Longitudinal trajectories of cognitive decline and temporal lobe atrophy based on baseline gonadotropins and testosterone

Introduction: Although previous studies have reported associations between gonadotropins, testosterone, and Alzheimer’s disease (AD), their longitudinal relationships with cognitive decline and temporal lobe atrophy remain insufficiently characterized. This study examined the association between baseline hormone levels and cognitive decline and temporal lobe volume loss trajectories, and whether these associations vary by sex or APOEε4 status.

Methods: This study included 490 participants (378 MCI/112 AD; 311 men/179 women; mean age = 75.01 ± 7.52) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Baseline plasma levels of gonadotropins (FSH, LH) and total testosterone (TT) were measured using Luminex xMAP multiplex immunoassay. Cognitive decline was assessed longitudinally through MMSE and ADAS-Cog 13 scores. Temporal lobe atrophy was quantified using tensor-based morphometry of 1.5T MRI scans, with bilateral temporal lobe volumes scaled to a normalized reference (1,000 = baseline). Linear mixed effects models were employed to relate baseline plasma hormones to longitudinal cognitive performance and temporal lobe volume.

Results: Longitudinal analyses showed that higher baseline FSH levels were associated with faster cognitive decline (MMSE: β = −0.025, P = 0.012; ADAS-cog: β = 0.066, P = 0.020) and accelerated temporal lobe atrophy (β = −0.115, P = 0.005) in fully adjusted models. LH was also associated with faster temporal lobe atrophy (β = −0.077, P = 0.034), while TT showed no significant association. Sex-stratified analyses showed that higher TT was associated with slower MMSE decline in women (β = 0.022, P = 0.032) but not in men (P = 0.762), with a significant sex interaction (P-interaction = 0.020). Modification effects of APOEε4 status on cognition and temporal lobe volume changes were not observed for FSH, LH, or TT.

Discussion: The results indicate that in individuals across the AD spectrum, elevated gonadotropin levels may exert deleterious, domain-specific effects on cognitive decline or temporal lobe atrophy. Women with lower TT levels may experience faster cognitive progression. Although future studies incorporating additional longitudinal hormone measurements and cognitive trajectories are warranted, our results underscore the importance of gonadotropins and testosterone in AD progression.

1 Introduction

Alzheimer’s disease (AD) is a global health challenge with increasing prevalence in the aged population (Ferretti et al., 2018; Nebel et al., 2018; Huque et al., 2023; Castro-Aldrete et al., 2025). It imposes a significant psychological and economic burden on affected individuals, families, and society. Epidemiological studies have shown that women comprise approximately two-thirds of the population with AD (Andersen et al., 1999; Satizabal et al., 2016), and they have a twofold higher lifetime risk of developing AD (Fisher et al., 2018) and a broader spectrum of dementia-related symptoms than men (Koran et al., 2017). These differences may originate from biological factors (e.g., chromosomal, epigenetic, or hormonal variations) or psychosocial–cultural factors (e.g., educational access, gender disparities) (Castro-Aldrete et al., 2025).

With advancing age, women experience a progressive arrest of reproductive function and the onset of menopause, which is characterized by the depletion of ovarian oocytes and profound changes in the hypothalamic–pituitary–gonadal (HPG) axis (Sauvé et al., 2024). In this context, estrogen deficiency has been suggested as a possible cause of the disease, indicating that hormone replacement therapy may reduce dementia risk (Nelson et al., 2002; Zandi et al., 2002). Nevertheless, data on hormone replacement therapy have been mixed—showing improvement, no change, or even a worsening of the cognition (Zandi et al., 2002; Viña and Lloret, 2010; O’Brien et al., 2014; Matyi et al., 2019). Beyond the widely discussed issue of treatment-timing windows, these contradictory results also suggest that additional factors may contribute to the increased disease risk observed in women (Matyi et al., 2019).

