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The Case of Missing Women in Frontotemporal Dementia: Expert Opinion from Dr. James Rowe

Serene Lee — Wed, 17 Jun 2026 00:29:21 GMT

About Dr. Rowe

Dr. James Rowe is a neuroscientist and cognitive neurologist. He is also a Professor of Cognitive Neurology at the University of Cambridge. His scientific work has been published in more than 600 peer-reviewed articles, including Nature, Neurology, and Science. Dr. Rowe also led the pivotal Pick’s disease and Progressive supranuclear palsy Prevalence and Incidence study (PiPPIN), an epidemiological study of disorders caused by frontotemporal lobar degeneration. He is a leading expert in cognitive neuroscience.

About Frontotemporal Dementia

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by atrophy of the frontal and temporal brain lobes. Behavioural changes, language difficulty, and compromised executive function are hallmark clinical presentations. FTD can be broadly categorized into genetic and sporadic forms. The genetic form is caused by an inherited familial mutation, while the sporadic form manifests with no known cause.

Although the incidence of genetic FTD is relatively equal across genders, extant literature indicates that women are less likely to develop FTD sporadically. Why might this be the case, given that women are otherwise overrepresented among other types of dementia cases? Dr. Rowe does not believe that women are less affected by sporadic FTD. Instead, he believes that these women are simply “missing”.

We asked Dr. Rowe a series of questions about his opinion on this phenomenon.

1. Many clinician-researchers believe that men simply just have a higher incidence of sporadic FTD, but you suspect the affected women are just unaccounted for. What first made you suspect that women with FTD were just missing from the literature?

“I’m always suspicious when people report gender differences. It’s obviously one of the first questions you ask in a study, but often people don’t ask the questions the right way, and they don’t look at confounds behind the data. What struck me about the FTD data was that whereas other common forms of dementia like Alzheimer’s disease where women are more affected, in FTD, it seemed to go the opposite way. You just have to kind of question that, given that the two diseases are common, what would drive the opposite effect in two age-related diseases? It just struck me as an anomaly. The next thing is that there’s a difference between the genetic and sporadic. So in terms of genetic FTD, it's equal men and women so again if women somehow had a mysterious resistance to the disease, surely you’d expect that to apply to the genetic and the sporadic. One of the things about the genetic form is that people are looking much more closely, and questioning their families about who’s had what types of symptoms. So maybe it’s an ascertainment bias in the sporadic FTD.”

2. In terms of diagnostic criteria and early referral bias for FTD, are there behaviours that would raise concern in a man but be viewed differently in a woman?

“Exactly, so you think about what lies behind the diagnostic criteria. A lot of the nature of behavioural FTD is breaking social norms: behaviours that are seen as improper or inappropriate. And social norms in many countries are just not equal for men and women; there are things that men can do that women can’t. So in diagnoses, it’s about breaking social conventions. Immediately you have to ask about if those criteria are fairly applied. Are you smoking, drinking, etc. So if these are the things you’re basing your diagnosis on, you have to be really thoughtful about implicit bias. Wives also might be more willing to bring husbands in for healthcare than husbands would for wives.”

3. Are women more likely to receive psychiatric diagnoses before receiving an FTD diagnosis?

“There’s some evidence of this. It’s common for men and women to be told FTD is an adjustment reaction, depression, or even get misdiagnosed as schizophrenia, bipolar, or personality disorder. All these things get mixed in. It’s common that these diagnoses are differentially applied to men and women. It’s not just about the wrong label, it’s about how long you live with the wrong label before the penny drops. Women could be more likely told this is depression or personality disorder or bipolar, and are also a lot likelier to live with the wrong diagnosis longer. The net effect of each of these biases is that women remain underdiagnosed.”

4. “True” differences between males and females might exist, but there is limited extant literature outlining possible differences, beyond the post-menopausal estrogen drop. What other biological differences do you suspect play a role?

