Midlife brain vulnerability: Sex differences in functional magnetic resonance imaging and Alzheimer's disease risk

Midlife represents a critical transition period when lifestyles and healthy habits increasingly influence dementia risk. ¹ Aging biomarkers exhibit two accelerated inflection points—around 44 and 60 years old. ² Capturing biomarkers in this age range can reveal mechanisms underlying age-related disorders and offer preventative interventions. Neuroimaging measures like functional magnetic resonance imaging (fMRI) might detect subtle alterations in brain health before neurodegeneration or measurable cognitive impairment. Mechanistically, researchers have proposed that synaptic dysfunction may be one of the earliest signs of brain abnormalities that give rise to neuroinflammation and the accumulation of pathology.^3–5 Research in monkeys recording both electrophysiological and blood-oxygen-level-dependent (BOLD) fMRI data have provided strong evidence that fMRI signals primarily index postsynaptic input via local field potentials rather than neuronal firing rates. ⁶ This finding implies that increased hippocampal activation in high-risk adults may reflect early synaptic dysfunction and thus might be sensitive to some of the earliest changes in preclinical Alzheimer's disease (AD).

Konishi et al. ⁷ examined middle-aged and ‘young-old’ adults to investigate how sex and AD risk factors relate to brain function to ultimately influence cognition, amyloid-β (Aβ) accumulation, and memory performance. All participants carried the apolipoprotein E (APOE) ε4 allele and had at least one additional risk factor—hypertension, type 2 diabetes (T2D), or depression—while low-risk participants had none. This comparison offers insight into early brain dysfunction that precede clinical symptoms and inform sex-specific detection and intervention strategies. The study revealed notable sex differences: high-risk women showed greater Aβ burden, poorer memory, and distinct fMRI activation patterns compared to low-risk women, with weaker associations in men. High-risk women exhibited left hippocampal hyperactivity during episodic encoding and right hippocampal hyperactivity during working memory tasks, both linked to poorer cognition and elevated Aβ.

A key strength of this study is its deliberate emphasis on sex-specific stratification starting in midlife, unlike prior studies that treat sex as a covariate or explore sex differences post hoc. Their findings dovetail with a recent study reporting that midlife women, but not men, exhibited 12-year memory decline associated with APOE ε4 and incident hypertension. ⁸ In contrast, men's memory was more influenced by social and lifestyle factors. These sex-based nuances in risk expression strengthens the case for precision medicine approaches that consider biological sex in AD research.

Another key contribution is the focus on two domains of cognition: working and episodic memory. Interestingly, the hippocampus emerged as a shared region of dysfunction across both tasks (albeit in different hemispheres). In contrast, low-risk men showed more robust parietal activity during both tasks (left in episodic memory and right in working memory). These findings suggest that task-specific activation patterns do not reflect global vulnerability, but rather sex- and task-dependent mechanisms.

The study also had several limitations that limit its generalizability and understanding of the mechanisms underlying sex differences. The sample is quite limited in its ethnoracial and educational diversity. About 96% of the low-risk group were White and nearly all had a college degree. Although slightly better, the high-risk group was 84% White and 74% were college educated. This imbalance raises questions about generalizability and replication in groups most at risk for AD. ⁹ Sociodemographic factors (e.g., race, education, and socioeconomic status) can influence AD risk through differences in healthcare access, comorbidities, and diagnostic bias. ¹⁰ Without adequate demographic representation, the implications of sex and risk interactions may not hold in more diverse or disadvantaged populations, where AD risk is higher.

Second, while the study assessed Aβ accumulation and brain function, the absence of tau PET imaging limits mechanistic accounts. Although Aβ is a hallmark of preclinical AD, Aβ alone is insufficient to predict cognitive decline. In contrast, tau pathology, particularly in the medial temporal lobe, is a key driver of clinical manifestations and could follow sex-specific trajectories. Women might accumulate tau earlier or more extensively than men.^11,12 Emerging models also indicate that tau can precede or evolve independently of Aβ.^11,12 Tau imaging could reveal whether hippocampal hyperactivity reflects pre-tau synaptic changes, early tau spread, or a profile of mixed pathology. Such distinct patterns might better differentiate preclinical AD from non-AD etiologies (e.g., vascular or mixed dementia), which are common in individuals with hypertension and T2D. Thus, including tau would have enabled clearer characterization of risk pathways and clarified whether brain alterations reflect tau-specific processes in high-risk women.

Thirdly, the authors point to estradiol decline and menopausal transition as plausible contributors to increased risk in women, but they did not assess any reproductive variables. Such variables could include age at menopause, hormone therapy use, or the duration of estrogen deprivation. This gap omits critical information given research showing postmenopausal estradiol decline can alter hippocampal function, prefrontal connectivity, and memory performance, particularly in APOE ε4 carriers.^13,14 A detailed hormonal history could allow better causal inferences shaping sex-dependent brain changes.

Fourth, the authors did not separate contributions of hypertension, T2D, and depression despite some degree of variability. Prior work showed that T2D and hypertension were associated with increased fMRI activity in occipital and subcortical areas, while depression and low education were linked to a distinct pattern involving increased prefrontal activity and decreased hippocampal activity. ¹⁵ A meta-analysis ¹⁶ reinforced these findings with depression being tied to hypoactivity in attention networks, whereas hypertension and T2D were linked to hyperactivation in sensorimotor and default mode networks. These converging findings underscore the limitations of aggregating risk into a single score that may obscure distinct neural mechanisms and clinical implications.

Lastly, interpreting fMRI activity in the presence of vascular changes is complicated. The BOLD signal reflects a coupling between neural activity and blood flow. Age and vascular risk factors (e.g., hypertension, T2D) alter cerebral blood flow and neurovascular coupling, hindering any inferences based on neural integrity or compensation.^17,18 In individuals with hypertension and T2D, apparent hyperactivity in memory networks may instead reflect impaired vascular reactivity rather than compensatory neural activity. Importantly, controlling for age and applying signal filtering do not correct for vascular contributions to BOLD variance, especially if neurovascular decoupling differs by sex or risk status. For example, “hyperactivity” associated with a greater accumulation of dementia risks disappeared when BOLD activity was calibrated, suggesting that some apparent neural effects were vascular. ¹⁵ This distinction matters: if BOLD differences reflect altered blood flow, the appropriate intervention might be vascular (e.g., antihypertensives); if neural, cognitive, or pharmacological therapies might be warranted. Once calibrated, differences found in high-risk women may disappear, implying that they were not related to neural dysfunction. Considering perfusion-based imaging (e.g., arterial spin labeling) quantifies cerebral blood flow and can be calibrated to disambiguate vascular from neural sources of activation. This would clarify whether hippocampal hyperactivity in high-risk women is truly synaptic or primarily vascular in origin.

Overall, Konishi's study has contributed further evidence that accumulating dementia risks can lead to increased BOLD activity in the hippocampus in women. To translate these findings to dementia prevention, a better understanding is needed of the mechanisms underlying this pattern to know which intervention methods might be most successful to prevent a diagnosis of AD or related dementia. Depending on the driving mechanism(s), various interventions could include antihypertensives for vascular changes, synaptic-preserving therapies for neural dysfunction, or menopausal interventions for hormonal contributions, as a few examples. Importantly, replicating the current work in more diverse samples, often accompanied by different health profiles, also can help better understand how to best tailor interventions.