Reproductive Aging, FSH, and Apolipoprotein Biology in Alzheimer’s Disease

Introduction

Methods

Overview of Canonical Cellular Alterations Underlying Neurodegeneration in Alzheimer’s Disease

Cholinergic Hypothesis

The cholinergic hypothesis is one of the first proposed models for AD pathogenesis. The basis of the hypothesis is the selective loss of cholinergic neurons that originate in the nucleus basalis of Meynert (NBM) that results in decreased choline acetyltransferase (ChAT) activity and subsequent decrease in acetylcholine synthesis, leading to cortical cholinergic dysfunction (Berry & Harrison, 2023). The cholinergic deficits in the cerebral cortex are accompanied by a significant increase in the deposition of senile plaques in these same regions (Serrano-Pozo et al., 2011). Overall, this hypothesis represents a model in which there is a clear link between basal forebrain cholinergic dysfunction and AD cognitive deficits (Hampel et al., 2019). The NBM, in addition to the medial septum and diagonal band of Broca (MS/DBB) project cholinergic innervation throughout the cerebral cortex and are some of the first regions to undergo neuronal degeneration (Schmitz et al., 2018).

Figure 1. Cholinergic projections originate from the basal forebrain nuclei (medial septum, abbreviated as MS, vertical limb of diagonal band of Broca, abbreviated as vDB, nucleus basalis of Meynert, abbreviated as NBM, and substantia innominata, abbreviated as SI), which project widely to the hippocampus, thalamus, olfactory bulb and cortical areas. Simultaneously, cholinergic neurons of the pontomesencephalon (laterodorsal tegmental nucleus, abbreviated as LDT and pedunculopontine tegmental nucleus, abbreviated as PPT) project to the hindbrain, thalamus, hypothalamus and basal forebrain, which are thought to be important for the regulation of arousal and behavioural state. The NBM and MS-DBB are two of the first regions in the brain to be selectively affected by neurodegeneration in Alzheimer’s disease and the loss of cholinergic innervation to the hippocampus and cortex is responsible for the deficits in memory and attention. Arrow thickness and color are for illustrative purposes and should not be assumed to be quantitative differences in projection density. Reproduced from Paul et al. (2015) under the Creative Commons Attribution License (CC BY).

Figure 1. Cholinergic projections originate from the basal forebrain nuclei (medial septum, abbreviated as MS, vertical limb of diagonal band of Broca, abbreviated as vDB, nucleus basalis of Meynert, abbreviated as NBM, and substantia innominata, abbreviated as SI), which project widely to the hippocampus, thalamus, olfactory bulb and cortical areas. Simultaneously, cholinergic neurons of the pontomesencephalon (laterodorsal tegmental nucleus, abbreviated as LDT and pedunculopontine tegmental nucleus, abbreviated as PPT) project to the hindbrain, thalamus, hypothalamus and basal forebrain, which are thought to be important for the regulation of arousal and behavioural state. The NBM and MS-DBB are two of the first regions in the brain to be selectively affected by neurodegeneration in Alzheimer’s disease and the loss of cholinergic innervation to the hippocampus and cortex is responsible for the deficits in memory and attention. Arrow thickness and color are for illustrative purposes and should not be assumed to be quantitative differences in projection density. Reproduced from Paul et al. (2015) under the Creative Commons Attribution License (CC BY).

ACh is synthesized in cholinergic neurons by the catalytic action of choline acetyltransferase (ChAT) on choline and acetyl-coenzyme A. ACh is loaded into synaptic vesicles by the vesicular acetylcholine transporter (VAChT) and is released from presynaptic terminals into the synaptic cleft upon presynaptic depolarization. ACh diffuses across the synaptic cleft and can bind to mAChRs and nAChRs on the postsynaptic cell (Paul et al., 2022). ACh signaling is terminated primarily by rapid enzymatic degradation of ACh by AChE to form choline. The choline is then taken back up by the presynaptic neuron (Berry & Harrison, 2023; Stanciu et al., 2019). Alterations in ChAT expression or activity cause a deficiency of ACh that can result in decreased cholinergic signaling. Cholinergic signaling deficits can influence a range of physiological processes that are modulated by cholinergic signaling, including cognitive function, attention, motor behaviors, and sleep-wake regulation (Walczak-Nowicka & Herbet, 2021).