“So there’s no doubt that menopausal symptoms are common at the age that FTD starts to pick up in the mid-50s, but actually, the average age of onset of FTD is 75, well past the age of menopausal onset for almost every woman. So I don’t think we can blame simple misattribution to menopause. There might be long-lasting effects of the estrogen drop on brain function, and I don’t want to dismiss that, but my money’s on the more tractable features of referral diagnosis and enabling to account for this differential effect. I think that’s much more likely. Partly because if it were biological, why wouldn’t this pattern show up in genetic FTD as well?”

5. In ten years, what would success look like in ensuring that women with FTD are no longer "missing" from diagnosis, care, and research?

“I think what we’d see is we would have done two things. We would know for certain whether it’s biological or non-biological factors that’s driving the difference, and for women getting diagnosed, they’d know just as quickly and just as accurately as men. That gives you the way forward for effective treatment in FTD.”

Childhood Trauma: How It Shapes The Brain, and How It Differs In Women

Ramy Elagan — Sat, 23 May 2026 21:42:59 GMT

Childhood experiences do not simply fade with time; they can become biologically and psychologically embedded within the developing brain, influencing mental and physical health long into adulthood, particularly in women.

Image Source: The Mulberry Bush

Childhood trauma can shape and alter the developing brain in various ways, as the brain is highly plastic, meaning it can continuously change and adapt in response to experiences and environmental influences. As the brain is still wiring itself during childhood and adolescence, it becomes more vulnerable to the different qualities of exposure. While positive experiences can help children gain emotional security and healthy coping mechanisms, traumatic experiences such as neglect, emotional abuse, physical abuse, sexual abuse, or chronic instability can significantly alter childhood development. Research in psychology and neuroscience has increasingly shown that childhood trauma (CT) not only affects emotional well-being but can also affect genetic, hormonal, and cellular mechanisms such as brain anatomy, stress regulation, relationships, and physical health later in life. These effects are crucial to study in women because women are statistically more susceptible and likely to develop trauma-related disorders such as anxiety, depression, post-traumatic stress disorder (PTSD), and borderline personality disorder (BPD) (Thomas et al., 2022). Biological and hormonal differences may influence how women respond to and process stress, causing trauma to manifest differently than in men.

One of the primary systems affected by childhood trauma is the body’s stress-response system, known as the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis regulates cortisol, the body’s natural stress hormone, which helps individuals respond to stressful or threatening situations to stay safe. However, chronic exposure to stress during childhood or CT can induce prolonged activation of this system, leading to elevated glucocorticoid levels that may negatively impact structural and functional brain development. According
to Rosada et al., the hippocampus and amygdala contain high densities of glucocorticoid
receptors, as they both play a crucial role in our stress system; repeated stress exposures can alter these neurological structures and hence impair emotional regulation and memory processing. Since the brain is still developing, the presence of excessive stress hormones can interfere with healthy neural growth and social-emotional functioning later in life.

Image Source: Nutrition Diets Clinic

Women may be particularly vulnerable to the long-term neurological and psychological effects of CT because of differences in biological stress responses and social conditioning, such as estrogen influence on emotional regulation. Rosada et al. (2021) specifically focused their study on pre-menopausal women due to evidence suggesting that estrogen may have neuroprotective effects related to stress. Despite this, women remain significantly more likely than men to internalize emotional distress following trauma exposure such as CT. Rather than expressing trauma outwardly through aggression or risk-taking behaviours, women more commonly experience internalized symptoms such as chronic anxiety, shame, emotional withdrawal, self-blame, eating disorders, and depression.

References

1. Thomas EHX, Rossell SL, Gurvich C. Gender differences in the correlations between childhood trauma, schizotypy and negative emotions in non-clinical individuals. Brain sciences. January 29, 2022. Accessed May 23, 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC8870285/.

2. Rosada C. PMC Home. National Center for Biotechnology Information. Accessed May 23, 2026. https://pmc.ncbi.nlm.nih.gov/

Perimenopause as an Inflammatory Pathway to Neurodegeneration

Farah Abdelhamid — Sat, 23 May 2026 21:24:49 GMT

What is Perimenopause?

