There have been several posts regarding a new study [1] (full text):
"Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer"
The Discussion section ends with:
"While our study suggests an association between ADT and subsequent dementia diagnosis, we were unable to further investigate possible biological mechanisms of this association. It is important to note that dementia may have a latency period of 1 decade or more prior to cognitive manifestations, with some cerebrospinal fluid, serum, and neuroimaging biomarkers present many years before diagnosis. Hence, it is possible that ADT has a modifying or augmenting, rather than de novo, effect on development of dementia." {my emphasis}
Testosterone levels begin to fall in our early 30s. We hardly notice the 1-2% annual drop, but by the time we have reached the PCa years, the loss has been significant.
Many men believe that testosterone [T] drives PCa - the proof being that castration is an effective treatment (for a while - it is not curative). Yet men diagnosed with PCa tend to have lower T than matched controls, & men with the lowest T have the poorest prognosis. And, it appears that PCa is able to lower T [2]:
{post-prostatectomy} "data further suggest that the normal prostate and/or prostate neoplasm could secrete a substance or substances that give negative feedback control to pituitary gonadotropin secretion." [Patrick Walsh, et al, 1998] {T levels increase after radical prostatectomy.}
From the intro. to a 2018 (non-PCa) paper:
"Alzheimer’s disease (AD) is a devastating neurodegenerative disorder showing sex-specific differences in prevalence and genetic risk, making sex hormones and their signaling putative disease modulators (Altmann et al., 2014). The major AD risk factor is age, and sex steroid levels decline with increasing age, precipitously for women with menopause and more gradually for men. While the effects of sex hormones on AD risk have been well-studied in women (Paganini-Hill and Henderson, 1994; Espeland et al., 2004), fewer studies on sex steroids and cognitive function and/or AD risk exist in men."
"Testosterone is the predominant androgen in men and binds to the androgen receptor (AR), regulating expression of multiple genes with diverse biological roles. AR is expressed in many brain regions, including hippocampus (Simerly et al., 1990), a region responsible for learning and memory that is heavily impacted in AD. Previous studies implicate low testosterone levels with cognitive impairment in healthy men, and higher testosterone associates with better performance in cognitive tests (Yaffe et al., 2002). Men diagnosed with mild cognitive impairment (MCI) or AD have lower testosterone levels compared to controls (Hogervorst et al., 2001; Paoletti et al., 2004). Low testosterone levels are also associated with greater risk of AD (Lv et al., 2016), and precede AD diagnosis by 5–10 years (Moffat et al., 2004). Interestingly, brains of cognitively normal men with early AD neuropathology at autopsy have lower testosterone, suggesting lower testosterone may precede onset of clinical AD (Rosario, 2004). Low testosterone levels have also been associated with higher brain amyloid levels in MCI patients (Verdile et al., 2014). Furthermore, the prolonged use of androgen deprivation therapy (ADT) in men with prostate cancer is associated with risk of both cognitive impairment (Gonzalez et al., 2015) and AD (Nead et al., 2015, 2016)."
& another 2018 paper [4]:
"We conducted a prospective longitudinal study of 4069 community-dwelling older men free of dementia aged 71-88 years at baseline. The main objective of the study was to determine if men with low circulating sex hormones were more likely to develop dementia over time. The main biochemical exposures of interest were collected at baseline between 2001 and 2004 and men were assessed for incident dementia via an electronic health records database to the 31 st of December 2013."
"Dementia developed in 499 men over a median of 10.5 years (range 9.4-12.2 years). The risk of developing dementia increased with decreasing total {testosterone} (hazard ratio [HR] 1.14 ...) and calculated free testosterone (HR 1.18 ...) after adjustment for age, baseline cognitive function, depression, body mass, hypertension, cardiovascular disease and total plasma homocysteine. Men in the lowest quartiles of total (adjusted HR 1.39, 95%CI 1.04-1.85) and calculated free testosterone (adjusted HR 1.43 ...) had increased risk of developing dementia compared to those in the highest quartiles."
...
IMO, many men at PCa diagnosis already have an increased risk of dementia. In those men, ADT may act as an accelerant.
...
From the new study [1]:
"Exposure to ADT, compared with no ADT exposure, was associated with a diagnosis of Alzheimer disease (13.1% vs 9.4%; difference, 3.7% ... hazard ratio [HR], 1.14 ...) and dementia (21.6% vs 15.8%; difference, 5.8% ... HR, 1.20 ...)"
I wonder how men with exposure to ADT differ from men with no ADT exposure? It might have been prudent to measure baseline T. Lower T possibly increases the chance of ADT exposure.
The paper only mentions T once:
"There may be a causative relationship between lower testosterone levels and impaired cognitive function, perhaps via impaired neuron growth and axonal regeneration or accumulation of abnormally folded β-amyloid protein."
The lack of interest in baseline T is a fatal flaw IMO. The increased risk of dementia may be overstated.
-Patrick
[1] jamanetwork.com/journals/ja...
[2] ncbi.nlm.nih.gov/pubmed/967...