Aβ

Amyloid precursor protein (APP) is a type I transmembrane glycoprotein that undergoes sequential cleavage in the amyloidogenic pathway by β-secretase and γ-secretase (Castellani et al., 2025). The γ-secretase complex is a multiprotein intramembrane protease containing either presenilin 1 (PS1) or presenilin 2 (PS2) as its catalytic subunit. Amyloidogenic processing produces Aβ peptides of varying lengths, most notably Aβ40 and Aβ42. Aβ42 has a greater propensity for β-sheet formation and fibrillogenesis because of its hydrophobic C-terminal region and is a major component of the senile plaques characteristic of AD (Lin et al., 2019).

The amyloid cascade hypothesis has remained a central model of AD pathogenesis, in part because of genetic evidence from familial disease. Mutations in APP on chromosome 21 cause autosomal dominant AD, while trisomy 21 is associated with the development of AD neuropathology with advancing age. Importantly, rare individuals with partial trisomy 21 that does not include APP appear to be spared this characteristic early amyloid pathology, further implicating APP dosage in disease development (Wiseman et al., 2015). Conversely, APP variants associated with reduced Aβ production have been linked to protection against age-related cognitive decline (Castellani et al., 2025).

Figure 2. Acetylcholine release and synaptic signaling. Diagram of cholinergic neurotransmission including (1) Ca²⁺-dependent exocytotic release of ACh from presynaptic vesicles, (2) activation of postsynaptic mAChRs and nAChRs by ACh to cause depolarization, and (3) hydrolysis of ACh by acetylcholinesterase (AChE) followed by reuptake of the choline moiety into the presynaptic cell via the high-affinity choline transporter. Impairments in this cycle, most notably reduced ChAT activity and ACh production, are well-known aspects of Alzheimer’s disease and the rationale for cholinesterase inhibitor therapy. Reproduced from Stanciu et al. (2019) under CC BY 4.0.

Figure 2. Acetylcholine release and synaptic signaling. Diagram of cholinergic neurotransmission including (1) Ca²⁺-dependent exocytotic release of ACh from presynaptic vesicles, (2) activation of postsynaptic mAChRs and nAChRs by ACh to cause depolarization, and (3) hydrolysis of ACh by acetylcholinesterase (AChE) followed by reuptake of the choline moiety into the presynaptic cell via the high-affinity choline transporter. Impairments in this cycle, most notably reduced ChAT activity and ACh production, are well-known aspects of Alzheimer’s disease and the rationale for cholinesterase inhibitor therapy. Reproduced from Stanciu et al. (2019) under CC BY 4.0.

Mutations in PS1 and PS2 provide additional evidence linking amyloidogenic processing to familial AD. However, PS1-associated disease can exhibit pathological features that are not necessarily representative of sporadic AD (Heilig et al., 2010). Increased insoluble Aβ is nevertheless observed in both familial and sporadic forms of the disease compared with non-pathological controls (van Helmond et al., 2010; Wang et al., 1999).

Whether Aβ accumulation alone is sufficient to account for the full clinical and pathological features of AD remains under debate (Castellani et al., 2025). Nonetheless, dysregulation of Aβ metabolism and deposition remains closely linked to AD pathogenesis. Aβ accumulation occurs within a broader network of age-related changes in protein homeostasis, metabolism, inflammation, and cellular signaling, and its precise position within the temporal and mechanistic hierarchy of AD remains an area of active investigation (Castellani et al., 2025; Riku et al., 2025).