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are other hormones affected by the menopausal process (Sauvé et al., 2024). As early as two decades ago, evidence began to link elevated levels of LH and FSH to AD diagnosis and cognitive decline (Bowen et al., 2000; Short et al., 2001; Casadesus et al., 2005; Meethal et al., 2005). In 2004, researchers first demonstrated that elevated serum LH could promote the secretion and deposition of Aβ in the aging brain (Bowen et al., 2004). Subsequent studies revealed that serum LH levels might be correlated with plasma Aβ concentrations (Verdile et al., 2014). Cohort studies further showed that serum FSH levels were correlated with cognitive function (Oh et al., 2025; Zhu et al., 2025). More recent experimental work has deepened this understanding. Specifically, FSH has been shown to act directly on hippocampal and cortical neurons to activate the C/EBPβ/δ-secretase pathway, thereby accelerating amyloid and Tau pathology (Xiong et al., 2022; Xiong et al., 2023). Similarly, LH overexpression or exogenous LH administration has been found to exacerbate Aβ deposition, neuronal injury, and behavioral deficits in AD mouse models (Casadesus et al., 2007; Berry et al., 2008; Jia et al., 2024). In a clinical trial, the suppression of gonadotropins was reported as a therapeutic approach that could halt cognitive decline in AD patients (Bowen et al., 2015). These study results support the biological plausibility of gonadotropins contributing to AD-related neurodegeneration. Despite these accumulated findings, current clinical research still primarily relies on cross-sectional analyses. The longitudinal effects of gonadotropins on cognitive trajectories and brain structural changes remain insufficiently investigated.

Testosterone, among the major sex hormones in men, has been found in experimental studies to exert neuroprotective effects by scavenging free radicals, improving synaptic signaling, and enhancing mitochondrial function (Grimm et al., 2014; Jia et al., 2016; Yan et al., 2019; Bianchi, 2022). Total testosterone (TT), the main indicator of testosterone, can be detected in blood. Recent population-based studies have found an association between baseline TT and the risk of cognitive decline in older men (Tang et al., 2024). Notably, current investigations of testosterone have predominantly excluded female cohorts, and whether it modulates longitudinal cognitive trajectories or neuroanatomical progression across the AD continuum remains insufficiently characterized.

In summary, although associations between gonadotropins, testosterone, and AD have been made, their longitudinal effects on cognitive decline and temporal lobe atrophy—two key markers of disease progression—remain insufficiently characterized. Moreover, whether these associations vary by sex or APOEε4 genotype has yet to be clarified. This study aimed to examine the relationships of baseline FSH, LH, and TT with cognitive decline and temporal lobe atrophy across the AD continuum and to evaluate the modifying effects of sex and APOEε4 status on these associations.

2 Materials and methods

2.1 Study participants

Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database on 30 December 2024. ADNI was launched in 2004 as a longitudinal observational study of aging that enrolls participants diagnosed as cognitively normal (CN), subjective memory concerns (SMC), mild cognitive impairment (MCI) (both early and late stages), and AD dementia. All ADNI data used in this analysis are publicly available online. For up-to-date information, see www.adni-info.org. Written informed consent was obtained from all participants. Site-specific institutional review boards approved the ADNI protocol. Our final analysis included 490 individuals with available hormone measurements and complete clinical information (average age 75.01 ± 7.52 years; 311 men/179 women), comprising 378 patients with MCI and 112 patients with AD at baseline. A flowchart of the participant selection process is shown in Figure 1. Diagnoses were made by ADNI based on criteria described in the ADNI1 procedure manual.¹

FIGURE 1

Figure 1. A flowchart of the inclusion and exclusion processes. ADNI, Alzheimer’s Disease Neuroimaging Initiative; MCI, mild cognitive impairment; AD, Alzheimer’s dementia.

2.2 Cognitive testing and genotyping

Cognitive decline was measured as change in the widely used the Mini-Mental State Examination (MMSE) and the 13-item Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog 13). The ABI 7900 real-time thermo-cycler (Applied Biosystems) was used to determine the APOE genotype of ADNI participants. TaqMan quantitative PCR was applied to DNA prepared from EDTA whole blood (Quesnel et al., 2024). We characterized participants as being “0” (i.e., zero APOEε4 alleles) or “1” (i.e., one or two APOEε4 alleles).

