Alzheimer’s disease (AD) represents one of the greatest challenges in modern neuroscience and medicine. It is the most common cause of dementia worldwide, progressively eroding memory, cognition, and functional independence in millions of individuals [1]. Since its first description in 1906 by Dr. Alois Alzheimer through the case of Auguste Deter, the disease has been characterized by its defining neuropathological features: amyloid plaques, consisting of insoluble deposits of amyloid-beta protein [2], and neurofibrillary tangles composed of hyperphosphorylated tau [3,4]. For decades, these hallmarks were seen as sufficient explanations for the clinical symptoms of dementia. Yet, as research has advanced, it has become increasingly clear that the clinical expression of AD cannot be understood solely through the presence of amyloid and tau pathology.

One of the most compelling insights into this discrepancy lies in the concept of neuroplasticity. Neuroplasticity refers to the ability of the brain to reorganize itself structurally and functionally in response to injury, experience, or disease. It encompasses mechanisms such as synaptic remodeling, dendritic spine turnover, long-term potentiation, neurogenesis, and network-level reorganization [5]. In the context of AD, neuroplasticity may act as a buffer, allowing some individuals to maintain cognitive function longer despite significant pathology, whereas in others, this compensatory capacity is more limited [6]. The brain’s ability to compensate unfolds along the course of disease. Early on, it can recruit extra resources and reorganize networks to preserve function, but as pathology builds, these mechanisms falter. Once synaptic loss and neuronal death reach a tipping point, compensation fails, and clinical decline accelerates. This trajectory underscores the importance of enhancing neuroplasticity early, before the brain’s reserves are depleted.

Importantly, neuroplasticity is not uniform across individuals. Emerging evidence demonstrates that biological sex profoundly shapes the capacity for plastic adoption in AD. Women are disproportionately affected by the disease: not only are they more likely to develop AD, but they also experience faster progression and more severe outcomes than men. This heightened burden is supported by epidemiological data showing that women constitute approximately two-thirds of AD patients globally [7], reflecting higher prevalence beyond mere differences in lifespan [8]. Longitudinal studies further indicate that women often exhibit accelerated cognitive decline and more rapid clinical progression, particularly among carriers of the APOE ε4 allele (genetic variant of the apolipoprotein E gene that increases risk for late-onset AD), underscoring biological mechanisms that exacerbate disease course [9]. These disparities are not explained by lifespan differences alone. “Lifespan differences” refers to the well-established fact that women in developed countries live, on average, four to six years longer than men. For many years, this longevity gap was thought to explain why nearly two-thirds of Alzheimer’s patients are women: simply put, women lived long enough to reach the ages when the disease typically emerges. Yet this demographic explanation tells only part of the story. Even after controlling for age, studies show that women face higher incidence rates, earlier onset in some groups, and often faster progression [10]. These patterns point to biological influences beyond survival alone that contribute to the disproportionate impact of Alzheimer’s on women. Rather, hormonal influences, genetic predispositions, and sex-specific patterns of brain connectivity converge to produce distinct neuroplastic trajectories in men and women [8,11].

This review provides a comprehensive and critical examination of sex differences in neuroplasticity within AD. It begins by discussing the mechanistic basis of neuroplasticity and how it is disrupted in AD. It then explores evidence for sex differences in AD pathology and plasticity, followed by a detailed analysis of hormonal and genetic influences. Additional sections expand on historical perspectives in neuroscience research, translational challenges, and societal implications. Finally, the review outlines future directions for advancing sex-aware research and therapeutic development.

This research work was conducted through systematic searches of PubMed, Web of Science, and Google Scholar covering January 2020 through August 2024. We focused on peer-reviewed studies addressing sex differences in neuroplasticity and AD, using combinations of search terms such as “sex differences,” “neuroplasticity,” “Alzheimer’s disease,” “estrogen,” “APOE ε4,” “hippocampal atrophy,” and “cognitive decline.” Recent work from 2020–2024 was prioritized to capture emerging discoveries in this rapidly advancing field, while landmark earlier studies were included to provide context. Articles were selected for their relevance to neuroplastic mechanisms, methodological rigor, and contribution to understanding sex-specific pathways in AD. Both human and translational animal studies were incorporated to bridge clinical and mechanistic perspectives. Studies with small cohorts or limited demographic representation were noted as limitations. Together, the evidence synthesized here spans neuroimaging, molecular, genetic, and clinical domains, offering an integrated view of how biological sex shapes neuroplastic responses in AD.

By weaving together molecular, clinical, and epidemiological findings, this review argues that sex is not a peripheral consideration but a central determinant of how AD unfolds in the brain. Recognizing and addressing sex-dependent differences in neuroplasticity holds promise for improving diagnosis, treatment, and care for all individuals affected by this devastating disease.