Endocrine Contributors to Female Alzheimer’s Disease Vulnerability

The Role of APOE Variants in AD Pathobiology

Figure 3. Isoform-dependent ApoE regulation of Aβ clearance kinetics and context-specific tau pathology. ApoE4 alters multi-compartment Aβ clearance kinetics - in part through lipoprotein receptors such as LRP1, LDLR, and HSPG - and results in impaired Aβ turnover, brain retention, and increased neuroinflammatory signaling. ApoE isoform relationships with tau pathology are context-specific and do not universally adhere to the canonical AD risk hierarchy: in primary tauopathy models (TauP301L and PSP) ApoE2 was associated with increased tau aggregation and hyperphosphorylation relative to ApoE3 or ApoE4 (ApoE2 > ApoE3 > ApoE4), while in the context of amyloid-β (as in AD) ApoE4 appeared to worsen tau-mediated neurodegeneration indirectly through mechanisms related to Aβ clearance and inflammation. Abbreviations: LRP1, low-density lipoprotein receptor-related protein 1; LDLR, low-density lipoprotein receptor; HSPG, heparan sulfate proteoglycan; BBB, blood-brain barrier; Aβ, amyloid-beta. Reproduced from Liu et al. (2026), Molecular Neurobiology, 63, 325, Springer Nature, with permission from Springer Nature Customer Service Centre GmbH. This material is not included under the CC BY license of this article.

Figure 3. Isoform-dependent ApoE regulation of Aβ clearance kinetics and context-specific tau pathology. ApoE4 alters multi-compartment Aβ clearance kinetics - in part through lipoprotein receptors such as LRP1, LDLR, and HSPG - and results in impaired Aβ turnover, brain retention, and increased neuroinflammatory signaling. ApoE isoform relationships with tau pathology are context-specific and do not universally adhere to the canonical AD risk hierarchy: in primary tauopathy models (TauP301L and PSP) ApoE2 was associated with increased tau aggregation and hyperphosphorylation relative to ApoE3 or ApoE4 (ApoE2 > ApoE3 > ApoE4), while in the context of amyloid-β (as in AD) ApoE4 appeared to worsen tau-mediated neurodegeneration indirectly through mechanisms related to Aβ clearance and inflammation. Abbreviations: LRP1, low-density lipoprotein receptor-related protein 1; LDLR, low-density lipoprotein receptor; HSPG, heparan sulfate proteoglycan; BBB, blood-brain barrier; Aβ, amyloid-beta. Reproduced from Liu et al. (2026), Molecular Neurobiology, 63, 325, Springer Nature, with permission from Springer Nature Customer Service Centre GmbH. This material is not included under the CC BY license of this article.

Figure 4. Isoform-dependent conformational properties of apolipoprotein E (ApoE). Schematic representation of the structural tendencies of ApoE2, ApoE3, and ApoE4 arising from amino acid differences at residues 112 and 158. ApoE2 contains cysteine at both positions, ApoE3 contains cysteine at residue 112 and arginine at residue 158, and ApoE4 contains arginine at both positions. These substitutions alter electrostatic interactions within the protein and influence communication between the N-terminal helical bundle and C-terminal lipid-binding domain. ApoE4 exhibits stronger domain-domain interactions and distinct conformational dynamics relative to ApoE2 and ApoE3, which generally sample more flexible conformational states. The additional interactions depicted for ApoE4 illustrate structural features proposed to influence lipid and receptor binding, proteolytic susceptibility, and other isoform-specific functions relevant to Alzheimer’s disease. The conformations shown are idealized schematic representations and should not be interpreted as single fixed three-dimensional structures, as ApoE isoforms exist as dynamic conformational ensembles. Reproduced from Butterfield and Mattson (2020), Neurobiology of Disease, 138, 104795, Elsevier, with permission from Elsevier.

Figure 4. Isoform-dependent conformational properties of apolipoprotein E (ApoE). Schematic representation of the structural tendencies of ApoE2, ApoE3, and ApoE4 arising from amino acid differences at residues 112 and 158. ApoE2 contains cysteine at both positions, ApoE3 contains cysteine at residue 112 and arginine at residue 158, and ApoE4 contains arginine at both positions. These substitutions alter electrostatic interactions within the protein and influence communication between the N-terminal helical bundle and C-terminal lipid-binding domain. ApoE4 exhibits stronger domain-domain interactions and distinct conformational dynamics relative to ApoE2 and ApoE3, which generally sample more flexible conformational states. The additional interactions depicted for ApoE4 illustrate structural features proposed to influence lipid and receptor binding, proteolytic susceptibility, and other isoform-specific functions relevant to Alzheimer’s disease. The conformations shown are idealized schematic representations and should not be interpreted as single fixed three-dimensional structures, as ApoE isoforms exist as dynamic conformational ensembles. Reproduced from Butterfield and Mattson (2020), Neurobiology of Disease, 138, 104795, Elsevier, with permission from Elsevier.