2.3 Plasma hormone

Plasma samples were drawn from the subjects after fasting overnight at the baseline visit, and 190 analytes that have been reported to be altered in cancer, cardiovascular disease, metabolic disorders, inflammation and AD were measured with the Human Discovery Map panel, a multiplex immunoassay panel developed on the Luminex xMAP platform by Rules Based Medicine. The analysis was performed using plasma gonadotropin (FSH, LH), and sex hormone (TT). All participants had FSH values within the detectable range. 4 cases had LH recorded as “LOW” and 18 cases had TT recorded as “LOW.” Values recorded as “LOW” will be imputed as LLD/2.

2.4 Cumulative temporal lobe atrophy

The data in this section is based on a dataset developed by Hua et al. (2013) at the Laboratory of Neuro Imaging UCLA School of Medicine (Cross-sectional and longitudinal tensor-based morphometry Version 2.0). MR scans (1.5T) were downloaded from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) public database (see text footnote 1). Downloaded images had been processed with the standard Mayo Clinic processing pipeline, identified with the term “scaled” (ADNI-1) in the file name. Methods for the improved longitudinal TBM (Hua et al., 2013) are as described before.

To derive a single-number summary of the 3D map of brain atrophy for each subject, a single numerical measure was derived by computing an average within a region-of-interest (ROI). The anatomically-defined ROI (stat-ROI) was used. The temporal lobe ROI (temp-ROI), including the temporal lobes of both brain hemispheres, was manually delineated on the MDT template by a trained anatomist using the Brainsuite software (version 2.11) (Shattuck and Leahy, 2002). Numerical of cumulative temporal lobe atrophy average within an anatomically defined region-of-interest including bilateral temporal lobes were selected, in which summaries are scaled by 1,000 (e.g., 1,000: no change, 1,200: 20% increase, 800: 20% loss). We ultimately included 447 subjects with at least 6, 12, 18, or 24 months of follow-up data (283 men/164 women, 345 MCI/102 AD at baseline).

2.5 Statistical analyses

In this study, quantitative variables are reported as mean ± standard deviation (SD) or median and interquartile range (IQR). Contingent upon the data distribution while representing the qualitative variables as counts and proportions. Analysis of continuous variables adhering to normal distribution utilized the t-test, whereas the Mann-Whitney U test was applied for variables diverging from normality. Categorical variables were assessed using the chi-square test or Fisher’s exact test (when expected frequencies were <5).

The Linear mixed effects (LME) models (“nlme” package) were to examine the interactive effects of baseline plasma hormone levels on longitudinal changes in cognitive trajectories (outcomes included MMSE and ADAS-cog) and cumulative temporal lobe atrophy over time. Time was operationalized as years from baseline assessment (up to 2 years of follow-up). The LME model included random intercepts and slopes. A progressive modeling approach was used. The first model (Model 1) investigated the crude, unadjusted association. Model 2 included adjustment for age, sex, education, APOEε4 status, BMI, and time-covariate interactions. The fully adjusted model (Model 3) included additional adjustments for history of hypertension, diabetes, hyperlipidemia, stroke, and time-covariate interactions. Secondary analyses examined the modifying effect of sex and APOEε4 status on the association of plasma hormones (FSH, LH, and TT) with cumulative temporal lobe atrophy and cognitive trajectories. All hormones were standardized (mean = 0 and standard deviation = 1) and time was mean centered. Corrections for multiple comparisons were made using the false discovery rate (FDR) method as an additional conservative adjustment (Benjamini et al., 1995). FDR-adjusted P-values were computed by grouping P-values within each unique combination of predictor and model type. FDR-adjusted P-values are provided in the results tables for reference. Because some borderline findings may be due to chance, these results should be interpreted with caution. Statistical analysis was done using R version 4.0.0. Significance was determined at P < 0.05 (two-tailed).

3 Results

3.1 Demographics

See Table 1 for demographics. In our sample of 490 participants, there were 179 (36.53%) women and 311 (63.47%) men (self-reported sex assigned at birth). Across all of the participants, 378 (77.14%) had been diagnosed with MCI, and 112 (22.86%) had been diagnosed with AD. Participants had a mean age of 75.01 years and a median of 16 years of education. Women in our sample were younger, had fewer years of education, and higher levels of FSH and LH. Men had higher levels of MMSE and TT. In the diagnostic stratification group, we observed no significant sex differences in baseline FSH, LH, and TT (Table 1).

TABLE 1

Table 1. Participant characteristics.

