after controlling for age, cognitive reserve, baseline cognitive performance and genetic risk for AD.

  • 4)

    CAG repeat lengths will influence the relationship between low baseline cFT levels, change in cFT levels and performance at 18-months across individual cognitive domains after controlling for age, cognitive reserve, baseline cognitive performance and genetic risk for AD.

The proposed model of these relationships is illustrated in Fig. 1.

Section snippets

Sample

This study utilised data collected from a subset of participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. AIBL is a prospective, longitudinal study of ageing, launched in 2006, recruiting individuals above the age of 60 at baseline and repeating assessments at 18-month intervals. Participants were cognitively normal older adults, AD patients, and those with mild cognitive impairment (MCI), residing in either Perth or Melbourne. A full description of the cohort

Sample characteristics

Laboratory and cognitive assessment data were obtained for all participants at baseline. Cognitive data were not available for some participants at follow-up, as illustrated in Fig. 2.

Descriptive statistics for key variables at baseline and at 18-month follow up are summarised in Table 1. Data from 304 male participants were included in this study and the mean age of the sample was 71 years. CAG repeat lengths in this sample ranged from 10 to 27 repeats, with a mean and median repeat length of

Discussion

This study aimed to examine the relationship between baseline cFT levels, ∆cFT and AR CAG repeat length on individual cognitive domains in a community-based sample of cognitively normal older men. Specifically, we were interested to explore if individual variations in CAG repeat length moderated the relationship between baseline cFT, change incFT levels and cognition. We also hypothesized that lower cFT levels at baseline, unusual levels of change in cFT levels by 18-month follow-up (i.e.

Conclusions

The current study suggests that individual variations in AR gene CAG repeat length may modify the relationship between testosterone and cognition in a cognitively normal older male sample, and that these findings warrant consideration in the design of future research, or in the retrospective analysis of collected data. The current study will benefit from replication in a larger sample to validate the current findings. More research is also needed to further elucidate the mechanisms involved in

Declaration of competing interest

ST's PhD has been supported by the Australian Alzheimer's Research Foundation and the University of Western Australia. HRS has received remunerations for previous activities with Pfizer and Takeda Pharmaceuticals and his research is supported partially by the Australian Alzheimer's Research Foundation. SML is on the Scientific Advisory Panel for Cytox Ltd. and has received research support from the Australian Alzheimer's Research Foundation. RNM is the Founder and owns stock in Alzhyme Ltd. All

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      However, a study by Lehmann and colleagues [43] suggested that men with short (≤20 repeats) rather than long CAG repeat lengths were more likely to have Alzheimer's disease (AD), whereas no association between CAG repeat length and AD was observed in a different cohort of older male and female adults [21]. Recently, it has been proposed that CAG repeat length interacts with testosterone levels, such that a short repeat length exacerbates negative effects of persistent low FT levels on attention and processing speed [69]. As such, effects of low androgenic levels over time may vary across individuals with short compared to long repeat lengths.

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    For a full list of the AIBL research group see www.aibl.csiro.au.

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