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AGE-RELATED TESTOSTERONE DEPLETION AND THE DEVELOPMENT OF ALZHEIMER'S
DISEASE
Pike, C.J.
Andrus Gerontology Center, University of Southern California, Los
Angeles, CA 90089 USA
Aging is the most significant risk factor for the development of
Alzheimer's disease (AD). It is unclear what age-related
changes interact to increase vulnerability to AD pathogenesis,
although several have been proposed. One normal age
change that is strongly associated with AD is the
estrogen depletion that occurs with menopause. Males
also exhibit age-related reduction in their primary
sex steroid hormone testosterone (T) and its active
metabolite dihydrotestosterone (DHT). In parallel
to postmenopausal women's increased occurrence of
disease and dysfunction in estrogen-responsive tissues,
aging men commonly exhibit a clinical syndrome of
impairment in androgen-responsive tissues called 'androgen
deficiency in aging males' or ADAM. As an androgen-responsive
tissue, the brain may also be vulnerable to normal
age-related reductions in T and DHT. We hypothesize
that if age-related androgen depletion in men is a
risk factor for the development of AD, then brain
levels of androgens should decrease as a function
of age. In fact, we observed that brain levels of
T and DHT, but not estradiol, are inversely correlated
with age in neuropathologically normal men. Further,
we would expect that men with relatively low androgen
levels would be more likely to develop AD. Consistent
with this prediction, we observed that brain levels
of T and DHT but not estradiol are lower in men with
moderate to severe AD in comparison to neuropathologically
normal men. To confirm that the low androgen levels
in AD cases is a putative contributing factor to rather
than a consequence of the disease process, we also
examined brain levels of sex steroid hormones in men
that exhibited the earliest evidence of AD-like neuropathology.
Importantly, we found significantly lower T and DHT
levels in men with mild neuropathology, suggesting
androgen depletion precedes the development of AD.
How androgen depletion may contribute to AD development
is unknown. However, our recent work has identified
two important neural functions of androgens: neuroprotection
and regulation of beta-amyloid, the protein implicated
in AD pathogenesis. In male rodents, we observed that
depletion of endogenous androgens increases the vulnerability
of the hippocampus to excitotoxic lesion and elevates
brain levels of beta-amyloid protein. Both effects
were prevented by treatment with DHT but not estradiol.
Thus, androgen depletion appears to create a more
hostile neural environment that promotes accumulation
of toxic beta-amyloid protein while leaving neurons
less able to survive the insult. Collectively, these
findings suggest that normal, age-related androgen
depletion in men acts as a risk factor not only for
disorders such as osteoporosis and sarcopenia, but
also for the development of AD. Further elucidation
of the physiological role of androgens in the aging
brain may provide innovative pharmacological targets
to combat AD.
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