3.2 Baseline plasma hormones and cognitive trajectories

Longitudinal analysis showed that a higher baseline FSH level was associated with faster cognitive decline in fully adjusted models (Model 3) (MMSE: β = −0.025, P = 0.012; ADAS-cog: β = 0.066, P = 0.020). LH and TT were initially associated with cognitive changes in univariate models but lost significance after covariate adjustment (Model 3, P > 0.05) (Figure 2 and Table 2). The results were similar in sensitivity analyses that did not adjust for medical history (Model 2) (Table 2).

FIGURE 2

Figure 2. Association of baseline plasma hormones with longitudinal changes in cognitive function and temporal lobe volume. Results are derived from linear mixed effect models adjusted for baseline age, sex, education, APOE ε4 status, hypertension, diabetes, hyperlipidemia, stroke, and the interaction between covariates and time. Estimates, derived from the plasma hormones × time interaction terms, represent the difference in annual change in cognitive scores or temporal lobe volume (β estimates) per standard deviation (SD) increase in baseline hormone.

TABLE 2

Table 2. Associations between baseline plasma hormones and longitudinal changes in cognitive trajectories.

Examination of effect modification by sex revealed an isolated TT × sex interaction on longitudinal change in cognitive trajectories (P-interaction = 0.032). Sex stratification analysis showed that higher baseline TT was associated with slower MMSE decline in women (β = 0.022, P = 0.032) but not in men (β = −0.003, P = 0.762). Sex did not modify the association of FSH and LH with brain volume change. Although a stronger association between FSH and cognitive trajectories was observed in women (MMSE: β = −0.027, P = 0.009; ADAS-cog: β = 0.069, P = 0.020), the sex interaction did not reach statistical significance (MMSE: P-interaction = 0.503; ADAS-cog: P-interaction = 0.874) (Figure 3 and Table 3). Moreover, the APOEε4 status did not modify the association of FSH, LH and TT with cognitive trajectories (Table 4).

FIGURE 3

Figure 3. The relationship between baseline plasma hormones and longitudinal changes in cognitive trajectories in both sexes. Results are derived from linear mixed effect models adjusted for baseline age, sex, education, APOE ε4 status, hypertension, diabetes, hyperlipidemia, stroke, and the interaction between covariates and time. Estimates, derived from the plasma hormones × time interaction terms, represent the difference in annual change in cognitive scores (β estimates) per standard deviation (SD) increase in baseline hormone.

TABLE 3

Table 3. The effects of sex on the relationship between baseline plasma hormones and longitudinal changes in cognitive trajectories.

TABLE 4

Table 4. The effects of apolipoprotein E ε4 allele (APOE ε4) status on the relationship between baseline plasma hormones and longitudinal changes in cognitive trajectories.

3.3 Baseline plasma hormones and cumulative temporal lobe atrophy

Higher baseline FSH and LH levels were associated with faster progression of temporal lobe atrophy in fully adjusted models (FSH: β = −0.115, P = 0.005; LH: β = −0.077, P = 0.034). TT showed no significant associations with atrophy rates (Figure 2 and Table 5). The results were similar in sensitivity analyses that did not adjust for medical history (Model 2) (Table 5).

TABLE 5

Table 5. Associations between baseline plasma hormones and longitudinal changes in temporal lobe volume.

Subgroup analysis revealed that the association of FSH and LH with faster declines in temporal lobe volume was more significant in women than in men (Figure 4 and Table 6), and the relationship between FSH and faster temporal lobe volume loss was more significant in APOEε4-negative participants. However, modification effects of sex and APOEε4 status on temporal lobe volume changes were not observed for FSH, LH, or TT (Table 6).

FIGURE 4

Figure 4. The relationship between baseline plasma hormones and longitudinal changes in temporal lobe volume in both sexes. Results are derived from linear mixed effect models adjusted for baseline age, sex, education, APOE ε4 status, hypertension, diabetes, hyperlipidemia, stroke, and the interaction between covariates and time. Estimates, derived from the plasma hormones × time interaction terms, represent the difference in annual change in temporal lobe volume (β estimates) per standard deviation (SD) increase in baseline hormone.

TABLE 6

Table 6. The effects of sex or apolipoprotein E ε4 allele (APOE ε4) status on the relationship between baseline plasma hormones and longitudinal changes in temporal lobe volume.

