Genetic influences on hippocampal volume differ as a function of testosterone level in middle-aged men
Highlights
► The brain is highly responsive to androgens such as testosterone. ► In men, the hippocampus is vulnerable to age-related changes in testosterone. ► We found no significant correlation between testosterone and hippocampal volume. ► The heritability of hippocampal volume increases as a function of testosterone. ► Testosterone level is likely a valuable biomarker for brain aging in men.
Introduction
As early as the fourth decade of life, testosterone levels in men begin to decline at a steady rate (Feldman et al., 2002, Ferrini and Barrett-Connor, 1998, Harman et al., 2001, Muller et al., 2003). This decline is especially pronounced for bioavailable or free testosterone, which is not bound to the sex hormone binding globulin and therefore is physiologically active (Feldman et al., 2002, Ferrini and Barrett-Connor, 1998, Harman et al., 2001, Muller et al., 2003). The gradual loss of testosterone leads to functional changes in androgen responsive tissue, those areas of the body in which androgen receptors (AR) are abundant (Morley, 2001, Vermeulen, 2000). In addition to the prostate (Cunha et al., 1987), heart (Marsh et al., 1998), skin (Blauer et al., 1991), and musculoskeletal tissue (Sheffield-Moore and Urban, 2004), the brain is highly responsive to androgens such as testosterone, with the hippocampus being one of the most strongly influenced regions (Beyenburg et al., 2000, Kerr et al., 1995, Simerly et al., 1990). Indeed, the level of AR expression in the hippocampus, as measured by AR mRNA concentration, has been shown to be of the same order of magnitude as expression in the prostate (Beyenburg et al., 2000). Thus, although testosterone is frequently associated with sexually dimorphic physical characteristics, as well as behavioral traits such as aggression, the gradual decrease in the availability of testosterone for hippocampal tissue is likely a key component of the processes underlying brain aging in men (Pike et al., 2006, Veiga et al., 2004).
Animal studies have demonstrated a significant positive association between testosterone and hippocampal volume (Galea et al., 1999), as well as effects of the hormone on hippocampal neural plasticity (Harley et al., 2000, MacLusky et al., 2006), synaptic density (Leranth et al., 2003, Parducz et al., 2006), and neurogenesis (Galea, 2008, Galea et al., 2006). In humans, testosterone level has been found to correlate positively with hippocampal volume during adolescence (Neufang et al., 2009). On a more global scale, levels of bioavailable testosterone from midlife (roughly age 60) have been shown to predict total cranial volume as well as frontal and parietal lobe volumes 10 to 16 years later (Lessov-Schlaggar et al., 2005). We are aware of no studies in adult humans that have established a direct relationship between testosterone and hippocampal volume; however, higher testosterone levels have been linked to increased regional cerebral blood flow within the human hippocampus (Moffat and Resnick, 2007). While there has been minimal investigation of the relationship between testosterone and the hippocampus in humans, numerous studies have found a positive correlation between testosterone and hippocampally-mediated cognitive processes (e.g., episodic memory and visual–spatial ability) in middle-aged and older adults (Barrett-Connor et al., 1999, Martin et al., 2008, Matousek and Sherwin, 2010, Yaffe et al., 2002).
In addition to associations with the hippocampus and cognition, low testosterone levels have been shown to be predictive of Alzheimer's disease (AD) in men (Hogervorst et al., 2004, Moffat et al., 2004), as well as amnestic mild cognitive impairment (Chu et al., 2008). Evidence indicates that testosterone regulates the accumulation of β-amyloid in the brain, potentially abating the neuropathology underlying AD (Gouras et al., 2000, Rosario et al., 2006). Interactions between testosterone and the apolipoprotein-E (APOE) ε4 allele have also been observed for measures of cognitive functioning and hippocampal volume (Raber, 2008, Panizzon et al., 2010), as well as for the risk of AD itself (Hogervorst et al., 2002). Findings such as these have promoted the hypothesis that androgens like testosterone are neuro-protective, sparking interest into hormone replacement as a possible therapeutic intervention (Hammond et al., 2001, Pike et al., 2009, Veiga et al., 2004). It should be noted, however, that the actual risks and benefits of such hormone replacement treatment remain largely undetermined.
The aim of the present study was to elucidate the nature of the relationship between testosterone and hippocampal volume in adult men. Using data from a cohort of middle-aged male twins we examined two potential mechanisms. First, given that multiple animal studies have shown a relationship between testosterone and structural aspects of the hippocampus (Galea et al., 1999, Galea et al., 2006, Leranth et al., 2003, MacLusky et al., 2006), as well as some evidence for a direct relationship in humans (Moffat and Resnick, 2007, Neufang et al., 2009), we examined whether testosterone level and hippocampal volume were significantly correlated with one another, and the extent to which any observed correlation was driven by shared genetic or environmental factors. Second, we tested whether testosterone modifies the degree to which hippocampal volume is influenced by genetic and environmental factors. In any type of tissue, testosterone primarily exerts its influence by binding with the AR (Li and Al-Azzawi, 2009). As a transcriptional activator the AR modulates the expression of numerous downstream genes by regulating the conversion (i.e., transcription) of DNA into RNA (Dalton and Gao, 2010, Li and Al-Azzawi, 2009). Thus, the function of the AR provides a mechanism by which testosterone may alter the degree to which a phenotype like hippocampal volume is influenced by genetic factors. Along these lines, a number of studies have to date shown that testosterone can alter the expression of specific genes within the hippocampus and other brain regions (Chowen-Breed et al., 1989, Kerr et al., 1996, Tirassa et al., 1997, Zhang et al., 1999). We therefore tested whether the heritability of hippocampal volume (i.e., the proportion of variance contributed by genetic factors) would vary as a function of testosterone level. Put another way, we examined whether the level of testosterone alters the balance of latent genetic and environmental factors that contribute to individual differences in hippocampal volume.