It kind of sneaks up on you - nothing dramatic at first, just little shifts. Periods become less predictable, focus feels a step behind, and you have less energy. Turns out, this “something feels off” phase has a name: perimenopause, and it’s a whole-body change, not just a hormonal one.

Every woman who reaches her mid-forties undergoes an essential period:
perimenopause. This is the transitional stage between regular menstrual cycles and menopause.² Characterized by fluctuating estrogen levels and decreasing progesterone
levels, this stage may trigger inflammatory and neurological changes beyond reproductive shifts, disproportionately risking women's long-term brain health.

Image Source: WomensHealth.gov

We are going to dive into the “need-to-know” details, adverse neurological impacts, and protective interventions surrounding perimenopause.

How does Perimenopause cause Inflammation?

Perimenopause is characterized by irregular ovarian hormone production, particularly fluctuating estrogen levels. Estrogen has anti-inflammatory effects, regulating the immune system and its supporters. When estrogen levels decrease, pro-inflammatory messenger molecules in the blood increase, activating the immune system. This results in persistent, silent inflammation that can affect multiple organ systems, including the brain.⁵

In the central nervous system (CNS), this inflammation activates microglia. Think of microglia as the soldiers of the immune system in the CNS, protecting it from danger. This is really important; however, constant microglial activation is like guards becoming suspicious of everyone and hurting what they should be protecting. On a biochemical level, this means that they aggravate synaptic dysfunction, linking it to neurodegeneration causing neuronal injury and the accumulation of toxic proteins.⁶

This inflammatory response can help us understand why biological females experience greater risk of certain chronic neurodegenerative disorders. Rather than being an isolated reproductive event, perimenopause may represent a systemic biological transition with consequences for brain aging. Recognizing perimenopause as an inflammatory phase could improve early identification of increased neurological risk factors.

Fast Fact: Because of perimenopause, people with female reproductive organs are more susceptible to autoimmune and inflammatory disorders, than those of the male sex. With the added changes in immune signalling during this phase, pre-existing disorders can exhibit worsened symptoms. These disorders may include rheumatoid arthritis, lupus, and multiple sclerosis.³

Image Source: Istock

How does Perimenopause impact Brain Health?

Estrogen plays a critical role in maintaining healthy brain metabolism. It supports mitochondrial energy production, glucose utilization, neuronal connections, and cerebral blood flow. During perimenopause, changes in estrogen levels may reduce the brain’s ability to efficiently generate energy, forcing neurons to rely on less effective fuel sources. This metabolic stress can contribute to memory lapse, brain fog, and reduced cognitive function. These symptoms are often seen during the menopausal transition.⁸

Over time, impaired energy metabolism can create the perfect environment for neurodegeneration. Research has linked falls in estrogen levels to the accumulation of misfolded proteins, oxidative damage, and mitochondrial dysfunction, all of which are characteristics of Alzheimer’s disease. ⅔ of all Alzheimer’s cases are those of the female sex. Given that the greatest risk factor for this disease is old age, people with a higher life expectancy are at greater risk of developing Alzheimer’s. Today, it is generally accepted that both life expectancy and hormonal changes are important factors in the pathology of Alzheimer’s disease.⁶

The same inflammatory and mitochondrial pathway changes can also risk the development of other neurodegenerative diseases, such as Parkinson’s.⁹ Unfortunately, symptoms emerging in midlife are often dismissed as symptoms of normal aging rather than early indicators of neurodegeneration. In fact, women are less likely to be diagnosed and more likely to be misdiagnosed due to the dismissal of female health issues by practitioners and the lack of research in women. Viewing perimenopause as a neurological transition highlights the need for earlier monitoring, cognitive screening, and preventive interventions during this critical window. ⁶

Things you can start now to decrease your Risk!

Although perimenopause may increase vulnerability, it also offers an opportunity for prevention. Lifestyle strategies are essential to reduce inflammation and support metabolic health, especially during midlife.