4 Discussion

The present study examined whether baseline plasma gonadotropins (FSH and LH) and sex hormone (TT) predict longitudinal changes in cognitive performance and temporal lobe volume in individuals with MCI and AD. We found that elevated baseline plasma FSH levels could accelerate cognitive decline and temporal lobe atrophy, and that higher baseline plasma LH levels could accelerate temporal lobe volume loss. These findings were more significant in women. Although plasma TT was not associated with cognitive and temporal lobe volumetric changes, we observed a potential sex-specific interaction effect between baseline TT and cognitive performance (MMSE score). These results provide important insights for assessing the risk of AD progression in clinical practice using baseline hormone levels. Understanding how these sex-specific hormones modulate disease progression across the AD spectrum can guide the development of more precise individualized intervention strategies.

Mounting evidence has demonstrated that FSH and FSHR perform actions outside the reproductive tract, including in the hippocampal and cortical neurons (Xiong et al., 2022), hepatocytes (Song et al., 2016; Qi et al., 2018; Guo et al., 2019), adipose tissue (Liu et al., 2015, 2017), and pancreatic islet (Cheng et al., 2023), and they play significant roles in postmenopausal diseases in females. In the present study, the finding that higher plasma FSH was associated with steeper longitudinal declines in cognitive function and temporal lobe volume aligns with previous basic research that found FSH contributed to the pathological burden of AD and subsequent cognitive impairment (Xiong et al., 2022). Moreover, sex-stratified analyses demonstrated stronger associations of FSH with cognitive decline and temporal lobe atrophy in women, along with rising FSH levels in older men (Araujo and Wittert, 2011) and systemic FSH-induced AD pathology in both sexes (Xiong et al., 2022). These findings suggest that the faster AD progression in women may be associated with higher exposure to FSH. Prior cohort studies have shown that some women experience cognitive decline during perimenopause (Meyer et al., 2003; Greendale et al., 2009; Epperson et al., 2013). Note that, at this stage, the estrogen level in women remains relatively stable, while the serum FSH begins to rise sharply (Randolph et al., 2011). Pituitary gonadotropin was first proposed as a potential mediating factor for the occurrence and development of AD 20 years ago (Bowen et al., 2000; Short et al., 2001). Nevertheless, the mechanistic connections between pituitary gonadotropins (FSH and LH) and AD pathogenesis remain unclear, and clinical evidence remains limited. Recently, a foundational study published in Nature demonstrated that FSH acted directly on hippocampal and cortical neurons to accelerate Aβ and Tau deposition, and that this effect was mediated by the neuronal C/EBPβ–δ-secretase pathway (Xiong et al., 2022). APOEε4 cooperates with FSH to activate the C/EBPβ/δ-secretase pathway, jointly triggering the occurrence of AD-like pathology (Xiong et al., 2023). Further, FSHR has been demonstrated to regulate intracellular cAMP levels through coupled Gαs protein in ovarian granulosa cells or Gαi protein in Sertoli cells, respectively (Simoni et al., 1997; Crépieux et al., 2001). Similarly, an in vitro study demonstrated that high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway (Cheng et al., 2023), which has been proved to be involved in the regulation of synaptic plasticity (Shen et al., 2016) and neuropsychiatric symptoms on the AD continuum (Jiang et al., 2025). In conclusion, targeting the FSH-related pathway may provide a novel therapeutic intervention for AD (Lemprière, 2022).

