Reproductive Aging, FSH, APO Proteins, and Alzheimer’s Disease: Endocrine Mechanisms Linking Ovarian Decline to Neurodegeneration

Introduction

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

Cholinergic Hypothesis

The cholinergic hypothesis represents one of the earliest frameworks proposed to explain AD pathogenesis. It posits that selective degeneration of cholinergic neurons in the nucleus basalis of Meynert (NBM) leads to reduced choline acetyltransferase (ChAT) activity, impairing acetylcholine synthesis and disrupting cortical cholinergic transmission (Berry & Harrison, 2023). This loss of cholinergic integrity is accompanied by increased deposition of senile plaques in affected cortical regions (Rodríguez et al., 2010; Serrano-Pozo et al., 2011). Collectively, this model highlights a strong association between basal forebrain cholinergic dysfunction and the cognitive deficits characteristic of AD (Hampel et al., 2019). Cholinergic neurons within the NBM, as well as those in the medial septum and diagonal band of Broca (MS/DBB), are particularly vulnerable to degeneration in this context (Schmitz et al., 2018).

Acetylcholine (ACh) is produced in cholinergic neurons through the enzymatic conversion of choline and acetyl-coenzyme A by choline acetyltransferase (ChAT). Once synthesized, ACh is transported into synaptic vesicles by the vesicular acetylcholine transporter (VAChT) and released into the synaptic cleft in response to presynaptic depolarization. In the synaptic space, ACh interacts with both muscarinic and nicotinic receptors (mAChRs and nAChRs) on postsynaptic cells to facilitate signal transmission (Paul et al., 2022). Termination of signaling is achieved through rapid enzymatic breakdown by acetylcholinesterase (AChE), generating choline, which is subsequently reclaimed by the presynaptic neuron for reuse (Berry & Harrison, 2023; Stanciu et al., 2019). Disruptions in ChAT expression or function reduce ACh availability, weakening cholinergic signaling. Such impairments affect multiple physiological processes governed by this system, including cognitive function, attentional regulation, motor control, and sleep–wake dynamics (Walczak-Nowicka & Herbet, 2021).

Figure 1. Cholinergic projections arise from basal forebrain nuclei - including the medial septum (MS), vertical limb of the diagonal band of Broca (vDB), nucleus basalis of Meynert (NBM), and substantia innominata (SI) - which send widespread projections to the hippocampus, thalamus, olfactory bulb, and cortical regions. In parallel, cholinergic neurons of the pontomesencephalon - specifically the laterodorsal tegmental nucleus (LDT) and pedunculopontine tegmental nucleus (PPT) - project to the hindbrain, thalamus, hypothalamus, and basal forebrain, contributing to the regulation of arousal and behavioral state. Adapted from Paul et al. (2015).

Figure 1. Cholinergic projections arise from basal forebrain nuclei - including the medial septum (MS), vertical limb of the diagonal band of Broca (vDB), nucleus basalis of Meynert (NBM), and substantia innominata (SI) - which send widespread projections to the hippocampus, thalamus, olfactory bulb, and cortical regions. In parallel, cholinergic neurons of the pontomesencephalon - specifically the laterodorsal tegmental nucleus (LDT) and pedunculopontine tegmental nucleus (PPT) - project to the hindbrain, thalamus, hypothalamus, and basal forebrain, contributing to the regulation of arousal and behavioral state. Adapted from Paul et al. (2015).

Figure 2. Acetylcholine release and synaptic signaling. Schematic of cholinergic neurotransmission showing (1) Ca²⁺-dependent release of acetylcholine (ACh) from presynaptic vesicles, (2) binding of ACh to postsynaptic receptors to induce depolarization, and (3) enzymatic breakdown of ACh by acetylcholinesterase (AChE) with subsequent reuptake of choline into the presynaptic neuron. Adapted from Stanciu et al., (2019).

Figure 2. Acetylcholine release and synaptic signaling. Schematic of cholinergic neurotransmission showing (1) Ca²⁺-dependent release of acetylcholine (ACh) from presynaptic vesicles, (2) binding of ACh to postsynaptic receptors to induce depolarization, and (3) enzymatic breakdown of ACh by acetylcholinesterase (AChE) with subsequent reuptake of choline into the presynaptic neuron. Adapted from Stanciu et al., (2019).

