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Age-Related Testosterone Depletion and the Development of Alzheimer Disease
To the Editor: Normal male aging is associated with declines in serum levels of the sex steroid hormone testosterone, which contributes to a range of disorders including osteoporosis and sarcopenia.1 Unknown is how this relationship applies to age-related disorders in the brain, an androgen-responsive tissue. We hypothesize that testosterone levels in the brain are depleted as a normal consequence of male aging and that low brain levels of testosterone increase the risk of developing Alzheimer disease (AD). Recent data suggest a correspondence between reduced serum levels of testosterone and the clinical diagnosis of AD.2-3 However, it is unclear whether testosterone depletion contributes to or results from the disease process. To investigate this issue, testosterone and estradiol levels were analyzed in postmortem brain tissue of elderly men and compared with their neuropathological diagnoses.
Methods
Brain tissue from men who had provided informed consent was collected at autopsy by repositories associated with Alzheimer's Disease Research Centers at University of Southern California; University of California, Irvine; University of California, San Diego; and Duke University. Tissue was collected between 1997 and 2003, with postmortem delay less than 8 hours (mean delay = 4.6 hours). Subjects with conditions associated with altered testosterone levels (eg, end-stage renal disease, liver disease, alcoholism, and diabetes) were excluded from the study. Included subjects satisfied 1 of the following neuropathological diagnoses: (1) neuropathologically normal (controls) (Braak stage 0-1 without evidence of other degenerative changes, and lacking a clinical history of cognitive impairment; n = 17), (2) AD (Braak stage 5-6 with neuropathological diagnosis of AD in the absence of other neuropathology; n = 19), and (3) mild neuropathological changes (Braak stage 2-3 in the absence of discrete neuropathology; n = 9). No subjects were neuropathologically diagnosed with Braak stage 4. Testosterone and estradiol levels were measured by radioimmunoassay of homogenates of brain samples from the mid-frontal gyrus following organic extraction and celite column partition chromotography.4 Hormone levels expressed as hormone weight per wet tissue weight were statistically compared using analysis of covariance with age as the covariate. This study was performed with institutional review board approval from the University of Southern California.
Results
We observed that brain levels of testosterone but not estradiol (Figure 1) were inversely correlated with age in men aged 50 to 97 years who were diagnosed as neuropathologically normal. To investigate whether this depletion of brain testosterone may be a risk factor for the development of AD, we compared hormone levels among elderly men who exhibited no neuropathology, mild neuropathological changes, or moderate to severe AD. Men in the 3 groups were of similar age, ranging from 60 to 80 years with mean (SD) ages of 70.9 (5.3), 72.9 (5.7), and 72.0 (6.5) years, respectively, using analysis of variance (F = 0.002, P = .97). We found that brain levels of testosterone but not estradiol (Figure 2) are significantly lower in AD subjects compared with the control subjects. We found that brain levels of testosterone are also significantly reduced in men with mild neuropathology consistent with early stage AD (Figure 2).
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Figure 1. Brain Levels of Testosterone and Estradiol in Elderly Men
The estradiol comparison shows only 16 data markers as there are 2 subjects aged 70 years with the same estradiol value (0.06 ng).
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Figure 2. Brain Levels of Testosterone and Estradiol in Men, by Neuropathological Diagnosis
Left, Testosterone levels in age-matched control subjects (controls), subjects with mild neurological changes (MNC), and subjects with Alzheimer disease (AD). Right, Estradiol levels in age-matched controls, subjects with MNC, and subjects with AD. For testosterone levels, P<.05 is the comparison of age-matched controls vs subjects with MNC and of age-matched controls vs subjects with AD by t test following analysis of covariance with age as a covariate. Error bars indicate SEM.
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Comment
Brain levels of testosterone significantly decrease with age in men who lack any evidence of neuropathology, suggesting that neural androgen depletion is a normal consequence of aging. In comparison with the control subjects, men with AD exhibit significantly lower testosterone levels in the brain. In contrast, the data suggest that estrogen levels in the male brain are affected by neither advancing age nor AD diagnosis. Notably, testosterone depletion likely precedes and thus may contribute to rather than result from the development of AD, since low brain testosterone is observed in men with early indications of AD neuropathology. Although it remains possible that low testosterone may reflect an unmeasured correlate of AD rather than be a contributing factor, we controlled for established causes of low testosterone by our exclusion criteria and statistical adjustment. How testosterone depletion may contribute to AD development is unknown. However, we have recently reported that androgen depletion in male rodents increases brain levels of  -amyloid,5 the protein implicated as a causal factor in AD pathogenesis, and decreases neuronal survival upon exposure to toxic insult.6 Collectively, these findings suggest that normal, age-related testosterone depletion in the male brain may impair beneficial neural actions of androgens and thereby act as a risk factor for the development of AD.
Funding/Support: This study was supported by a grant from the National Institute on Aging (AG14751 to Dr Pike). Tissue was obtained from the Alzheimer's Disease Research Centers at the University of Southern California AG05142, University of California Irvine AG16573, University of California San Diego AG05131, and Duke University AG05128.
Emily R. Rosario, MS
Neuroscience Graduate Program
Lilly Chang, MD;
Frank Z. Stanczyk, PhD
Department of Obstetrics and Gynecology
Keck School of Medicine
Christian J. Pike, PhD
cjpike{at}usc.edu
Andrus Gerontology Center
University of Southern California
Los Angeles
1. Morley JE. Androgens and aging. Maturitas. 2001;38:61-73.
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2. Hogervorst E, Lehmann DJ, Warden DR, McBroom J, Smith AD. Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer's disease in men. Int J Geriatr Psychiatry. 2002;17:938-940.
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3. Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD. Serum total testosterone is lower in men with Alzheimer's disease. Neuroendocrinol Lett. 2001;22:163-168.
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4. Goebelsmann U, Bernstein GS, Gale JA, et al. Serum gonadotropin, testosterone, estradiol, and estrone levels prior to and following bilateral vasectomy. In: Lepow IH, Crozier R, eds. Vasectomy: Immunologic and Pathophysiologic Effects in Animals and Man. New York, NY: Academic Press; 1979:165.
5. Ramsden M, Nyborg AC, Murphy MP, et al. Androgens regulate beta-amyloid levels in male rat brain. J Neurochem. 2003;87:1052-1055.
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6. Ramsden M, Shin TM, Pike CJ. Androgens modulate neuronal vulnerability to kainate lesion. Neuroscience. 2003;122:573-578.
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Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2004;292:1431-1432.
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