Low bioavailable testosterone linked to Alzheimer’s disease

January 07, 2011

     “Having low testosterone may make you more vulnerable to Alzheimer’s disease” states John E Morley, director of the division of geriatric medicine at Saint Louis University and coauthor of a study showing that low levels of the male sex hormone testosterone, in older men is associated with Alzheimer’s disease. He says “The take-home message is we should pay more attention to low testosterone, particularly in people who have memory problems or other signs of cognitive impairment.”

     Researchers studied 153 Chinese men who were at least 55 years of age, lived in the community and were free of dementia. Of those men, 47 had mild cognitive impairment – or memory loss with problems with clear thinking. Within the year 10 of these men developed probable Alzheimer’s disease. A low level of bioavailable testosterone independently increased the risk of developing Alzheimer’s disease, and so did high blood pressure, and elevated levels of the ApoE 4 protein (apolipoprotein E). Dr Morley states “It’s a very exciting study because we’ve shown that a low level of testosterone is one of the risk factors for Alzheimer’s disease.”

Background information:

    The APOE epsilon4 allele is an established risk factor for Alzheimer disease (AD), yet findings are mixed for how early its effects are manifest. The E4 variant is the largest known genetic risk factor for early-onset Alzheimer's disease (AD) in a variety of ethnic groups. For instance Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. While the exact mechanism of how E4 causes such dramatic effects remains to be fully determined, evidence has been presented suggesting an interaction with beta-amyloid protein. Alzheimer's disease is characterized by build-ups of aggregates of beta-amyloid protein. Apolipoprotein E enhances enzymatic break-down of this peptide, both within and between cells. Some isoforms of ApoE are not as efficient as others at catalyzing these reactions. In particular, the isoform ApoE-ε4 is not very effective, resulting in increased vulnerability to Alzheimer's in individuals with that gene variation.

     In a different study published in the September 2010 issue of the journal Neurology there may have been a partial explanation for this finding. 375 men from the Vietnam Era Twin Study of Aging with an average age of 56 had their testosterone and genes tested. Those with both a ApoE-ε4 allele and low testosterone had the smallest hippocampal volumes but not significantly smaller than normal testosterone groups. The hippocampus is a complex neural structure (shaped like a sea horse) consisting of grey matter involved in memory and emotion that is absolutely necessary for making new memories. AD affects the hippocampus first and severely and this is why it affects memories early on. The hippocampus shrinks in AD. Men negative for the AD gene allele but with low testosterone had healthy hippocampal volume.

Low Testosterone Linked to Heightened Risk of Early Death

     Again low testosterone levels are found to be linked to a heightened risk of premature death from heart disease and all causes, suggests research published online in Heart.

The finding refutes received wisdom that the hormone is a risk factor for cardiovascular disease.

     The researchers base their findings on 930 men, all of whom had coronary artery heart disease, and had been referred to a specialist heart centre between 2000 and 2002. Their heart health was then tracked for around 7 years. On referral, low testosterone was relatively common. One in four of the men were classified as having low testosterone, using measurements of either bioavailable testosterone (bio-T) -- available for tissues to use -- of under 2.6 mmol/l or total testosterone (TT) of under 8.1 mmol/l. These measures indicate clinically defined testosterone deficiency, referred to as hypogonadism, as opposed to a tailing off in levels of the hormone as a result of ageing.

     During the monitoring period almost twice as many men with low testosterone died as did those with normal levels. One in five (41) of those with low testosterone died, compared with one in eight (12%) of those with normal levels.

     The only factors that influenced this risk were heart failure (left ventricular dysfunction), treatment with aspirin or a high blood pressure drug (beta blocker) and low bio-T levels. A low bio-T level was an independent risk factor for premature death from all causes and from heart disease, after taking account of other influential factors, such as age, other underlying health problems, smoking and weight. Borderline levels of low total testosterone (15.1mmol/l) also increased the risk of an early death.

     While high doses of testosterone found in anabolic steroids are harmful to health, the evidence suggests that low, rather than high, levels of the hormone are associated with obesity, risky blood fats, and insulin resistance, all of which are risk factors for diabetes and heart disease, say the authors. Men at high risk of these diseases may stand most to gain from testosterone replacement, they suggest.

     An accompanying editorial points out that there is increasing interest in looking at the impact of testosterone replacement.