Endocrine Drivers of Female-Related 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. Collectively, ApoE4 disrupts multi-compartment Aβ clearance kinetics, leading to impaired Aβ turnover, prolonged brain retention, and enhanced neuroinflammatory signaling. However, the relationship between ApoE isoforms and tau pathology is more context-dependent and does not strictly follow the canonical AD risk hierarchy. In primary tauopathy models (e.g., TauP301L and PSP), ApoE2 promotes greater tau aggregation and hyperphosphorylation than ApoE3 and ApoE4 (ApoE2 > ApoE3 > ApoE4). In contrast, in the presence of amyloid-β - as in Alzheimer’s disease - ApoE4 appears to exacerbate tau-mediated neurodegeneration, likely through indirect mechanisms linked to impaired Aβ clearance and heightened inflammatory signaling. Adapted from Liu et al., 2025.

Figure 3. Isoform-dependent ApoE regulation of Aβ clearance kinetics and context-specific tau pathology. Collectively, ApoE4 disrupts multi-compartment Aβ clearance kinetics, leading to impaired Aβ turnover, prolonged brain retention, and enhanced neuroinflammatory signaling. However, the relationship between ApoE isoforms and tau pathology is more context-dependent and does not strictly follow the canonical AD risk hierarchy. In primary tauopathy models (e.g., TauP301L and PSP), ApoE2 promotes greater tau aggregation and hyperphosphorylation than ApoE3 and ApoE4 (ApoE2 > ApoE3 > ApoE4). In contrast, in the presence of amyloid-β - as in Alzheimer’s disease - ApoE4 appears to exacerbate tau-mediated neurodegeneration, likely through indirect mechanisms linked to impaired Aβ clearance and heightened inflammatory signaling. Adapted from Liu et al., 2025.

Figure 4. Structural conformations of apolipoprotein E (apoE) isoforms. Schematic representation of the distinct conformational differences among apoE2, apoE3, and apoE4, illustrating how amino acid substitutions at key positions alter intramolecular interactions. Replacement of cysteine residues with positively charged arginine residues - particularly in apoE4 - modifies electrostatic interactions within the protein, promoting domain–domain interactions between the N-terminal and C-terminal regions. In contrast, apoE2 and apoE3, which retain cysteine at these positions, exhibit reduced intramolecular interaction and adopt more flexible conformations. These structural differences influence lipid binding, receptor interactions, and isoform-specific functional properties relevant to disease risk. Adapted from Butterfield and Mattson (2020).

Figure 4. Structural conformations of apolipoprotein E (apoE) isoforms. Schematic representation of the distinct conformational differences among apoE2, apoE3, and apoE4, illustrating how amino acid substitutions at key positions alter intramolecular interactions. Replacement of cysteine residues with positively charged arginine residues - particularly in apoE4 - modifies electrostatic interactions within the protein, promoting domain–domain interactions between the N-terminal and C-terminal regions. In contrast, apoE2 and apoE3, which retain cysteine at these positions, exhibit reduced intramolecular interaction and adopt more flexible conformations. These structural differences influence lipid binding, receptor interactions, and isoform-specific functional properties relevant to disease risk. Adapted from Butterfield and Mattson (2020).

Table 1. Structural and functional hierarchy of amyloid-β aggregation states and their relevance to Alzheimer’s disease. This table summarizes the progressive aggregation states of amyloid-β (Aβ), spanning from soluble monomeric peptides to insoluble extracellular plaques, and highlights their distinct structural, biochemical, and pathological characteristics. Early-stage species, particularly soluble oligomers, are highly dynamic and exhibit the greatest neurotoxicity, with strong associations to synaptic dysfunction and cognitive decline. Intermediate assemblies such as protofibrils represent transitional forms with significant pathogenic potential. In contrast, mature fibrils and plaques are structurally stable end-products of aggregation that, while defining histopathological features of Alzheimer’s disease, show weaker correlations with clinical symptoms. Collectively, the table emphasizes that Aβ toxicity is not solely dependent on aggregate presence, but is critically influenced by aggregation state, solubility, and molecular dynamics.