Table 1. Structural and functional characteristics of amyloid-β aggregation states in Alzheimer’s disease. The table summarizes major Aβ species from soluble monomers through oligomers, protofibrils, fibrils, and plaques, with emphasis on differences in structure, solubility, stability, biological relevance, and relative neurotoxicity. Toxicity and AD relevance are qualitative characterizations based on the cited literature rather than quantitative measurements. Aβ, amyloid-beta; AD, Alzheimer’s disease.

Proposed Neurobiological Pathways Linking Elevated FSH to Alzheimer’s Disease

Elevated FSH and Neuronal Bioenergetic Dysfunction

Deficits in glucose metabolism and oxidative phosphorylation are well-recognized features of AD in both experimental and clinical studies. Cerebral hypometabolism, commonly assessed using fluorodeoxyglucose positron emission tomography (FDG-PET), is a prominent feature of the disease (Christodoulou et al., 2026). C/EBPβ signaling may contribute to this phenotype by interfering with neuronal insulin signaling and glucose utilization. C/EBPβ represses FOXO1 activity and inhibits Akt, a central mediator of insulin-dependent glucose uptake, thereby promoting a pseudo-insulin-resistant state within neurons (Tsukada et al., 2011; Gabbouj et al., 2019). Reduced neuronal glucose uptake may therefore contribute to the impaired metabolic state observed in AD. FSH can also exert direct metabolic effects outside the CNS. In adipose tissue, blockade of FSH signaling increased thermogenic activity and mitochondrial density while reducing adiposity, providing experimental evidence that FSH can regulate mitochondrial and metabolic function in a non-gonadal tissue (P. Liu et al., 2017). Together, these findings provide a systemic precedent for the broader metabolic actions of FSH, although whether comparable mechanisms operate within neurons during reproductive aging remains to be established.

C/EBPβ signaling may also impair mitochondrial energetics through regulation of key metabolic proteins. Activation of this pathway promotes degradation of nicotinamide phosphoribosyltransferase (NAMPT), resulting in depletion of nicotinamide adenine dinucleotide (NAD⁺), which is required for mitochondrial respiration and ATP production (Li et al., 2025). C/EBPβ itself is regulated by gonadotropin signaling. Under physiological conditions, gonadotropins including FSH and LH induce C/EBPβ to regulate genes involved in steroidogenesis and inflammatory responses, including steroidogenic acute regulatory protein (StAR) and prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2) (Sirois & Richards, 1993; Duffy et al., 2019). Whereas periovulatory C/EBPβ induction is temporally restricted, whether chronic gonadotropin elevation during reproductive aging produces more sustained C/EBPβ activity remains uncertain.

Importantly, the metabolic trajectory of AD may not consist of progressive hypometabolism from the outset. Evidence suggests that cerebral hypometabolism may be preceded by a period of mitochondrial hyperactivity and neuronal hyperexcitability (Christodoulou et al., 2026; Naia et al., 2023). During this earlier stage, C/EBPβ-dependent signaling may transiently increase mitochondrial output, in part through increased TFAM promoter activity and mitochondrial biogenesis (Sierra-Magro et al., 2023). At the same time, C/EBPβ-mediated repression of FOXO1 and REST may reduce inhibitory neuronal programs, particularly within GABAergic neuronal populations, contributing to loss of inhibitory tone and aberrant network excitation (Mattson, 2020; Xia et al., 2022). Consistent with this model, hypermetabolic changes have been reported during preclinical and prodromal stages of AD (Christodoulou et al., 2026; Naia et al., 2023).

Figure 5. Convergent drivers and consequences of mitochondrial perturbation in Alzheimer’s disease. Amyloid-β (Aβ) deposition, tau pathology, oxidative stress, and electron transport chain (ETC) dysfunction converge to perturb mitochondrial quality control. Excessive fission (via upregulation of dynamin-related protein 1 (DRP1), fission protein 1 (FIS1), and mitochondrial fission factor (MFF)) at the expense of fusion (optic atrophy protein 1 (OPA1); mitofusins (MFN1/2)), mitophagy (PTEN-induced kinase 1 (PINK1); Parkin; microtubule-associated protein light chain 3 (LC3)) and MDV formation underlies a shift in mitochondrial dynamics, turnover and trafficking that favors accumulation of fragmented, dysfunctional mitochondria. Reproduced from Li et al. (2022) under CC BY 4.0.

