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Alzheimer's disease (AD) is characterized by the age-related deposition of beta-amyloid (Abeta) 40/42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for Abeta in the pathophysiology of AD. Abeta peptides are generated by the regulated cleavage of an approximately 700-aa Abeta precursor protein (...
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Context 1
... the steroid concentration to 2 M (data not shown). The effects of testosterone were slightly less in magnitude than those of 17-estradiol, but none of the differ- ences observed was statistically significant. When primary neuronal cultures were treated with testoster- one, an increase in sAPP and a decrease in A release also were observed (Fig. 3). Treatment for 10 days with testosterone or 17-estradiol, at 200 nM or 1 M, stimulated secretion of sAPP by 20-30%. Concomitantly, these steroids reduced secretion of A4042 by 30-40%. The effect of testosterone on A release increased with days of treatment up to 10 days (Fig. 3c). Primary neuronal cultures were not consistently viable ...
Context 2
... an increase in sAPP and a decrease in A release also were observed (Fig. 3). Treatment for 10 days with testosterone or 17-estradiol, at 200 nM or 1 M, stimulated secretion of sAPP by 20-30%. Concomitantly, these steroids reduced secretion of A4042 by 30-40%. The effect of testosterone on A release increased with days of treatment up to 10 days (Fig. 3c). Primary neuronal cultures were not consistently viable in the absence of serum for periods longer than 10 days. Increasing the concentration of testosterone to 2 M did not reduce A release ...
Context 3
... caused reductions in the secretion of both the 4-kDa A1-4042 peptides and the 3-kDa Ax-4042 peptides from both N2a cells (Fig. 2a) and primary neuronal cultures (Fig. 3a). Using both radiosequencing and immunoprecipitation mass spectrometry, we demonstrated previously in primary rat neuronal cultures that the predominant 3-kDa secreted Ax- 4042 species are composed mainly of A11-4042 peptides and, to a lesser extent, A17-4042 peptides (11). Immunopre- cipitationmass spectrometric analysis of A peptides ...
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Citations
... Furthermore, the relationship of testosterone to the AD-specific pathologies of amyloid-beta and phospohorylated tau (p-Tau) has been studied in cellular and animal models. Testosterone treatment of cultured rat neurons reduced amyloid-beta precursor protein and soluble amyloid-beta secretion over time [35] and protected hippocampal neurons from amyloid-beta induced cell death [36]. In male rats with gonadectomies, testosterone treatment reversed amyloid-beta accumulation in the brain [37]. ...
... As mentioned in the introduction, testosterone has neuroprotective effects [20,[22][23][24] including those specifically against AD pathology [35][36][37][38][39], lending biological plausibility to our findings of higher testosterone relating to better cognition across the AD continuum. Another possibility is that the observed testosterone and cognition links in females may be driven by estrogen related mechanisms. ...
Background:
Past research suggests that low testosterone levels relate to poorer cognitive function and higher Alzheimer's disease (AD) risk; however, these findings are inconsistent and are mostly derived from male samples, despite similar age-related testosterone decline in females. Both animal and human studies demonstrate that testosterone's effects on brain health may be moderated by apolipoprotein E ε4 allele (APOE-ε4) carrier status, which may explain some previous inconsistencies. We examined how testosterone relates to cognitive function in older women versus men across healthy aging and the AD continuum and the moderating role of APOE-ε4 genotype.
Methods:
Five hundred and sixty one participants aged 55-90 (155 cognitively normal (CN), 294 mild cognitive impairment (MCI), 112 AD dementia) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), who had baseline cognitive and plasma testosterone data, as measured by the Rules Based Medicine Human DiscoveryMAP Panel were included. There were 213 females and 348 males (self-reported sex assigned at birth), and 52% of the overall sample were APOE-ε4 carriers. We tested the relationship of plasma testosterone levels and its interaction with APOE-ε4 status on clinical diagnostic group (CN vs. MCI vs. AD), global, and domain-specific cognitive performance using ANOVAs and linear regression models in sex-stratified samples. Cognitive domains included verbal memory, executive function, processing speed, and language.
Results:
We did not observe a significant difference in testosterone levels between clinical diagnostic groups in either sex, regrardless of APOE-ε4 status. Across clinical diagnostic group, we found a significant testosterone by APOE-ε4 interaction in females, such that lower testosterone levels related to worse global cognition, processing speed, and verbal memory in APOE-ε4 carriers only. We did not find that testosterone, nor its interaction with APOE-ε4, related to cognitive outcomes in males.
