Testosterone Loss in Aging Men May Increase Risk of Cognitive Decline, Dementia

Cognitive impairment and dementia are associated with lower testosterone concentrations in aging men, according to recent findings from an article published in Reviews in Endocrine and Metabolic Disorders.

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“Understanding the relationships between male ageing, declining circulating testosterone concentrations, and increasing cognitive impairment and dementia, may provide important insights into novel preventive strategies,” the study authors wrote in the article.

Circulating total testosterone concentrations decline as men get older. Middle-aged men may have less total testosterone concentrations for numerous reasons, which can include obesity, type 2 diabetes, medical comorbidities, or less activity in the hypothalamic-pituitary–testicular (HPT) axis. Further, lower testosterone concentrations are also more likely to cause cardiovascular events and mortality.

These low levels may even place aging men at greater risk of dementia, although it’s not causally proven. Worsening cognitive function can affect memory, thinking, learning capacity, and language, and may be associated with changes in mood, emotional control, behavior, motivation, and social functioning. This review aims to discuss the current literature and possible strategies to reduce the risk of dementia in aging men.

In a mechanistic study of testosterone, dementia, and Alzheimer disease, testosterone was shown to prevent β-amyloid from developing in the subiculum, hippocampus, and amygdala of transgenic mice whose testes were removed. The mice were shown to have better memory and attention, according to the investigators, who noted β-amyloid buildup is thought to contribute to the development of dementia and Alzheimer disease.

The prospective Baltimore Longitudinal Study of Aging observed that at baseline, men with more testosterone than sex hormone-binding globulin (SHBG)—a protein that carries testosterone/sex steroids and decreases free testosterone (FT)—were less likely to develop Alzheimer disease and have better cognitive function.

The Health In Men Study (HIMS) observed that lower testosterone, cFT, and estradiol (hormone) concentrations at baseline led to increased risk of dementia during follow-up, although SHBG was not a factor. This study highlights the impact of age as a risk factor (mean age of diagnosis was 78.7 years)—with a 15% increased risk of dementia per year of increased age.

Unlike HIMS, the United Kingdom (UK) Biobank study, which evaluated who among 159,411 men aged 50–73 years of age developed dementia or dementia due to Alzheimer disease. The study largest prospective cohort analysis to link these diseases with testosterone and SHBG, according to the authors.

However, a large longitudinal study of older twin men found no link between sex hormones and cognitive function. A separate study observed that cFT was associated with hippocampal volume but not Alzheimer pathology. Some studies have also reported poor cognitive outcomes associated with androgen deprivation therapy (ADT) to treat prostate cancer. In a study of 23,651 older men with prostate cancer, 1525 were diagnosed with incident dementia during follow-up, which was attributed to ADT.

There are interventions to increase circulating testosterone levels, including testosterone treatment. Lifestyle interventions to reduce excess weight, improve diet, and increase physical activity could prevent type 2 diabetes and reduce dementia risk. Concurrent testosterone treatment and lifestyle interventions address obesity and diabetes (risk factors for dementia), although it is not causally preventative.

The authors concluded, “additional research is warranted, pending which lower testosterone concentrations in ageing men should be regarded as a biomarker rather than a proven therapeutic target for risk reduction of cognitive decline and dementia, including dementia due to Alzheimer disease.”

Reference

Yeap BB, Flicker L. Testosterone, cognitive decline and dementia in ageing men. Rev Endocr Metab Disord 23, 1243–1257 (2022). DOI: 10.1007/s11154-022-09728-7