Elsevier

Experimental Gerontology

Volume 39, Issues 11–12, November–December 2004, Pages 1633-1639
Experimental Gerontology

Low free testosterone is an independent risk factor for Alzheimer's disease

https://doi.org/10.1016/j.exger.2004.06.019Get rights and content

Abstract

The purpose of this study was to assess pituitary gonadotropins and free testosterone levels in a larger cohort of men with Alzheimer's disease (AD, n=112) and age-matched controls (n=98) from the Oxford Project to Investigate Memory and Ageing (OPTIMA). We measured gonadotropins (follicle stimulating hormone, FSH, and luteinizing hormone, LH), sex hormone binding globulin (SHBG, which determines the amount of free testosterone) and total testosterone (TT) using enzyme immunoassays.

AD cases had significantly higher LH and FSH and lower free testosterone levels. LH, FSH and SHBG all increased with age, while free testosterone decreased. Low free testosterone was an independent predictor for AD. Its variance was overall explained by high SHBG, low TT, high LH, an older age and low body mass index (BMI). In controls, low thyroid stimulating hormone levels were also associated with low free testosterone. Elderly AD cases had raised levels of gonadotropins. This response may be an attempt to normalize low free testosterone levels. In non-demented participants, subclinical hyperthyroid disease (a risk factor for AD) which can result in higher SHBG levels, was associated with low free testosterone. Lowering SHBG and/or screening for subclinical thyroid disease may prevent cognitive decline and/or wasting in men at risk for AD.

Introduction

Several recent studies have reported that low bio-available or free testosterone is associated with cognitive decline (Moffat et al., 2002, Yaffe et al., 2002) and Alzheimer's disease (AD) in men (Hogervorst et al., 2003, Moffat et al., 2004, Paoletti et al., 2004) and women (Paoletti et al., 2004). The fact that most studies reported low free (FT) but not total testosterone (TT) as a risk factor suggests that increased levels of sex hormone binding globulin (SHBG, which binds testosterone thus reducing bio-available levels) may play an important role in AD. SHBG is raised with age, in wasting syndrome, thyroid and liver dysfunction (Kaufman and Vermeulen, 1998) but it is unclear why it would be higher in cases with AD. Previous studies also did not determine whether the lower levels of testosterone had a primary (testicular) or secondary (hypothalamic-pituitary) origin. The gonadotropins—follicle-stimulating hormone (FSH) and luteinizing hormone (LH) produced by the pituitary gland—normally regulate sex steroid hormone production. While higher levels of gonadotropins in men with AD were reported (Bowen et al., 2000), this was no longer the case in another cohort when the analyses were adjusted for age (Short et al., 2001). No overall difference was found in our earlier cross-sectional study, but older (>73 years of age) AD cases did seem to have higher gonadotropin levels than older controls (Hogervorst et al., 2003). In the present study we increased the number of AD cases included (from n=45 to n=112) and did repeated measures to investigate why SHBG was raised in cases and how this related to gonadotropin levels in men with and without AD. As markers for thyroid function we included TSH and T4, as an indication of liver dysfunction we included albumin and alcohol abuse and as a marker of wasting syndrome we included body mass index (BMI) and creatinine. We controlled for diabetes mellitus as insulin has been known to affect free testosterone levels (Kaufman and Vermeulen, 1998).

Section snippets

Subjects

The Oxford Project To Investigate Memory and Ageing (OPTIMA) started in 1988 and has since included over 600 subjects. For the present study, serum samples of n=210 male participants over the age of 46 years were available. AD cases (n=112) and age-matched controls (n=98) had been followed up yearly with a full assessment, which included a physical examination (including weight and height measurements from which BMI was derived), blood tests, a detailed history corroborated by a close relative

Results

Mann–Whitney analyses showed that cases overall had significantly higher log FSH and slightly higher creatinine levels than controls. Trend differences (P<0.10) were seen for higher log LH and lower FAI, TT and TSH in the AD cases (Table 1).

There was no overall difference in age between AD cases and controls (average age 73.8 SD=9.2, P=0.73). GLM analyses including age showed that AD cases had significantly higher levels of log FSH [F(1,206)=4.65, P=0.03] and lower levels of FAI [F(1,921

Discussion

In cross sectional analyses, we found that elderly AD cases had higher levels of FSH than controls, but this was not apparent in the younger cases. For LH there were trends in a similar direction. Although FSH does not affect testosterone production directly, it has strong associations with LH levels. FSH is a more robust measure, has a longer half life and shows less circadian fluctuations than LH and could therefore be expected to be less sensitive to different types of confounds (slight

Acknowledgements

We would like to thank T. James and M. Gales at the Clinical Biochemistry Department of the John Radcliffe Infirmary for the testosterone, LH, FSH and SHBG assays. Richard Bowen made very helpful suggestions after reading a first draft of the paper. We would also like to thank the members and participants of OPTIMA for making this study possible. This work was supported by grants from Research Into Ageing/Help the Aged, Voyager Pharmaceutical, The Alzheimer's Association (NIRG 00-2258), the

References (23)

  • E. Hogervorst et al.

    Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer's disease in men

    Int. J. Geriatr. Psychiatr.

    (2002)
  • Cited by (0)

    View full text