Stepwise Neurobiological Dysregulation Driven by Elevated FSH in Alzheimer’s Disease

Elevated FSH Disrupts Oxidative Phosphorylation (OXPHOS) in Aging Neurons, Shifting Cellular Energetics Toward Dysfunction

Impairments in glucose metabolism and oxidative phosphorylation are well-established features of AD, consistently documented across both experimental and clinical settings. These deficits are routinely observed using fluorodeoxyglucose positron emission tomography (FDG-PET), which reveals characteristic patterns of cerebral hypometabolism in affected individuals (Christodoulou et al., 2026). Among the pathways implicated in this dysfunction, the C/EBPβ-δ-secretase signaling axis has emerged as a key contributor, with FSH acting as a positive regulator of this pathway (Xiong et al., 2023). C/EBPβ, a stress-responsive transcription factor upregulated with aging and in AD, disrupts neuronal glucose utilization by interfering with insulin signaling (Tsukada et al., 2011). Specifically, C/EBPβ suppresses FOXO1 activity and inhibits Akt (protein kinase B), a central mediator of insulin-dependent glucose uptake. Because Akt signaling is required for efficient glucose transport and downstream metabolism, its inhibition induces a functional insulin-resistant state within neurons (Gabbouj et al., 2019). As a result, brain cells are unable to effectively utilize glucose despite adequate substrate availability, directly contributing to the hypometabolic profile observed on FDG-PET imaging in AD. Notably, the metabolic effects of FSH extend beyond the central nervous system, influencing processes such as adipogenesis and cardiovascular function in both men and women, suggesting broader systemic consequences of dysregulated FSH signaling (Kim et al., 2026).

Beyond its effects on glucose utilization, the C/EBPβ-δ-secretase pathway further compromises cellular energetics by targeting key regulators of mitochondrial function. Activation of this axis promotes degradation of nicotinamide phosphoribosyltransferase (NAMPT), leading to depletion of nicotinamide adenine dinucleotide (NAD⁺) (Li et al., 2025), an essential cofactor for mitochondrial respiration and energy production. Upstream regulation of C/EBPβ provides an additional layer of relevance in aging. C/EBPβ is physiologically induced by gonadotropins, including follicle-stimulating hormone FSH and LH, where it regulates genes involved in steroidogenesis and inflammatory signaling, such as steroidogenic acute regulatory protein (StAR) and prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2) (Sirois & Richards, 1993; Duffy et al., 2019). Under normal conditions, LH surges produce transient increases in C/EBPβ that support tightly regulated periovulatory transcriptional programs. However, in the context of aging, sustained elevations in gonadotropins-particularly chronic exposure to FSH can drive persistent activation of C/EBPβ (Zaidi et al., 2024). Such prolonged induction may shift signaling away from adaptive, temporally restricted responses toward sustained inflammatory and proteolytic activity. Correspondingly, both ApoE4 and FSH have been shown to additively activate the C/EBPβ-δ-secretase pathway, promoting proteolytic processing of amyloid precursor protein (APP) and tau, and thereby enhancing amyloid-β accumulation and neurofibrillary tangle formation (Xiong et al., 2022; Xiong et al., 2023; Zaidi et al., 2024).

Importantly, the hypometabolic state observed in AD is not necessarily a primary event, but may instead be preceded by a phase of heightened mitochondrial activity and neural hyperexcitability (Christodoulou et al., 2026; Naia et al., 2023) . During these early stages, C/EBPβ-dependent signaling can transiently enhance mitochondrial output - partly through increased transcriptional activity at the TFAM promoter - thereby supporting mitochondrial biogenesis and oxidative capacity in response to elevated cellular demand (Sierra-Magro et al., 2023). Concurrently, C/EBPβ-mediated suppression of FOXO1 and REST disrupts inhibitory neuronal programs, particularly within GABAergic circuits, leading to reduced inhibitory tone and aberrant network excitation (Mattson M. P. 2020; Xia et al., 2022) . This state of hyperexcitability is consistent with early hypermetabolic signals detected in 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 deposition, tau pathology, oxidative stress, and electron transport chain (ETC) impairment. These stressors disrupt mitochondrial quality control by promoting excessive fission (e.g., DRP1, FIS1, MFF upregulation) while suppressing fusion (OPA1, MFN1/2), mitophagy (PINK1, Parkin, LC3), and mitochondrial-derived vesicle (MDV) formation. The resulting imbalance favors mitochondrial fragmentation, reduced turnover of damaged organelles, and accumulation of dysfunctional mitochondria. Adapted from Li et al., (2022).

Figure 5. Convergent drivers and consequences of mitochondrial perturbation in Alzheimer’s disease. Amyloid-β deposition, tau pathology, oxidative stress, and electron transport chain (ETC) impairment. These stressors disrupt mitochondrial quality control by promoting excessive fission (e.g., DRP1, FIS1, MFF upregulation) while suppressing fusion (OPA1, MFN1/2), mitophagy (PINK1, Parkin, LC3), and mitochondrial-derived vesicle (MDV) formation. The resulting imbalance favors mitochondrial fragmentation, reduced turnover of damaged organelles, and accumulation of dysfunctional mitochondria. Adapted from Li et al., (2022).

