Are Females at a Higher Risk of Alzheimer’s Disease?

By Franklin Faust

Back when the Alzheimer’s research field was in its infancy, researchers were working to understand the scope of the disease’s consequences for public health. Prevalence studies took “Alzheimer’s censuses,” which showed a higher number of females living with Alzheimer’s disease than males, igniting the widespread idea that females are at higher risk. Other researchers thought that more females may be affected because they tend to live longer than males, and the risk of disease increases with age. The complex problem sparked curiosity among researchers, leading to efforts to crack what is now an age-old question: how does biological sex affect dementia risk?

Haydeh Payami, PhD, Professor of Neurology and Genetics at the University of Alabama, prior research scientist at Oregon and Health Sciences University’s Alzheimer’s Disease Center, and collaborator with the UW ADRC, waded into this scientific debate in 1996 with a study examining two familial Alzheimer’s disease kindreds. She found that the females in these families were more likely to develop Alzheimer’s with age, and that they tended to develop the disease at a younger age than the males.

Payami investigated the trend further, looking specifically at the risk tied to APOE ε4, one of three key alleles (variants) of the APOE gene, the strongest known risk factor other than age for late-onset Alzheimer’s disease in European populations. Her research showed that males had no significant added risk from carrying a single copy of APOE ε4, but that females did. The study suggested that this sex-based APOE ε4 effect might be a factor that put females at a higher risk for Alzheimer’s disease than males.

In 1997, an influential meta-analysis out of Boston University School of Medicine, supported the UW ADRC’s findings. The team crunched the numbers on thousands of Alzheimer’s disease cases and controls pooled from clinical studies with volunteer participants, producing an analysis that established a sex difference in APOE ε4’s influence in these participants, showing that females with one APOE ε4 allele have a fourfold higher odds of Alzheimer’s disease than male carriers.  “That paper fairly firmly settled the field’s acceptance of the hypothesis that sex effects were interacting with APOE genotype effects to put women at greater risk,” says ADRC’s Ellen Wijsman, PhD, Professor of Biostatistics, who collaborated on Payami’s papers in 1996. For a time, she notes, the study largely put the debate to rest. This paper ended with a caution about the generalizability of the results to risk in the population at large, and the need for prospective cohort studies to provide estimates of absolute risk of Alzheimer’s disease.

In 2017, the possibility of elevated female risk was called back into question. New data sources became available thanks to the Framingham and Rotterdam studies, two long-running longitudinal cohort studies that continuously recruit, in mid-life, and follow groups of individuals as they age. Whereas clinical studies select for demographics more likely to volunteer for research, these cohort-based longitudinal studies take participants earlier and at random from a larger community – resulting in a less biased, more complete picture of risks to individuals. 

Wijsman points to a 2017 study that analyzed the Framingham and Rotterdam data and found little to no evidence that males and females get Alzheimer’s disease at different rates, regardless of APOE status. “The best data today shows that if you have a seventy-year-old man and a seventy-year old woman, their risk of Alzheimer’s disease does not seem to be different,” says Wijsman. “That’s a change from what we thought 30 years ago.” The bottom line: Current evidence suggests that the overall risk for Alzheimer’s disease is no different for females than it is for males. Researchers now look forward to results from the Atherosclerosis Risk in Communities Study, which includes non-white populations.

Sex may not affect overall risk of Alzheimer’s dementia, but more recent findings from the ADRC and elsewhere indicate that male and female brains may tend towards different Alzheimer’s-associated neurological hazards as they age. 

In 2017, longtime ADRC researcher Elaine Peskind, MD, Professor in the UW Department of Psychiatry and Behavioral Sciences, brought her unique expertise to bear on the question of how differences in sex and APOE status affected the presence of biomarkers for Alzheimer’s and vascular disease in cerebrospinal fluid (CSF). The ADRC study found that females carrying a copy of APOE ε4 variant had more Alzheimer’s protein in CSF, while males, regardless of APOE genetics, had larger indications of vascular injury to the brain—both of which are factors that are thought to put a burden on the brain and contribute to dementia. 

Recent research out of University of California San Francisco, including two major figures in ADRC history—UW’s Walter Kukull, PhD and University of Pennsylvania’s Gerard Schellenberg, PhD—found evidence to suggest that differences in male and female neurogenetics may be important for predicting disease progression. This finding adds even more complexity to the longstanding question of what determines sex-based differences in dementia risk.

There are likely to be many sex-related factors at play in the trajectory of a person’s cognitive wellbeing, and fortunately, our Center has the tools to tackle complex, biological problems. Guided by a framework of biological heterogeneity, ADRC scientists will continue to work to make sense of these risk profiles and progress the science towards precision medicine treatments that benefit the brains of each sex and the wide variety of biological factors therein. •