Figure 5. Convergent drivers and consequences of mitochondrial perturbation in Alzheimer’s disease. Amyloid-β (Aβ) deposition, tau pathology, oxidative stress, and electron transport chain (ETC) dysfunction converge to perturb mitochondrial quality control. Excessive fission (via upregulation of dynamin-related protein 1 (DRP1), fission protein 1 (FIS1), and mitochondrial fission factor (MFF)) at the expense of fusion (optic atrophy protein 1 (OPA1); mitofusins (MFN1/2)), mitophagy (PTEN-induced kinase 1 (PINK1); Parkin; microtubule-associated protein light chain 3 (LC3)) and MDV formation underlies a shift in mitochondrial dynamics, turnover and trafficking that favors accumulation of fragmented, dysfunctional mitochondria. Reproduced from Li et al. (2022) under CC BY 4.0.

Sustained activation of this metabolic program has been associated in preclinical models with a transition from compensatory activity toward mitochondrial dysfunction. Chronic C/EBPβ activation, persistent Akt inhibition, and mitochondrial stress have each been linked to declining metabolic efficiency and progressive mitochondrial impairment (Shaerzadeh et al., 2014; Yu et al., 2014; S. Wang et al., 2025), although the extent to which this phenotype results specifically from FSH-driven C/EBPβ activation during human aging remains unresolved. As mitochondrial quality-control mechanisms become increasingly compromised, an initially compensatory hypermetabolic state may eventually give way to the hypometabolism characteristic of established AD (Naia et al., 2023; Christodoulou et al., 2026).

The consequences of this transition may themselves reinforce disease progression. Impaired oxidative metabolism can promote cytosolic acidification and lactate accumulation, changes that may further disrupt lysosomal acidification and autophagic flux, both of which are altered in the AD brain (Chen et al., 2022; Hagihara & Miyakawa, 2024; X. Wang et al., 2025). Lysosomal distention and autophagosome accumulation are well-documented features of AD and can further impair the clearance of damaged cellular components and proteinaceous material (Quick et al., 2023). These changes are also associated with microglial activation and neuroinflammatory signaling, creating a potentially self-reinforcing relationship among metabolic dysfunction, impaired protein clearance, inflammation, and neurodegeneration (Jung et al., 2025; Wu et al., 2025).

Beyond these metabolic effects, C/EBPβ also engages proteolytic pathways directly relevant to AD pathology. An important downstream effector is asparagine endopeptidase (AEP; also known as δ-secretase). Increased C/EBPβ activity can promote AEP expression, while AEP can cleave APP at N585 and tau at N368, generating fragments with increased aggregation propensity (Wu et al., 2020). In experimental AD models, FSH and ApoE4 have been reported to enhance signaling through the C/EBPβ-AEP axis, providing one proposed mechanism through which reproductive aging could influence both amyloid and tau pathology (Xiong et al., 2022; Xiong et al., 2023).

FSH and ApoE4 Convergence on Autophagic-Lysosomal Dysfunction.

Potential Links Between FSH Signaling and Glial Activation in Alzheimer’s Disease

C/EBPβ serves as a central regulator of inflammatory signaling. Numerous pro-inflammatory genes contain consensus C/EBPβ binding sites, and both macrophages and glial cells exhibit marked upregulation of C/EBPβ in response to inflammatory stimuli (J. Wang et al., 2025). Consistent with this role, C/EBPβ-deficient brains display reduced expression of pro-inflammatory genes and attenuated neurotoxic effects of activated microglia (Straccia et al., 2011; Yao et al., 2024). Moreover, loss of C/EBPβ activity confers neuroprotection in experimental models of ischemic and excitotoxic injury, underscoring its contribution to neuroinflammatory damage (Wu et al., 2023).