However, sustained activation of this pathway appears to shift the system toward metabolic failure. Chronic C/EBPβ activity - together with persistent Akt inhibition and progressive mitochondrial damage - promotes the accumulation of dysfunctional mitochondria and reduces overall metabolic efficiency (Shaerzadeh et al., 2014; Yu et al., 2014; Wang et al., 2025). As mitochondrial quality control mechanisms become compromised, this initially compensatory hypermetabolic state transitions into overt hypometabolism (Naia et al., 2023; Christodoulou et al., 2026). The downstream consequences of this metabolic shift are both multifaceted and self-reinforcing. Impaired oxidative metabolism promotes cytosolic acidification and lactate accumulation, which in turn disrupt lysosomal acidification and autophagic flux (Chen et al., 2022; Hagihara & Miyakawa, 2024; Wang X et al., 2025). These alterations contribute to lysosomal swelling, autophagosome accumulation, and impaired clearance of cellular debris (Quick et al., 2023). In parallel, these metabolic disturbances sustain microglial activation and inflammatory signaling, further amplifying neurodegenerative processes (Jung et al., 2025; Wu et al., 2025). The mechanisms by which metabolic perturbations bias microglial cells toward pro-inflammatory phenotypes are beyond the scope of this review; however, readers are referred to prior work for a more detailed treatment of this topic (Ball et al., 2025; Shaikh & Nicholson, 2009).

FSH-Mediated Augmentation of 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 (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 (Wang, J. 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., 2016). 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. Adapted from Wang, J., et al. (2025).

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. Adapted from Wang, J., et al. (2025).

Figure 7. FSH-FSHR signaling as a driver of amyloidogenic, tau-directed, and inflammatory pathology in Alzheimer’s disease. FSH binding to FSHR in cortical and hippocampal neurons activates Gαi-dependent ERK1/2 and AKT signaling, leading to phosphorylation of C/EBPβ and SRPK2. These pathways upregulate asparagine endopeptidase (AEP), promoting cleavage of APP and tau into aggregation-prone species (Aβ, Tau368). These products further activate microglial and inflammasome signaling, amplifying cytokine production and sustaining neuroinflammation. Collectively, this axis links elevated FSH to proteolysis, inflammation, and accumulation of neurotoxic substrates in AD. Adapted from Li et al., (2024).

Figure 7. FSH-FSHR signaling as a driver of amyloidogenic, tau-directed, and inflammatory pathology in Alzheimer’s disease. FSH binding to FSHR in cortical and hippocampal neurons activates Gαi-dependent ERK1/2 and AKT signaling, leading to phosphorylation of C/EBPβ and SRPK2. These pathways upregulate asparagine endopeptidase (AEP), promoting cleavage of APP and tau into aggregation-prone species (Aβ, Tau368). These products further activate microglial and inflammasome signaling, amplifying cytokine production and sustaining neuroinflammation. Collectively, this axis links elevated FSH to proteolysis, inflammation, and accumulation of neurotoxic substrates in AD. Adapted from Li et al., (2024).

Despite the lack of evidence concerning microglial expression of FSH-receptors, considering the regulatory influence of FSH on C/EBPβ, it follows that elevated FSH signaling may directly promote microglial activation through C/EBPβ-dependent and related inflammatory pathways. Consistent with this, accumulating evidence indicates that FSH acts as a positive modulator of neuroinflammatory processes and glial activation. To directly assess these effects, Xiong et al. (2023) developed an Alzheimer’s disease mouse model using ovariectomy to disrupt endogenous sex hormone balance, while maintaining physiological estrogen levels through replacement. Under these conditions, FSH elevation was associated with increased accumulation of Alzheimer’s disease-related markers in the brain, including Aβ and hyperphosphorylated tau (Tau368), indicating that FSH may promote disease pathology independently of estrogen.

Importantly, Aβ and hyperphosphorylated tau act as reciprocal amplifiers of neuroinflammation. Aβ facilitates microglial recruitment and clustering within plaque-dense regions (Gao et al., 2023) and induces activation of the NLRP3 inflammasome, leading to the release of apoptosis-associated speck-like protein containing a CARD (ASC) aggregates. These ASC specks can bind Aβ, further promoting its aggregation and propagation (Venegas et al., 2017). In parallel, chronic activation of microglia and astrocytes enhances amyloidogenic APP processing and upregulates tau-directed kinases, including glycogen synthase kinase-3β (GSK-3β), thereby accelerating tau hyperphosphorylation, synaptic dysfunction, and neurodegenerative spread (Chen & Yu, 2023; Zhang et al., 2021). Further supporting a causal role, treatment with FSH-neutralizing antibodies has been shown to reduce Aβ accumulation and tau pathology in experimental models, reinforcing the contribution of FSH signaling to Alzheimer’s disease progression (Xiong et al., 2022).