In the current study, we found that higher LH was associated with faster progression of temporal lobe atrophy. LH, a pituitary gonadotropin, has also been implicated in the pathogenesis of memory deficits (Palm et al., 2014). For example, LH over-expressed mice were found to develop cognitive impairment (Casadesus et al., 2007; Berry et al., 2008). In vivo studies reported that the exogenous injection of LH exacerbated behavioral impairments in mice and resulted in worsened neuronal damage and increased Aβ deposition (Jia et al., 2024). In addition, increased LH levels have been detected both in the cytoplasm of pyramidal neurons and within neurofibrillary tangles in the brain of those with AD (Bowen et al., 2002). Although tremendous strides have been made in understanding the mechanism of LH in AD over the last few years, longitudinal clinical cohort studies on this topic remain insufficient. Our study aims to build upon this foundation to further investigation. However, the lack of an association between LH levels and the progression of cognitive function is unexpected, particularly in the context of the robust associations between LH and temporal lobe atrophy. Given that declines in brain volume typically precede cognitive impairment (Hansson, 2021), the selective impact of LH on temporal lobe atrophy progression may correlate with early-stage pathological alterations in AD development. A recent study reported that higher pTau-181 and GFAP were indicative of future brain volume loss in cognitively normal older adults, while Aβ_42/40 and GFAP levels were associated with faster subsequent cognitive decline in specific cognitive domains (Dark et al., 2024). The consecutive investigations from the Australian imaging, biomarkers, and lifestyle cohort showed that the serum levels of LH were correlated with plasma Aβ_1–40 levels in cognitively normal or older males diagnosed with MCI. These findings suggest the potential progressive involvement of LH in the early preclinical stages of AD (Verdile et al., 2008, 2014). The interaction between LH and AD biomarkers requires further investigation, and the translation of these pathological or structural changes into detectable cognitive decline may require longer-term follow-up studies. Moreover, as gonadotropins is affected by the menopausal transition, LH and FSH both trigger androgen or estrogen production and are often regulated in the same direction (Lopez-Lee et al., 2024). Thus, future studies should aim to elucidate the potential synergistic roles of FSH and LH in AD progression.

Age-related decline in circulating total testosterone (TT) concentrations parallels the increasing prevalence of geriatric comorbidities in aging men (Shi et al., 2013; Marriott et al., 2022b). For example, in vitro cell experiments found that treatment with testosterone increased cleavage of the β-amyloid precursor protein to enhance secretion of non-amyloidogenic fragments (Goodenough et al., 2000; Gouras et al., 2000), and that testosterone was more effective in preventing β-amyloid-induced cell death compared with estradiol (Pike, 2001; Park et al., 2007). Animal studies also demonstrated that testosterone supplementation increased spine synapses in the rat hippocampus (Leranth et al., 2003). Low testosterone levels have been proved to be associated with poorer cognitive function and a higher risk of AD (Moffat et al., 2004; Seidl and Massman, 2015; Tang et al., 2024). However, these studies were not consistent and were mainly derived from male samples (Geerlings et al., 2006), despite similar age-related testosterone decline in females (Dratva et al., 2024). Testosterone has been historically regarded as a male hormone and is often overlooked in female brain health research. In fact, although circulating levels of testosterone in women are on average one tenth of that in men (Judd et al., 1974), the levels of testosterone in the brain are similar between the two sexes (Hammond et al., 1983; Rosario et al., 2011). Only limited studies have suggested that low testosterone levels in elderly female APOEε4 carriers may exert detrimental and domain-specific effects on cognitive performance across the aging-MCI–AD continuum (Dratva et al., 2024). In the present study, we observed an association between low TT levels and accelerated MMSE score decline in women, whereas no analogous association was detected for ADAS-cog score. Besides, we observed no association between higher plasma TT abundance and accelerated decline in either cognitive performance or temporal lobe volume in the overall cohort and male subgroup. Several factors could explain why the protective effects of higher plasma TT were only observed in women, a pattern that differs from prior reports of testosterone-related benefits primarily being found in men. First, most earlier studies were conducted in cognitively normal aging men (Ford et al., 2018; Tang et al., 2024), whereas our study additionally included female participants. Moreover, all participants in our cohort had already progressed to the stages of MCI or AD. Because hormonal regulation and androgen receptor signaling may become dysregulated as AD pathology advances, testosterone’s neuroprotective effects may diminish or become more heterogeneous in symptomatic male patients. In contrast, women have inherently low circulating TT levels, so a further reduction in TT is more likely to constitute a risk factor, resulting in a more pronounced association between TT and disease progression in the middle and late stages. Second, it is now well accepted that serum testosterone levels decline progressively with aging in men (Huang et al., 2016). Most prior studies demonstrating a protective effect of TT in males were conducted in cohorts with mean ages typically ranging from 60 to 70 years (Marriott et al., 2022a; Tang et al., 2024). In contrast, participants in our cohort were substantially older, with a mean age of approximately 75 years. At this advanced age, the age-related decline in TT levels among men may have reduced the detectability of associations with cognitive trajectories. Therefore, future large cohort studies may benefit from incorporating age stratification to better disentangle the stage-dependent effects of testosterone across the aging continuum. Third, as the principal androgen (Heijboer and Hannema, 2023), testosterone exerts neuroprotective effects by facilitating the clearance of Aβ through the modulation of microglial activity (Gouras et al., 2000; Du et al., 2025), enhancing synaptic plasticity (Schulz and Korz, 2010; Yan et al., 2019), inhibiting neuroinflammation (Jayaraman et al., 2014), and improving neuronal energy metabolism. These protective effects could occur directly through pathways mediated by the androgen receptor or partially through its conversion to estradiol (Gillies and McArthur, 2010). Some studies have reported that the neuroprotective effects of testosterone can be blocked by aromatase inhibitors, suggesting that its neurobiological actions may depend, at least in part, on aromatization to estradiol. Testosterone and estradiol have been shown to share overlapping mechanisms in exerting anxiolytic and antidepressant effects (Yaffe, 2004; Carrier et al., 2015). In addition, the effects of TT in women may depend more heavily on aromatization pathways (Gillies and McArthur, 2010). These complex hormonal metabolic networks may contribute to the aforementioned differences. Future research should incorporate assessments of estradiol and investigate its interactions with testosterone and gonadotropins to achieve a more comprehensive understanding.

