Why do twice as many women as men get Alzheimer’s disease (AD)?

Some explain this asymmetrical epidemiology on the grounds that women live longer than men, so attain the age of dementia more often than men do. A refinement of the theory attributes AD to a post-menopausal decline in estrogen, a hormone thought to protect against the disease.

“I believe women are at greater risk,” observed neuropathologist Sozos Papasozomenos at the University of Texas in Houston, “because they have less testosterone than men do. You can say there are fewer men with AD because they make more of the hormone, or because their testosterone declines very gradually.”

He reached this hypothesis by experiments with male and female laboratory rats, as reported in the current online early edition of the Proceedings of the National Academy of Sciences (PNAS), released Jan. 22, 2002. The paper, of which Papasozomenos is senior author, bears the title: “Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3b . . . and concomitantly abolishes hyperphosphorylation of t: Implications for Alzheimer’s disease.”

“Here we report our finding,” he told BioWorld Today, “of why in some way male rats are protected against phosphorylation [addition of phosphate to an organic compound] because of their testosterone. This hormone inhibits the enzyme the kinase that phosphorylates the tau protein, which is found in the fibrillary tangles of AD brains. For me, the exciting thing in this PNAS paper,” Papasozomenos continued, “is that we were able to pin down the glygogen synthase kinase 3-beta [GSK] as the responsible enzyme of which testosterone blocks the over-activation. Earlier we found out in the heat-shock model we developed that testosterone, not estrogen, prevents hyperphosphorylation of tau.

“Male individuals predisposed to AD are at risk if they have a high family history of the disease,” he pointed out. “When they become old, perhaps their testosterone gives out. But our finding was from a rat model, so [it] needs clinical confirmation. I think this is going to be important, not only for Alzheimer’s but also for heart disease, diabetes, cancer and so on. Because the glycogen synthase kinase 3-beta is a multifunctional enzyme, it plays a role in diabetes and cancer, so physicians who treat such patients should pay attention to this paper. The body-builders and athletes,” he pointed out, “take testosterone because it has the ability to speed up the body, thanks perhaps to that inhibiting GSK kinase.”

Stressed-Out Rats Yield Unexpected Answers

Over more than a decade of research, Papasozomenos formed the hypothesis that, “AD probably involves environmental stress factors. Something in it stresses the neurons, which try to defend themselves. So to test this hypothesis, I tried to find an in vivo model of stress. The classical paradigm in stressing an animal is the heat-shock model. So I started heat-stressing the rats. I didn’t know what I was supposed to get. I didn’t expect to find a difference between male and female rats.

“I worked first with female rats, and saw this tau phosphorylation. When I tried to do it in male rats, I couldn’t see the reaction, or it was very weak. That’s why I got into this gender dichotomy.

“In the hospital’s pediatric/maternity unit,” he said, “I came across a cast-off incubator for premature Infants. Babies born pre-term are put in them to keep warm. So I put the rats in there, sedated them mildly and watched the temperature go up to 42 degrees Centigrade about 107 degrees Fahrenheit. Then, after 15 minutes, I took the animals out. They recovered in two or three hours and started being active again. But during that time I sacrificed them. Three to six hours after heat shock, I observed the hyperphosphorylation of tau. By 12 hours the tau returned to normal, so the test rats looked like the unaffected controls.

“When I started at the beginning,” Papasozomenos went on, “I didn’t know what heat-shock would do to tau. When I saw this phosphorylation, it was very similar to what we find in the brains of AD patients. So we were able to reproduce tau phosphorylation in our animal model, as a close correlative to the human disease.” Those rodent AD-modelling brains revealed the neuronal hallmark of the disease neurofibrillary tangles.

“In AD,” the neuropathologist explained, “these tangles are bundles of abnormal tau filaments. They are the polymerized form of the tau protein, which forms the bundles inside the neurons. Each tangle is highly phosphorylated. It has too many phosphates on it. We think that the high phosphorylation of tau is the key abnormality that leads to the abnormal paired helical filaments.

“If you analyze the postmortem brains of patients who died with AD, what correlates best with the degree of dementia is the number of neurofibrillary tangles. Many times, the associated senile amyloid plaques around the neurons don’t correlate with dementia. Knowing that tau is all the time hyperphosphorylated in tangles leads to a key biochemical abnormality.”

Are Clinical Testosterone Trials On The Horizon?

“So we are now able, in this rat model, which is very reproducible and simple, to produce at least the hyperphosphorylation. Formation of tangles is a cumulative process that takes many years to develop because they need a susceptible human host. Rats, given their short lifespan compared to people, don’t generate so many tangles. But what we see in human brains is the hyperphosphorylated form of tau, which we are able to model in these rats in just six hours.”

Papasozomenos hopes that the NIH or the Alzheimer’s Association will underwrite his ongoing efforts “to define the molecular mechanism by which testosterone inhibits its kinase. I think what we have so far is the strong basic science evidence that could serve to initiate clinical studies of testosterone replacement in people at risk both men and women. Physicians who treat patients gerontologists, neurologists or psychiatrists should design a clinical-trial protocol. This should not start from the general population, but test individuals with a strong family history of AD.

“The biotech community,” Papasozomenos concluded, “should lobby NIH or the Alzheimer’s Association to start clinical trials of testosterone, which has been neglected for too many years.”