FSH-Mediated Disruption of the Blood-Brain Barrier

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 tightly regulate molecular exchange between the circulation and the central nervous system, restrict the entry of neurotoxic substances, and maintain neural homeostasis (Kim et al., 2025).

Circulating FSH levels are inversely associated with vascular compliance, such that higher FSH concentrations correlate with increased arterial stiffness and endothelial dysfunction (Ferretti et al., 2018; Laakkonen et al., 2021; Wang et al., 2026; Xue et al., 2025). Experimental and clinical studies further indicate that elevated FSH promotes vascular calcification and progressive loss of arterial elasticity, contributing to age-related vascular remodeling (Li et al., 2024; Roelofs et al., 2022). In parallel, FSH has been shown to disrupt endothelial junctional integrity by altering the expression of adherens junction proteins, including E-cadherin and V-cadherin, thereby increasing vascular permeability (Kolnes et al., 2020; Rocca et al., 2024).

Beyond its effects on peripheral vasculature and neural cells (Xue et al., 2025), emerging evidence suggests that FSH can also influence cerebrovascular function (Alkhalifa et al., 2023; Wilson et al., 2008). Because BBB integrity depends on adherens and tight junction mechanisms shared across vascular beds, FSH-mediated disruption of endothelial junctional signaling observed in peripheral tissues may extend to the BBB. Such destabilization would be expected to increase permeability, facilitating the entry of inflammatory mediators, lipids, and circulating factors into the brain parenchyma.

In addition to adherens junction disruption, BBB impairment may also arise through FSH-associated alterations in gap junction signaling. In a mouse model, ovariectomy followed by treatment with a gonadotropin agonist (leuprolide acetate) resulted in increased expression of connexin-43 and enhanced Evans blue dye extravasation into the brain, indicating elevated BBB permeability (Wilson et al., 2008). Notably, BBB dysfunction is now recognized as an early feature of Alzheimer’s disease, emerging prior to overt neurodegeneration and clinical symptoms (Alkhalifa et al., 2023).

Figure 8. FSH-mediated contributions to blood–brain barrier dysfunction and cerebrovascular pathology. Elevated FSH promotes blood-brain barrier (BBB) disruption, vascular stiffness, and reduced cerebral blood flow (CBF) through inflammatory signaling, lipid dysregulation, and structural vascular changes. These alterations facilitate the entry of peripheral risk factors into the brain, amplifying neuroinflammation, cerebral lipid accumulation, cerebral amyloid angiopathy (CAA), and intracranial atherosclerosis. Collectively, these processes contribute to the development of Alzheimer’s disease-like pathology. Adapted from Xue, Y., et al. (2025).

Figure 8. FSH-mediated contributions to blood–brain barrier dysfunction and cerebrovascular pathology. Elevated FSH promotes blood-brain barrier (BBB) disruption, vascular stiffness, and reduced cerebral blood flow (CBF) through inflammatory signaling, lipid dysregulation, and structural vascular changes. These alterations facilitate the entry of peripheral risk factors into the brain, amplifying neuroinflammation, cerebral lipid accumulation, cerebral amyloid angiopathy (CAA), and intracranial atherosclerosis. Collectively, these processes contribute to the development of Alzheimer’s disease-like pathology. Adapted from Xue, Y., et al. (2025).

Astrocyte aging represents an additional layer of vulnerability. Aged astrocytes exhibit reduced capacity to support neuronal function and maintain homeostasis, and have been identified as a strong cellular predictor of Alzheimer’s disease risk (Bronzuoli et al., 2019; Cohen & Torres, 2019; Monterey et al., 2021). Given that astrocytic endfeet provide near-complete coverage of the cerebral vasculature (Mathiisen et al., 2010), age-related astrocytic dysfunction is likely to further compromise BBB stability. Consistent with this, aging itself is associated with progressive increases in BBB permeability, with older women demonstrating greater BBB vulnerability than younger individuals (Goodall et al., 2018; Knox et al., 2022).

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

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

Conclusions

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