The study had some limitations. First, the study lacked estrogen data, which precluded an evaluation of its potential effects on the biological actions of TT and cognitive function. Future investigations should incorporate estrogen to explore the complex feedback loops within the HPG axis in AD pathogenesis. Second, the study only included baseline hormone levels and thus failed to analyze the impact of hormone dynamic changes on AD progression. Incorporating longitudinal, multi-timepoint hormone assessments in future studies will provide stronger evidence regarding their temporal relationship with AD progression and potential causal mechanisms. Third, the null finding regarding APOEε4 status suggests that gonadotropins and testosterone may affect AD pathology through mechanisms unrelated to APOEε4. However, the homozygous sample size of APOEε4 was limited, so further verification is still needed. Finally, ADNI was a single-center study. Therefore, the current findings still need to be tested in other cohort studies to determine if the results can be generalized outside of ADNI.

5 Conclusion

This study elucidated the critical roles of gonadotropins (FSH and LH) and sex hormones (TT) in AD progression in older populations. We demonstrated that elevated baseline FSH levels accelerated both cognitive decline and temporal lobe atrophy, while increased LH was specifically associated with faster temporal lobe volume loss, and that these associations were more pronounced in women. Although TT did not show a significant association with cognitive or neuroimaging changes overall, we found a potential sex-specific interaction between TT and MMSE scores. In women, lower TT levels were associated with a faster decline in MMSE scores. Our results suggest that the sex-specific hormones may offer reliable targets for future interventions aimed at modifying AD progression in older adults.

Data availability statement

Publicly available datasets were analyzed in this study. This data can be found here: the datasets for this study were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu/).

Ethics statement

The studies involving humans were approved by data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Written informed consent was obtained from all participants. Site-specific institutional review boards approved the ADNI protocol. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

MZ: Data curation, Formal analysis, Methodology, Writing – original draft. JJ: Data curation, Investigation, Methodology, Writing – review & editing. LW: Data curation, Investigation, Writing – original draft. SY: Data curation, Investigation, Writing – original draft. WL: Data curation, Software, Writing – original draft. QR: Data curation, Software, Writing – original draft. HZ: Data curation, Writing – original draft. TJ: Data curation, Writing – original draft. SJ: Data curation, Writing – original draft. JZ: Data curation, Writing – original draft. JX: Conceptualization, Funding acquisition, Methodology, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0505804), Beijing Natural Science Foundation (7254343), National key R&D Program of China (2024YFF0507503), Youth Brain Health Fund - Precision Diagnosis and Treatment Research for Alzheimer’s Disease 2025 Annual Project (SMIDF-150-2025A24), and the National Natural Science Foundation of China (82471212 and 82071187).

Acknowledgments

We are grateful to all of the study participants for their patience and cooperation.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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Footnotes

1. ^https://adni.loni.usc.edu/

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