Neuroplasticity is the foundation upon which the brain maintains resilience against degeneration. The hippocampus, prefrontal cortex, and parietal association cortices are key hubs of plasticity, supporting memory consolidation, executive function, and spatial navigation—domains prominently impaired in AD. The mechanisms of plasticity span multiple levels of organization. At the synaptic level, long-term potentiation (LTP) is the electrophysiological basis of memory. LTP depends on N-methyl-D-aspartate (NMDA) receptor activation, calcium influx, and downstream signaling cascades that strengthen synaptic connections [12]. In AD, amyloid-beta oligomers interfere with NMDA receptor function, suppressing LTP and facilitating long-term depression, leading to synaptic weakening. Similarly, tau pathology disrupts microtubule stability and axonal transport, compromising synaptic communication. At the structural level, dendritic spine remodeling represents a physical correlate of plasticity. Healthy brains maintain a dynamic balance of spine formation and pruning, allowing circuits to adapt to learning and experience. In AD, spine density is markedly reduced, particularly in hippocampal pyramidal neurons [13]. This structural loss correlates with impaired synaptic function and cognitive decline. Neuroplasticity encompasses a range of adaptive processes that help the brain preserve function in the face of pathology. In the hippocampus, reports of adult neurogenesis, together with synaptic remodeling and long-term potentiation, support cellular flexibility and connectivity. At the systems level, circuit reorganization enables networks to compensate for damage, collectively providing a dynamic foundation for cognitive resilience against neurodegenerative insults [14].

Finally, at the systems level, functional reorganization allows other brain regions to compensate for damage. For instance, functional MRI studies show increased activation of prefrontal areas in AD patients during memory tasks, suggesting recruitment of alternative networks [15]. However, this compensation has limits, and when exhausted, clinical decline accelerates. Sex differences permeate these processes. Estrogen enhances synaptic spine density, upregulates NMDA receptor expression, and promotes neurogenesis, whereas testosterone supports dendritic remodeling and is converted to estrogen locally in the brain. Genetic and epigenetic modifiers further influence these mechanisms. Understanding how these processes differ between men and women is essential for clarifying why AD disproportionately impacts one sex over the other.

For much of the twentieth century, biomedical research largely ignored sex as a biological variable. Clinical trials predominantly recruited male participants, while animal studies often used only male rodents to minimize variability associated with female hormonal cycles [16]. As a result, sex-specific biology was underexplored, and findings from male models were generalized to all populations. In AD research, this oversight proved costly. Epidemiological evidence consistently showed that women represented the majority of AD patients, yet their overrepresentation was often attributed solely to greater longevity. Only in the last two decades has it become evident that women not only live longer but also face unique biological vulnerabilities. For instance, the role of menopause in modulating risk was historically underappreciated, as was the differential impact of the APOE ε4 allele between sexes. The recognition of sex differences has been accelerated by policy changes. The National Institutes of Health (NIH) mandated in 2016 that sex be considered as a biological variable in all funded research [17]. This shift has catalyzed a surge of studies explicitly examining male-female differences in AD pathology, neuroimaging, and molecular biology. Today, the field increasingly acknowledges that understanding AD requires an integrative framework that places sex differences at its core.

Within this evolving framework, significant sex differences have been identified in hippocampal atrophy, synaptic plasticity markers, and functional connectivity. Neuroimaging studies reveal that women with AD demonstrate greater hippocampal atrophy than men, even when controlling for baseline brain size. Williamson et al. [18] found weaker interhemispheric hippocampal connectivity in women, suggesting more profound network disruption. This aligns with clinical findings of faster memory decline in female patients. Although women often exhibit greater hippocampal atrophy, men appear to follow a different path toward cognitive decline. Vascular conditions such as small vessel disease and atherosclerosis not only disrupt cerebral blood flow but also intensify neurodegenerative changes, creating a landscape in which Alzheimer’s pathology can progress more aggressively [19]. At the same time, the gradual decline of testosterone in aging men has been tied to weaker memory performance and greater neuronal vulnerability, likely reflecting a loss of the hormone’s usual protective influence on synaptic health. Together, these vascular and hormonal factors weave a distinct pattern of risk that sets men apart from women, whose vulnerability is shaped more strongly by estrogen loss. Recognizing these sex-specific pathways is essential for a deeper understanding of why AD unfolds differently across genders [20,21]. Molecular studies corroborate the above findings. Kolahchi et al. [11] reviewed evidence that women show downregulation of glutamatergic signaling pathways and loss of excitatory synapses, pointing to impaired excitatory plasticity. They also reported that female APOE ε4 carriers exhibit higher amyloid and tau burden, coupled with greater structural impairment. These molecular changes provide a mechanistic explanation for the clinical disparities observed. Moreover, AD reshapes the brain well beyond the hippocampus. Neuroimaging shows that vascular burden is a powerful predictor of future dementia and reflects cerebrovascular contributions that hippocampal atrophy alone does not capture [22]. Structural imaging likewise reveals widespread cortical and subcortical change, underscoring how network-level degeneration replaces focal loss as the disease progresses [23]. Molecular imaging adds further depth: positron emission tomography (PET) studies find that amyloid and tau extend into distributed cortical systems and that the relationships among amyloid, tau, neurodegeneration and cognition can differ by sex. For example, women may show greater tau burden in medial temporal regions for a given amyloid level, whereas men can show stronger associations between tau, neurodegeneration and cognitive impairment in some settings. These convergent findings argue for a whole-brain, multimodal approach to Alzheimer’s research and cautious interpretation of sex effects that are still being defined [24]. Nevertheless, not all findings are consistent. Boccalini et al. [25], using multimodal biomarker analysis, found no significant sex differences in amyloid or tau burden. Their conclusion that neurodegeneration progresses similarly in both sexes contrasts with the majority of literature. However, their reliance on the Mini-Mental State Examination (MMSE) as the primary cognitive measure limited sensitivity. Subtle cognitive differences, particularly in episodic memory or executive function, may have been overlooked. Critically, methodological heterogeneity across studies complicates synthesis. Small sample sizes, cross-sectional designs, and demographic homogeneity limit generalizability. Nonetheless, the convergence of neuroimaging, molecular, and genetic evidence supports a consistent conclusion: women experience faster hippocampal degeneration and weaker synaptic resilience than men, translating into more severe clinical decline.

