Recently published research has turned an overdue spotlight on the disproportionate burden of dementia borne by women. It is encouraging to see this research progressing, and inspiring to see it stimulating public awareness and discussion of a disparity that has too long been overlooked: women are twice as likely as men to develop Alzheimer’s disease.

By Andrea Pfeifer

We have been searching for new treatments for Alzheimer’s disease for decades and are now able to offer patients medicines that can slow the rate of memory loss. The research that led to the approval of these effective new medicines created a tremendous bank of knowledge about how Alzheimer’s causes damage to the brain – knowledge that enables us now, for the first time, to work on strategies to prevent damage before it happens.

As much as we have learned, however, we still do not understand why women are more prone to developing dementia and Alzheimer’s than men, nor do we know whether or how approaches to diagnosis, treatment and prevention should differ based on sex.

Researchers around the world are urgently studying questions about what causes these differences, and what they mean for treatment and prevention. In addition, new and exciting research is investigating sex-based differences in the effects of lifestyle and environmental factors that could lead to precision prevention approaches tailored for women and for men.

For this research to continue, its crucial to support public health strategies – and for us to continue to talk about dementia risk with the women in our lives to raise awareness of the ways we already have to preserve brain health.

Factors at play

Worldwide, about two-thirds of people living with Alzheimer’s are women. Women face a disproportionate burden in terms of care and lost economic productivity, and this is true across high-, middle- and lower-income countries.

Multiple reasons have been suggested to explain this difference. Among the hypotheses are higher life expectancy in women, because age is a risk factor for Alzheimer’s, and lower education in women, because limited education also is a risk factor. Geographical differences have been found, and we also know that one of the genetic factors that increases the risk of Alzheimer’s, a gene variant called APOE e4, has a stronger effect in women.

Women who carry APOE e4 are more likely than male carriers to accumulate toxic proteins in the brain, called amyloid plaques and tau tangles, which drive the loss of memory and cognition in Alzheimer’s. In addition, women who have amyloid and tau accumulation have faster disease progression rates compared with men.

Hormonal changes, particularly the decline in oestrogen during menopause, also may contribute to increased Alzheimer’s risk in women. But all women experience menopause, and not all women develop Alzheimer’s, so researchers are still working to understand how and why changes in hormones affect Alzheimer’s risk.

A study recently published in Science Advances by a team at Massachusetts General Hospital led by Dr. Gillian Coughlan investigated associations between hormone therapy and tau accumulation in menopausal women. The results further support a role for hormones in Alzheimer’s, and also highlighted a highly complex relationship between hormones and other factors such as age that need continued study.

Environmental and lifestyle factors also play a role in Alzheimer’s risk, and we are just beginning to study whether there are sex-based differences here as well.

All of these factors need more study, and understanding how they combine to affect risk for women as a group and for men and women as individuals will take time. Fortunately, there is a clear path forward.

Charting a way forward

The balance between women and men in clinical trials for Alzheimer’s treatments, which have historically underrepresented women, have improved in recent years. Yet detailed analyses of sex-specific differences in these studies are still lacking.

For example, trials of both the new Alzheimer’s medicines showed some difference in treatment results for women vs. men. However, neither trial was designed to draw conclusions about how important or meaningful those differences are, or to understand whether such differences could be related to other factors such as hormone profiles, education, and so on.

Going forward, we need to ensure that the participation of women and men in clinical trials reflects the prevalence of Alzheimer’s in both sexes. There is a need for sex-based data collection and analysis across all stages of research, from basic biology research to clinical trials.

One way to ensure this is to make the integration of sex and gender in research plans a requirement for funding or publishing. Another is to enhance diversity in teams in research, policy, and healthcare practice.

We also need to redouble our efforts to reduce dementia risk globally, and to increase awareness of the tools that we already know can make a difference.

My goal, as the CEO of a biotech working in Alzheimer’s disease and the co-founder and Chair of the Global BHP Braintrust, is to develop and promote effective strategies to reduce the overall risk of dementia using a Precision Prevention approach that includes active immunotherapy and lifestyle changes.

Active immunotherapy is a type of medicine that stimulates the immune system to clear or prevent the accumulation of pathological proteins like amyloid or tau. These medicines are still in development but could be available in as little as five years.

Lifestyle interventions enable everyone to target modifiable risk factors such as diet, exercise, cognitive and social stimulation, and vascular health.

It is estimated that at least 40 per cent of cases worldwide can be linked to modifiable facets of lifestyle including cardiovascular, metabolic and environmental factors. A landmark study called the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) showed that a multi-faceted lifestyle intervention program could improve brain health and prevent cognitive decline by about 30 per cent.

The intervention combined healthy food, physical activity, mental stimulation, social activities, and cardiovascular risk monitoring.

The benefit of the intervention on cognitive outcomes did not differ significantly between men and women. Sex-specific differences in certain cognitive domains, as well as in the adoption of lifestyle changes, point to the opportunity to further improve the impact of the intervention.

The Global BHP BrainTrust is now collaborating on FINGERS Plus for Women, a research initiative to explore the potential for gender-specific interventions to further reduce the risk of dementia.

A better future

Used together, both active immunotherapy and lifestyle interventions could enable a more personalized risk reduction strategy based on an individual’s sex, genetic risk, biomarkers, and lifestyle factors.
Many of us have family or friends who suffer from dementia. We know that it is a global scourge that silently ravages millions of lives.

Together with other researchers, companies, and policymakers, we have the capacity to close the gap between women and men, addressing this pressing public health concern for all.

Prof. Andrea Pfeifer is co-Founder and CEO of AC Immune, a Swiss biopharmaceutical company pioneering precision prevention for neurodegenerative diseases. She has led the company since founding in 2003 and through an IPO and multiple partnerships with leading pharmaceutical companies. She was previously Head of Nestlé Research Centre, where she played a major role in connecting science and business.

Prof. Pfeifer is a key member of the CEOi initiative on Alzheimer’s Disease and the Davos Alzheimer’s Collaborative (DAC), a Founding Chair of the Global BHP Braintrust, and in 2021 was awarded the first SEF.WomenAward for CEO of the Year by the Swiss Economic Forum. She holds a Ph.D. in Toxicology (Cancer Research) from the University of Würzburg, Germany and is an Honorary Professor at the Ecole Polytechnique Fédérale de Lausanne (EPFL).