C/EBPβ plays a central role in regulating genes involved in inflammasome activation (J. Wang et al., 2025). Inflammasomes - particularly the NLRP3 complex - are activated by a range of cellular stressors, including misfolded protein aggregates, oxidative stress, and mitochondrial dysfunction (Wu, D. et al., 2022; Baragetti et al., 2020; Hamilton & Anand, 2019; Halliday & Mallucci, 2015; Jones et al., 2021). Within this context, C/EBPβ directly regulates the transcription of key inflammasome components by binding to their promoter regions. Notably, C/EBPβ has been shown to upregulate expression of NLRP3, a core structural component of the inflammasome complex (Ma et al., 2018; Chen, J. et al., 2021). It similarly enhances expression of AIM2, a cytosolic DNA sensor that forms a caspase-1–activating inflammasome (Hornung et al., 2009; Zou et al., 2023). Through these actions, C/EBPβ contributes to the priming phase of inflammasome activation, increasing cellular sensitivity to downstream activating signals. In addition to its direct transcriptional effects, C/EBPβ functions synergistically with other inflammatory transcription factors, most notably NF-κB, to amplify cytokine production (McClure et al., 2017). NF-κB is a well-established regulator of inflammatory gene expression, and its cooperation with C/EBPβ enhances transcriptional output at shared target loci. For example, both factors bind to adjacent promoter regions of IL-1β and IL-18, driving coordinated upregulation of these cytokines (Ma et al., 2018).

Figure 6. C/EBPβ-dependent transcriptional regulation of inflammasome activation and pro-inflammatory signaling. This figure illustrates the role of C/EBPβ as a central transcriptional regulator linking upstream inflammatory cues to inflammasome activation. In panel A, C/EBPβ cooperates with NF-κB to induce expression of key inflammasome components, including NLRP3 and AIM2, promoting assembly of ASC-containing complexes, activation of caspase-1, and subsequent maturation of IL-1β and IL-18. In panel B, distinct C/EBPβ isoforms differentially regulate inflammasome gene expression, thereby modulating downstream inflammatory responses through calcium-dependent signaling and cytokine production. Collectively, the figure highlights C/EBPβ as a key integrator of transcriptional control and innate immune activation, coordinating inflammasome pathways implicated in neuroinflammation and neurodegenerative disease. Reproduced from J. Wang et al. (2025) under the Creative Commons Attribution License (CC BY). Created with BioRender.com.

Figure 6. C/EBPβ-dependent transcriptional regulation of inflammasome activation and pro-inflammatory signaling. This figure illustrates the role of C/EBPβ as a central transcriptional regulator linking upstream inflammatory cues to inflammasome activation. In panel A, C/EBPβ cooperates with NF-κB to induce expression of key inflammasome components, including NLRP3 and AIM2, promoting assembly of ASC-containing complexes, activation of caspase-1, and subsequent maturation of IL-1β and IL-18. In panel B, distinct C/EBPβ isoforms differentially regulate inflammasome gene expression, thereby modulating downstream inflammatory responses through calcium-dependent signaling and cytokine production. Collectively, the figure highlights C/EBPβ as a key integrator of transcriptional control and innate immune activation, coordinating inflammasome pathways implicated in neuroinflammation and neurodegenerative disease. Reproduced from J. Wang et al. (2025) under the Creative Commons Attribution License (CC BY). Created with BioRender.com.

Evidence that microglia directly express functional FSHR is currently lacking, so a direct FSH-FSHR signaling mechanism in microglia cannot yet be assumed. FSH may instead influence glial activation indirectly. Increased neuronal C/EBPβ-AEP signaling, together with the downstream accumulation of Aβ and pathological tau species, could generate inflammatory stimuli that activate microglia and amplify C/EBPβ- and inflammasome-dependent responses. This model is consistent with the broader neuroinflammatory effects observed in experimental systems, although the specific cellular route linking elevated FSH to microglial activation remains unresolved.

An additional consideration is that aging may alter the cellular origin of the brain’s myeloid compartment. Using somatic mutations to trace cell lineage in the human brain, Belk et al. (2026) identified a widespread age-associated influx of bone-marrow-derived myeloid cells, some of which acquired microglia-like characteristics and contributed substantially to the microglial population. This finding introduces the possibility that peripheral myeloid biology becomes increasingly relevant to the aging brain. Of particular interest in the present context, FSHR expression has been demonstrated in experimental bone-marrow-derived macrophages, where FSH stimulation increased production of inflammatory cytokines, including TNF-α and IL-6, and activated NF-κB signaling (Chen et al., 2025). These findings provide a peripheral myeloid precedent for direct FSH responsiveness. However, they do not establish that FSH promotes myeloid-cell entry into the brain, nor do they demonstrate that infiltrating myeloid cells mediate the neuroinflammatory effects associated with elevated FSH. Whether these processes intersect during reproductive and brain aging therefore remains an open question.