Section snippets
Participants
Data were obtained as part of the Vietnam Era Twin Study of Aging (VETSA), a longitudinal study of cognitive and brain aging with baseline in midlife (Kremen et al., 2006). Participants in the VETSA were sampled from the Vietnam Era Twin (VET) Registry, a nationally distributed sample of male–male twin pairs who served in the United States military at some point between 1965 and 1975 (Goldberg et al., 2002). Detailed descriptions of the VET Registry's composition and method of ascertainment
Results
Prior to statistical adjustment, the average testosterone level was 98.4 pg/ml (SD = 29.3), and a small but significant correlation was observed between the hormone level and age, r = −.13 (p = .01). The unadjusted, average left and right hippocampal volumes were 3974.7 mm3 (SD = 393.7) and 4198.0 mm3 (SD = 426.1), respectively. These volumes are consistent with those reported for similarly aged samples that were collected utilizing nearly identical imaging and post-processing methods (Walhovd et al., 2011
No correlation between testosterone and hippocampal volume
In the present study, there was no evidence for either a phenotypic or genetic correlation between testosterone level and hippocampal volume. In other words, hippocampal volumes did not increase or decrease as a function of testosterone levels, and there was no evidence of shared genetic variance between the hormone and the brain structure. A small but significant unique environmental correlation was observed between testosterone level and right hippocampal volume; however, the magnitude of
Disclosure statement
Dr. Anders M. Dale is a founder and holds equity in CorTechs Laboratories, Inc., and also serves on the Scientific Advisory Board. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. All other authors state that there are no actual or potential conflicts of interest.
Acknowledgments
The VETSA project is supported by National Institutes of Health/National Institute on Aging (NIH/NIA) Grants , , , . The U.S. Department of Veterans Affairs has provided support for the development and maintenance of the Vietnam Era Twin Registry. Numerous organizations have provided invaluable assistance, including VA Cooperative Studies Program; Department of Defense; National Personnel Records Center, National Archives and Records Administration; the Internal Revenue Service; National
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2019, Frontiers in NeuroendocrinologyCitation Excerpt :In fact, these studies show that testosterone was a better predictor of hippocampal volumes than pubertal stage or age (Neufang et al., 2009; Wierenga et al., 2018; Herting et al., 2014). Circulating testosterone levels were positively related to hippocampal volumes in young adult women (Pletzer, 2019) and elderly men (Lee et al., 2017), while no association was observed in young adult men (Pletzer, 2019) (Panizzon et al., 2012). However, patients with Klinefelter syndrome (XXY caryotype), who typically show lower circulating testosterone levels, also have lower hippocampal volumes compared to controls (Skakkebaek et al., 2014).
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2016, NeuroImageCitation Excerpt :Prior estimates show that total hippocampal volume is highly heritable in both healthy adults (h2 = 0.66–0.71) (den Braber et al., 2013; van Erp et al., 2004; Wright et al., 2002) and children (h2 = 0.64–0.72) (Swagerman and Brouwer, 2014). However, structural variance within the whole hippocampus may be less heritable in elderly adults (h2 = 0.4–0.65) (DeStefano et al., 2009; Mather et al., 2015; Sullivan et al., 2001), possibly due to environmental stressors (Hedges and Woon, 2010), alterations in testosterone levels (Panizzon et al., 2012) or other endogenous biological factors. Similarly, total hippocampal volume is only moderately heritable in schizophrenia (h2 = 0.36–0.73) (Kaymaz and Os, 2009; Roalf et al., 2015).
Heritability of brain volumes in older adults: The Older Australian Twins Study
2014, Neurobiology of AgingCitation Excerpt :An increasing influence of genetic factors on hippocampal volume as a function of increasing testosterone level has also been observed previously (Panizzon et al., 2012). Although some studies have reported that same genes are influencing different human phenotypes in men and women (Vink et al., 2012), the sexual differences of genetic influences is suggested to be under the influence of a complex gene-by-hormone interaction (Menger et al., 2010; Panizzon et al., 2012). Menger et al. (2010) in a review study have shown that hormonal activations are controlled by the epigenetic mechanisms, whereas these mechanisms might themselves be under the control of hormones.
The heritability of volumes of brain structures and its relationship to age: A review of twin and family studies
2014, Ageing Research ReviewsGenetic and environmental influences of daily and intra-individual variation in testosterone levels in middle-aged men
2013, PsychoneuroendocrinologyCognitive reserve moderates the association between hippocampal volume and episodic memory in middle age
2013, NeuropsychologiaCitation Excerpt :These models controlled for the nested family data (twins within families), age, and eTIV. Both study sites used only one MRI scanner; because there was no scanner effect on hippocampal volume measures, we did not use scanner variable as a covariate in these analyses (see Panizzon et al., 2012). Because the mixed models controlled for the twin relatedness, the degrees of freedom in these models refer to number of families (twin pairs).