Beyond differences in methodology, the field struggles with fundamental limits in biomarker sensitivity and study design. Even our most advanced imaging tools may fall short of detecting the subtle, sex-specific shifts in synaptic density or microstructural connectivity that occur before obvious tissue loss. Blood and cerebrospinal fluid measures, while rapidly improving, still lack the precision to capture the distinct molecular cascades shaping vulnerability in men and women during preclinical stages [26]. These gaps are compounded by the heavy reliance on cross-sectional studies, which offer only static snapshots rather than the unfolding trajectories of neuroplastic adaptation. This is especially limiting for understanding sex differences, as hormonal transitions like menopause span years and interact dynamically with genetic risk and emerging pathology.

The role of hormones in shaping neuroplasticity is among the most compelling explanations for sex differences in AD. Estrogen, in particular, exerts widespread neuroprotective effects. It enhances synaptic spine density, supports long-term potentiation, regulates mitochondrial function, and reduces oxidative stress. During reproductive years, these effects provide women with substantial cognitive resilience. Menopause represents a critical inflection point. As estrogen levels decline, protective mechanisms weaken, and vulnerability to AD pathology increases [27]. Simultaneously, follicle- stimulating hormone (FSH) and luteinizing hormone (LH) rise, exerting pro-amyloid and pro-tau effects [28]. The combined hormonal shift accelerates neurodegeneration. Empirical studies support this model. Kadlecova et al. [27] demonstrated in rodent models that estrogen supplementation preserved synaptic density and improved memory performance, findings partially replicated in human data.  Johnson et al. [28] added nuance by linking menopause-related hormonal decline with sleep disruption, another independent risk factor for AD. By highlighting the intertwined effects of hormones and sleep, they underscored the multifactorial nature of women’s risk. Literature is not without limitations. Animal models often fail to fully replicate human menopause, and observational human studies struggle with confounding factors [29]. Furthermore, interventions such as hormone replacement therapy (HRT) have yielded mixed results, with its effectiveness shaped by both timing and genetics. Evidence suggests the greatest benefit comes when therapy begins during the menopausal transition, while estrogen receptors remain responsive and neural networks are still adapting to hormonal change. By contrast, initiating HRT years after menopause, once these systems have already adjusted, tends to be less effective and may even pose risks. Genetics further complicate the picture, as carriers of the APOE ε4 allele may respond differently to HRT than non-carriers. Still, the consensus is clear: estrogen decline is a central driver of sex differences in AD, interacting with genetic and environmental factors to shape neuroplastic trajectories.

Genetics adds another dimension to sex differences in AD. The APOE ε4 allele is the strongest genetic risk factor for sporadic AD, increasing risk and lowering age of onset. Yet its effects are strikingly sex-dependent. Women carrying ε4 face a higher likelihood of developing AD than men with the same genotype [9,30]. Guo et al. [30] employed multi-omics analyses to reveal sex-specific gene expression differences in ε4 carriers. Although correlational, these findings suggest distinct molecular cascades are activated in women versus men. Guo et al. [31] extended this work by analyzing gene networks rather than single loci, demonstrating the complexity of interactions. Lopez-Lee et al. [9] synthesized evidence that APOE4 interacts with estrogen receptor expression, sex chromosome dosage, and epigenetic regulation, amplifying risk in women. These findings highlight the importance of considering sex and genotype together. Genetic vulnerability is not uniform; it is filtered through hormonal and epigenetic contexts that differ profoundly between sexes. This synergy likely explains the disproportionate burden borne by women.