Such an indirect mechanism would also fit with the well-described relationship between AD protein pathology and neuroinflammation. Aβ promotes microglial recruitment and clustering around plaque-rich regions (Gao et al., 2023) and can activate the NLRP3 inflammasome, resulting in the release of apoptosis-associated speck-like protein containing a CARD (ASC) aggregates. These ASC specks can themselves bind Aβ and promote further aggregation and propagation (Venegas et al., 2017). In parallel, sustained activation of microglia and astrocytes can enhance amyloidogenic APP processing and increase the activity of tau-directed kinases, including glycogen synthase kinase-3β (GSK-3β), thereby promoting tau hyperphosphorylation, synaptic dysfunction, and neurodegenerative spread (Chen & Yu, 2023; Zhang et al., 2021).

Figure 7. Proposed FSH-FSHR signaling pathway linking reproductive aging to amyloidogenic, tau-directed, and inflammatory pathology in Alzheimer’s disease. This figure illustrates a proposed signaling model derived primarily from experimental studies. FSH binding to FSHR in cortical and hippocampal neurons has been reported to engage signaling involving Gαi, ERK1/2, Akt, and SRPK2, leading to increased C/EBPβ/AEP activity and downstream APP and tau processing. Whether Gαi represents the predominant coupling mechanism of neuronal FSHR remains unresolved, and the complete pathway has not been demonstrated in humans. Reproduced from Li et al. (2024) under the Creative Commons Attribution License (CC BY). Created in BioRender. gN, fh. (2024), BioRender.com/s03s437.

Figure 7. Proposed FSH-FSHR signaling pathway linking reproductive aging to amyloidogenic, tau-directed, and inflammatory pathology in Alzheimer’s disease. This figure illustrates a proposed signaling model derived primarily from experimental studies. FSH binding to FSHR in cortical and hippocampal neurons has been reported to engage signaling involving Gαi, ERK1/2, Akt, and SRPK2, leading to increased C/EBPβ/AEP activity and downstream APP and tau processing. Whether Gαi represents the predominant coupling mechanism of neuronal FSHR remains unresolved, and the complete pathway has not been demonstrated in humans. Reproduced from Li et al. (2024) under the Creative Commons Attribution License (CC BY). Created in BioRender. gN, fh. (2024), BioRender.com/s03s437.

An additional layer of this glial response involves APOE-dependent alterations in lipid handling. Haney et al. (2024) identified an ACSL1-positive, lipid-droplet-accumulating microglial state in human AD brain tissue that was most abundant in individuals carrying the APOE ε4/ε4 genotype. In human iPSC-derived microglia, fibrillar Aβ increased triglyceride synthesis and lipid-droplet accumulation in an APOE-dependent manner, with a more pronounced response in APOE ε4/ε4 cells. Conditioned media from lipid-laden microglia subsequently promoted tau phosphorylation and neurotoxicity in human neurons, again in an APOE-dependent manner.

FSH-Associated Vascular Dysfunction and Blood-Brain Barrier Integrity

The blood-brain barrier (BBB) is formed by specialized brain endothelial cells connected by tight junctions and supported by perivascular cell populations, including pericytes, astrocytes, microglia, and oligodendrocytes. Together, these components regulate molecular exchange between the circulation and the central nervous system, restrict the entry of potentially neurotoxic substances, and maintain neural homeostasis (Kim et al., 2024).

BBB dysfunction is increasingly recognized as an early component of AD pathophysiology rather than simply a consequence of advanced amyloid and tau pathology. Nation et al. (2019) demonstrated increased hippocampal BBB permeability and markers of pericyte injury in individuals with early cognitive dysfunction, with these vascular abnormalities occurring independently of Aβ and tau biomarker status. Montagne et al. (2020) further showed that APOE ε4 carriers exhibit accelerated BBB breakdown in the hippocampus and medial temporal regions, with greater pericyte injury associated with cognitive decline independently of cerebral Aβ and tau burden. Together, these findings support the possibility that vascular dysfunction represents a partly independent pathway through which aging and genetic susceptibility contribute to AD vulnerability.