Conclusions:
Findings suggest that low testosterone levels in older female APOE-ε4 carriers across the aging-MCI-AD continuum may have deleterious, domain-specific effects on cognitive performance. Although future studies including additional sex hormones and longitudinal cognitive trajectories are needed, our results highlight the importance of including both sexes and considering APOE-ε4 carrier status when examining testosterone's role in cognitive health.
... Previous studies have shown that androgen depletion can increase the susceptibility to neurodegenerative diseases (23). In addition, appropriate supplementation with androgens may be neuroprotective by preventing β-amyloid deposition and the hyperphosphorylation of tau proteins (24). However, the association between genetically determined androgenic steroids (e.g., epiandrosterone sulfate) and neurodegenerative diseases remains obscure. ...
Background
Dysregulation of circulating metabolites may affect brain function and cognition, associated with alterations in the cerebral cortex architecture. However, the exact cause remains unclear. This study aimed to determine the causal effect of circulating metabolites on the cerebral cortex architecture.
Methods
This study utilized retrieved data from genome-wide association studies to investigate the relationship between blood metabolites and cortical architecture. A total of 1,091 metabolites and 309 metabolite ratios were used for exposure. The brain cortex surface area and cortex thickness were selected as the primary outcomes in this study. In this study, the inverse variance weighting method was used as the main analytical method, complemented by sensitivity analyses that were more robust to pleiotropy. Furthermore, metabolic pathway analysis was performed via MetaboAnalyst 6.0. Finally, reverse Mendelian randomization (MR) analysis was conducted to assess the potential for reverse causation.
Results
After correcting for the false discovery rate (FDR), we identified 37 metabolites and 9 metabolite ratios that showed significant causal associations with cortical structures. Among these, Oxalate was found to be most strongly associated with cortical surface area (β: 2387.532, 95% CI 756.570–4018.495, p = 0.037), while Tyrosine was most correlated with cortical thickness (β: −0.015, 95% CI −0.005 to −0.025, p = 0.025). Furthermore, pathway analysis based on metabolites identified six significant metabolic pathways associated with cortical structures and 13 significant metabolic pathways based on metabolite ratios.
Conclusion
The identified metabolites and relevant metabolic pathways reveal potential therapeutic pathways for reducing the risk of neurodegenerative diseases. These findings will help guide health policies and clinical practice in treating neurodegenerative diseases.
... Some of the biochemical reactions in the brain that have been associated with Alzheimer's disease include an increase in beta amyloid, a decreased brain cell glucose metabolism, and a reduction in blood flow to the brain. Studies have shown that in women, both testosterone and estradiol can counter many of these and thus reduce beta amyloid deposition, improve the brain's ability to metabolize glucose, and improve blood flow [15][16][17]. ...
Hormone replacement therapy continues to be a controversial topic in medicine, with certain narratives regarding safety concerns that are not scientifically established in peer-reviewed literature. These negative narratives, specifically undermining the use of testosterone in women, have caused women to remain without any Food and Drug Administration (FDA)-approved testosterone therapies, while more than 30 FDA-approved testosterone therapies are available for men in the United States. This has resulted in millions of women suffering in silence with very common symptoms of perimenopause and menopause that could easily be addressed with the use of testosterone. There is growing evidence to support the use of physiologic doses of testosterone for sexual function, osteoporosis prevention, brain protection, and breast protection. The safety of testosterone use in women has been evaluated for the past 80 years. A recent publication on the complications of subcutaneous hormone-pellet therapy, looking at a large cohort of patients over 7 years, demonstrated long-term safety. In addition, there have been two large long-term peer-reviewed studies showing a significant reduction in the incidence of invasive breast cancer in women on testosterone therapy. Perhaps it is time for the FDA to consider approving products that would benefit testosterone-deficient women.
... Since 25(OH)D appears to act on testosterone synthesis in men, and serum 25(OH)D deficiency is associated with lower testosterone [42], we believe this mechanism may enhance the process of muscle atrophy in men. Regarding the CNS, due to the protective effect that testosterone exerts on the CNS [43] and the fact that its synthesis is dependent on serum concentrations of 25(OH)D [44], we assume that it is possible that low 25(OH)D concentrations may reduce testosterone levels and favor earlier and more gradual cognitive decline in men than in women. ...
... Finally, information on parathyroid hormone (PTH) and testosterone serum concentration was also not collected. Serum PTH concentrations are high in the presence of serum 25(OH)D deficiency, which characterizes secondary hyperparathyroidism, a condition associated with reduced strength that can compromise functionality [13], while testosterone is related to the preservation of musculoskeletal and cognitive function [41,43]. ...