Recognizing sex differences in neuroplasticity has profound clinical implications. Diagnostic tools must be refined to capture sex-specific trajectories. Reliance on crude instruments such as the MMSE obscures early deficits, particularly in women. Developing sensitive, sex-aware neuropsychological tests could enable earlier detection and intervention. Therapeutically, sex-specific strategies may be required. Hormone replacement therapy has shown promise when initiated near menopause but may be ineffective or harmful when started later. Selective estrogen receptor modulators (SERMs) represent a potential avenue, offering neuroprotective benefits without systemic risks. Personalized approaches that consider sex, genotype, and hormonal history may prove most effective. Non-pharmacological interventions such as exercise, cognitive training, and sleep regulation also show promise. Exercise enhances hippocampal neurogenesis, but sex differences in response suggest tailored regimens may be beneficial [32]. Similarly, sleep interventions may disproportionately benefit women by mitigating the combined effects of hormonal decline and disrupted circadian rhythms.

Despite progress, translating sex-specific insights into practice faces challenges. Animal models often fail to capture human-like menopause or lifespan differences, limiting translational relevance. Clinical trials frequently underrepresent women or fail to stratify results by sex [33]. Moreover, genetic diversity across populations remains underexplored, raising concerns about generalizability. One of the biggest hurdles in translation is that our current biomarkers are not sensitive enough to capture sex-specific patterns of neuroplasticity. Most imaging protocols are tuned to detect later-stage pathology, overlooking the subtle early changes that may unfold differently in men and women. Molecular markers face a similar limitation, often blurring sex-related vulnerabilities into broader disease signals. Added to this is the field’s dependence on cross-sectional studies, which miss the dynamic ebb and flow of plasticity as the brain compensates and eventually declines. What is urgently needed are long-term, longitudinal studies that follow individuals across the reproductive years, through menopause in women and andropause in men—yet such efforts remain rare, hampered by both cost and complexity. Opportunities lie in integrating multi-omics data with neuroimaging and clinical phenotyping. Large- scale consortia, such as the AD Neuroimaging Initiative (ADNI), provide powerful platforms for sex-aware analyses. Advances in single-cell sequencing, epigenomics, and connectomics offer unprecedented resolution for dissecting sex-dependent mechanisms. Harnessing these tools will require deliberate commitment to sex-inclusive study designs.

The disproportionate burden of AD on women extends beyond biology. Women represent the majority of patients and also the majority of caregivers. The economic, emotional, and societal impact is profound. Recognizing sex differences in AD is therefore not only a scientific imperative but also a matter of equity and public health policy. Policies should prioritize funding for sex-aware research, ensure equitable representation of women in clinical trials, and support caregivers who disproportionately shoulder the burden of AD. Public health messaging should also address sex-specific risk factors, such as menopause and sleep disruption, empowering individuals to make informed decisions about their health.

Future research must prioritize longitudinal, sex-aware designs that track neuroplasticity over time. Moving this field forward will depend on developing next-generation biomarkers that can reveal sex-specific patterns of neuroplasticity even before symptoms appear. High-resolution diffusion imaging, PET tracers sensitive to synaptic density, and network-based connectivity measures all hold promise, but they need to be tested for their ability to capture these early, sex-dependent shifts. Just as crucial is shifting from one-time snapshots to longitudinal studies that follow neuroplastic changes across key hormonal transitions and periods of genetic risk. Distinguishing the roles of sex chromosomes from sex hormones will be essential, potentially through genetically engineered models. Expanding demographic diversity in study populations will enhance generalizability and address disparities. Therapeutic innovation should explore SERMs, neurotrophic factor enhancers, and personalized lifestyle interventions. Integrating molecular, genetic, and neuroimaging approaches will enable precision medicine tailored to sex-specific biology. Ultimately, addressing sex differences offers not only scientific clarity but also the possibility of more equitable and effective care.

This review underscores that neuroplasticity in AD is not uniform but profoundly shaped by sex. Women, particularly APOE ε4 carriers, experience greater hippocampal atrophy, impaired synaptic connectivity, and accelerated clinical decline. Estrogen loss during menopause compounds vulnerability, while genetic and epigenetic interactions amplify risk. Yet neuroplasticity also represents a source of resilience. Understanding its sex-specific modulation holds promise for developing tailored diagnostic tools and therapies. By integrating hormonal, genetic, and mechanistic insights, the field can move toward precision medicine that acknowledges the unequal burden of AD while striving for equitable outcomes. AD is not merely a disease of plaques and tangles, but of disrupted plasticity shaped by sex-dependent biology. Recognizing this truth is essential for advancing both science and care in the decades to come.