Against this background, elevated FSH may represent an additional source of vascular stress during reproductive aging. Circulating FSH levels have been associated with reduced vascular compliance, including greater arterial stiffness and endothelial dysfunction (Ferretti et al., 2018; Laakkonen et al., 2021; Xue et al., 2025). Experimental and clinical studies have further linked elevated FSH with vascular calcification and progressive loss of arterial elasticity (Li et al., 2024; Roelofs et al., 2022). In peripheral endothelial systems, FSH has also been reported to alter adherens-junction proteins, including E-cadherin and V-cadherin, with corresponding increases in vascular permeability (Kolnes et al., 2020; M. S. Rocca et al., 2024).

Whether these vascular effects extend directly to the BBB remains less certain. Because endothelial junctional mechanisms are shared across vascular beds, FSH-associated disruption of peripheral endothelial signaling provides a plausible basis for effects on cerebrovascular integrity. However, direct evidence demonstrating that elevated FSH itself disrupts the human BBB remains limited. The proposed connection between reproductive-age FSH elevation and BBB breakdown should therefore be regarded as a mechanistic hypothesis requiring direct investigation in cerebrovascular tissue.

Some experimental evidence is consistent with this proposed connection. In a mouse model, ovariectomy followed by treatment with the gonadotropin agonist leuprolide acetate increased connexin-43 expression and enhanced Evans blue dye extravasation into the brain, indicating greater BBB permeability (Wilson et al., 2008). These findings suggest that gonadotropin-associated changes may influence cerebrovascular barrier function, although the experimental design does not isolate a direct effect of FSH and should therefore be interpreted cautiously.

Astrocyte aging may further compound this vulnerability. Aged astrocytes exhibit a reduced capacity to support neuronal function and maintain homeostasis and have been implicated in AD-related cellular dysfunction (Bronzuoli et al., 2019; Cohen & Torres, 2019; Monterey et al., 2021). Because astrocytic endfeet provide near-complete coverage of the cerebral vasculature (Mathiisen et al., 2010), age-related impairment of astrocyte function could further destabilize BBB integrity. Consistent with this, BBB permeability increases with age, with evidence suggesting greater vulnerability in older women compared with younger individuals (Goodall et al., 2018; Knox et al., 2022).

Figure 8. Proposed links between elevated FSH, vascular dysfunction, and blood-brain barrier disruption in Alzheimer’s disease. Elevated FSH is associated with vascular stiffness, endothelial dysfunction, and reduced vascular integrity, while BBB breakdown and reduced cerebral blood flow (CBF) may contribute to the entry or accumulation of inflammatory and lipid-associated factors within the brain. The model incorporates inflammatory mediators, including lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), together with lipid dysregulation involving apolipoprotein E4 (ApoE4), low-density lipoprotein (LDL), and lipoprotein receptor-related protein 1 (LRP1). The right panel illustrates a proposed two-hit model in which vascular dysfunction and increased BBB permeability may precede or facilitate subsequent neuroinflammatory and neurodegenerative changes. Reproduced from Xue et al. (2025) under the Creative Commons Attribution License (CC BY).

Figure 8. Proposed links between elevated FSH, vascular dysfunction, and blood-brain barrier disruption in Alzheimer’s disease. Elevated FSH is associated with vascular stiffness, endothelial dysfunction, and reduced vascular integrity, while BBB breakdown and reduced cerebral blood flow (CBF) may contribute to the entry or accumulation of inflammatory and lipid-associated factors within the brain. The model incorporates inflammatory mediators, including lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), together with lipid dysregulation involving apolipoprotein E4 (ApoE4), low-density lipoprotein (LDL), and lipoprotein receptor-related protein 1 (LRP1). The right panel illustrates a proposed two-hit model in which vascular dysfunction and increased BBB permeability may precede or facilitate subsequent neuroinflammatory and neurodegenerative changes. Reproduced from Xue et al. (2025) under the Creative Commons Attribution License (CC BY).

Integrative Mechanistic Framework: How Reproductive Aging in Biological Females Reconfigures Alzheimer’s Disease Risk

Endocrine and Metabolic Targets: Translational Opportunities in Alzheimer’s Disease

Limitations

Conclusion

References

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