Vitamin D deficiency compromises elements underlying the disability process; however, there is no evidence demonstrating the association between vitamin D deficiency and the incidence of disability in instrumental activities of daily living (IADL). We investigated the association between vitamin D deficiency and the risk of incidence of IADL disability separately in men and women. A total of 4768 individuals aged ≥50 years from the English Longitudinal Study of Aging (ELSA) and without IADL disability according to the Lawton scale were available. Vitamin D was evaluated at baseline by serum 25(OH)D concentrations and classified as sufficient (>50 nmol/L), insufficient (>30 to ≤50 nmol/L) or deficient serum (≤30 nmol/L). IADL were reassessed after 4 years. Poisson models stratified by sex and controlled by covariates demonstrated that deficient serum 25(OH)D was a risk factor for the incidence of IADL disability in men (IRR: 1.43; 95% CI 1.02, 2.00), but not in women (IRR: 1.23; 95% CI 0.94, 1.62). Men appear to be more susceptible to the effect of vitamin D deficiency on the incidence of IADL disability, demonstrating the importance of early clinical investigation of serum 25(OH)D concentrations to prevent the onset of disability.
... 27 Experimental studies suggest an effect of testosterone to decrease secretion of Aβ peptides and protect against oxidative stress in neuronal cells. [28][29][30] Furthermore, men undergoing androgen deprivation therapy for prostate cancer, which reduces testosterone concentrations to castrate levels, are at greater risk of developing dementia compared to men with prostate cancer who do not receive such therapy. 31,32 However, a Mendelian randomization analysis, which utilized genetic variants associated with calculated free testosterone, did not find evidence that these were predictive for dementia. ...
Introduction:
The association of testosterone concentrations with dementia risk remains uncertain. We examined associations of serum testosterone and sex hormone-binding globulin (SHBG) with incidence of dementia and Alzheimer's disease.
Methods:
Serum total testosterone and SHBG were measured by immunoassay. The incidence of dementia and Alzheimer's disease (AD) was recorded. Cox proportional hazards regression was adjusted for age and other variables.
Results:
In 159,411 community-dwelling men (median age 61, followed for 7 years), 826 developed dementia, including 288 from AD. Lower total testosterone was associated with a higher incidence of dementia (overall trend: P = .001, lowest vs highest quintile: hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.13-1.81), and AD (P = .017, HR = 1.80, CI = 1.21-2.66). Lower SHBG was associated with a lower incidence of dementia (P < .001, HR = 0.66, CI = 0.51-0.85) and AD (P = .012, HR = 0.53, CI = 0.34-0.84).
Discussion:
Lower total testosterone and higher SHBG are independently associated with incident dementia and AD in older men. Additional research is needed to determine causality.
... 267 Androgens also rapidly phosphorylate cyclic-AMP response element binding protein (CREB) in cultured hippocampal neurons, which can have neuroprotective effects, but this effect was found to involve the protein kinase C pathway rather than the MAPK pathway. 268 Testosterone application also reduces b-amyloid production in neurons 269,270 and blocks formation of neurofibrillary tangles, 271 both distinctive symptoms of AD. There is evidence that this neuroprotective effect against Ab neurotoxicity occurs through both the MAPK pathway and by upregulating the enzyme neprilysin. ...
... Recent studies have shown role of testosterone in reducing neuronal secretion of beta amylopeptide, a protein found in plaques of patients with Alzheimer's disease 38 . TRT has also been found to increase cerebral perfusion in addition to improved cognitive functions. ...
... Additionally, the Baltimore Longitudinal Study of Aging (BLSA) with an average follow-up time of 19.1 years suggests that higher levels of free testosterone in serum at baseline are associated with lower risk of developing AD dementia (Moffat et al., 2004). Similarly, animal studies indicate a beneficial role of testosterone against tau phosphorylation (Papasozomenos and Shanavas, 2002) and β-amyloid (Aβ) production (Gouras et al., 2000). Further, Sundermann et al. (2020) found that lower testosterone levels in plasma were associated with higher CSF p-tau levels among APOE4 carriers. ...
... First, it is possible that testosterone may reduce levels of amyloid plaques and tangles in the brain, thus contributing to higher brain glucose metabolism. For example, animal studies indicate a beneficial role of testosterone against tau phosphorylation (Papasozomenos and Shanavas, 2002) and Aβ production (Gouras et al., 2000). Second, testosterone has been reported to be beneficial to human primary neurons, and this beneficial effect is not dependent on estrogen action (Hammond et al., 2001). ...