Below are a few crucial steps to optimal neurological health:

● Regular aerobic and resistance exercise improves insulin sensitivity, cerebral blood flow, and mood while lowering inflammatory markers.₇

● Diets rich in omega-3 fatty acids, fiber, fruits, vegetables, and polyphenols may further protect neuronal health.₇

● Sleep optimization and stress reduction are also important, as both poor sleep and chronic stress amplify inflammation.⁷

^{Image Source: Istock}

Hormone therapy has received attention as a possible neuroprotective intervention.¹In medical trials, it has been used on candidates who are approaching the menopause phase. There is now evidence that suggests estrogen-based therapy may help relieve symptoms and potentially support brain metabolism.¹ However, the benefits of this therapy may depend on timing, formulation, and individual risk factors, which refers to the “critical window” hypothesis. Unfortunately, hormone therapy is not universally appropriate and should be specific to patient’s needs under a clinician’s guidance.⁷

Supportive strategies include:

● Management of comorbidities, such as hypertension, diabetes, obesity, and depression, all of which increase the risk of dementia.

● Practising cognitive engagement activities, social connection, and continued learning may strengthen cognitive abilities later in life.⁴

Together, these interventions suggest that perimenopause should not only be viewed as a risk period, but also as a key stage for proactive brain health promotion.⁴

References

1. Barth, C., Galea, L. A. M., Jacobs, E. G., Lee, B. H., Westlye, L. T., & de Lange, A. G. (2025). Menopausal hormone therapy and the female brain: Leveraging neuroimaging and prescription registry data from the UK Biobank cohort. eLife, 13, RP99538. https://doi.org/10.7554/eLife.99538

2. Brinton, R. D., Yao, J., Yin, F., Mack, W. J., & Cadenas, E. (2015). Perimenopause as a neurological transition state. Nature reviews. Endocrinology, 11(7), 393–405. https://doi.org/10.1038/nrendo.2015.82

3. Desai, M. K., & Brinton, R. D. (2019). Autoimmune disease in women: endocrine transition and risk across the lifespan. Frontiers in Endocrinology, 10, 265. https://doi.org/10.3389/fendo.2019.00265

4. Kang, H., Ihara, E. S., Tompkins, C. J., & Lauber, M. S. (2025). Boosting Cognitive Training through Social Engagement: Impacts on Older Adults With Subjective Cognitive Decline. Sage Open Aging, 11, 30495334251366575. https://doi.org/10.1177/30495334251366575

5. McCarthy, M., & Raval, A. P. (2020). The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease. Journal of Neuroinflammation, 17(1), 317. https://doi.org/10.1186/s12974-020-01998-9

6. Mishra, A., & Brinton, R. D. (2018). Inflammation: bridging age, menopause and APOEΕ4 genotype to Alzheimer’s disease. Frontiers in Aging Neuroscience, 10, 312. https://doi.org/10.3389/fnagi.2018.00312

7. Philip, A. E., Singh, H., Nanjundiah, S. Y., Samudrala, P. C., Theunissen, W., Robinson, J., & Banerjee, I. (2025). Impact of Exercise on Perimenopausal Syndrome: A Systematic Review of Randomized Controlled Trials. Cureus, 17(3), e80862. https://doi.org/10.7759/cureus.80862

8. Rettberg, J. R., Yao, J., & Brinton, R. D. (2013). Estrogen: A master regulator of bioenergetic systems in the brain and body. Frontiers in Neuroendocrinology, 35(1), 8–30. https://doi.org/10.1016/j.yfrne.2013.08.001

9. Unda, S. R., Marciano, S., Milner, T. A., & Marongiu, R. (2022). State-of-the-art review of the clinical research on menopause and hormone replacement therapy association with Parkinson’s disease: What meta-analysis studies cannot tell us. Frontiers in Aging Neuroscience, 14, 971007. https://doi.org/10.3389/fnagi.2022.971007