Objective
There is growing evidence that testosterone may be implicated in the pathogenesis of Alzheimer’s disease (AD). We aimed to examine the relationship between plasma total testosterone levels and change in brain glucose metabolism over time among non-demented older people.
Methods
The association of plasma total testosterone levels with change in brain glucose metabolism among non-demented older people was investigated cross-sectionally and longitudinally. Given a significant difference in levels of plasma total testosterone between gender, we performed our analysis in a sex-stratified way. At baseline, 228 non-demented older people were included: 152 males and 76 females.
Results
In the cross-sectional analysis, no significant relationship between plasma total testosterone levels and brain glucose metabolism was found in males or females. In the longitudinal analysis, we found a significant association of plasma total testosterone levels with change in brain glucose metabolism over time in males, but not in females. More specifically, in males, higher levels of total testosterone in plasma at baseline were associated with slower decline in brain glucose metabolism.
Conclusion
We found that higher levels of total testosterone in plasma at baseline were associated with slower decline in brain glucose metabolism in males without dementia, indicating that testosterone may have beneficial effects on brain function.
... It has been shown that ApoE4 female carriers do not respond fully to the treatment as do non-carriers and male carriers. 63 Some research suggests that at an older age, both sexes have a similar risk of AD. 64 As men age, they also have decreased levels of testosterone, which has been linked to an increased risk of AD 65 due to the diminished protective effect of testosterone on the deposition of Aβ. 66,67 This effect was also associated in ApoE4 allele carriers. 68 In the treatment process of prostate cancer, men will be deprived of hormones, which will reduce the testosterone level in their body, also exposing them to a higher risk of AD. ...
Alzheimer disease (AD) is a chronic neurodegenerative condition that affects an indi-vidual's cognitive function over an extended period. Treatment and prevention for AD have long been sought after; however, no strategy has yet been successful, as individuals with cognitive impairment usually present to the clinic when they have reached an advanced stage of the disease. The disease is progressive and multifacto-rial in its pathogenesis. Precision medicine (PM) is the new era of medicine comprising a holistic approach in dealing with diseases. With scientific innovations, PM has improved our disease knowledge, altered diagnoses and therapy approaches resulting in a more precise, predictive, preventative and personalized patient care. PM in AD focuses, among other things, on stratifying individuals according to their risk factors of developing the disease and applying preventative strategies and personalized treatment approaches for a better outcome. In this mini-review, we have focused on a few modifiable and non-modifiable risk factors and presented recommendations for future consideration to implement.
... In Alzheimer's disease, an overproduction of amylogenic precursors, such as amyloid beta-peptide, and their accumulation in several areas of brain is involved in the pathophysiology of neurodegeneration [39,40]. T was found to reduce the secretion of amyloid beta-peptide and increase the secretion of the non-amyloidogenic fragment, sbetaAPPalpha, from mouse neuroblastoma cells line (N2a) and rat primary cortico-cerebral neurons, thus demonstrating to positively modulate the intracellular metabolism and protect against Alzheimer's disease evolution [41]. This protective effect exerted by androgens, including T and its metabolites, has been confirmed by other observations [42][43][44][45]. ...
Background:
Epidemiological data report that male hypogonadism may play a role in cognitive impairment in elderly. However, the effect of testosterone replacement therapy (TRT) on cognitive abilities in this cluster of patients has not been well established. Methods. PubMed/MEDLINE, Google Scholar, Cochrane Library, and Web of Science were searched by using free text words and medical subject headings terms related with "male hypogonadism", "late-onset hypogonadism", elderly, cognition, "mild cognitive impairment", memory, "testosterone replacement therapy" used in various combinations according to the specific clinical questions. Original articles, reviews, and randomized controlled trials written in English were selected. Results. A long-term TRT could improve specific cognitive functions, such as verbal and spatial memory, cognitive flexibility, and physical vitality. However, randomized controlled trials do not provide positive results, and in most of the cases TRT might not induce beneficial effects on cognitive function in elderly men. Discussion and conclusions. Since the lengthening of life expectancy, the prevalence rate of cognitive decline in elderly men is expected to increase remarkably over the next decade with considerable healthcare and economical concerns. Therefore, this remains a relevant clinical topic and further investigations are needed for clarifying the role of TRT especially in elderly men with hypogonadism.
