Different Risk Factors and Progression of Alzheimer’s Disease in Women Have Implications for Diagnosis and Care

Research reported at the Alzheimer’s Association International Conference (AAIC) in Los Angeles July 14-18, 2019 identifies a number of differences in risk for and progression of Alzheimer’s disease (AD) in women, including sex-specific genes, structural brain network differences, and different glucose metabolism during verbal memory tasks. Prevalence of AD is higher in women vs men (2:1), and although, it has long been thought that this is because of a longer life-span in women, this new evidence suggests other biologic mechanisms are involved. 

Rebecca M. Edelmeyer, MD, PhD, director of scientific engagement for the AAIC said, “A key take-away of this data for clinicians is that they may need to consider talking with women earlier about whether or not they may have higher risk of AD and should also consider that because of women’s stronger verbal memory, the symptoms of AD may be masked in women, which may have implications for diagnosis. Subjective cognitive complaints by women should be taken seriously and assessed to see if an individual with such complaints should be referred to a specialist for more in-depth assessment.”

Glucose and Verbal Memory
In a study that examined brain glucose metabolism with fluorodeoxyglucose (FDG)-PET in people with different levels of amyloid and tau burden, it was shown that women had higher glucose metabolism despite similar amyloid burden compared with men (P = .001) and cerebrospinal fluid levels of phosphorylated tau (p-tau). 

Further, it was shown that this difference could account for the relatively preserved verbal memory seen in women vs men during earlier stages of AD. Specifically women with amyloid burden below 75% of the maximum in the group studied outperformed men on delayed recall tests, which was not seen for women whose amyloid burden was above 75% of the group maximum (P = .16). After adjusting for metabolism, the differences were reduced minimally (3% to 9%) for women with less than the median amyloid or tau burden and moderately (21% to 41%) for women with 50% to 75% of the highest amyloid/tau burdens.

“As the field moves towards using brain changes and biomarkers to measure Alzheimer’s risk, this research is important in understanding how these changes differ by sex,” said Erin Sundermann, PhD, a neuropsychologist at the University of California San Diego School of Medicine. “By doing so, we can develop more personalized dementia risk measurements and interventions.” 

Genetics
A whole-exome sequencing study (n = 5,522) gound sex-specific genetic associations with AD, which was replicated with the Alzheimer’s Disease Genetics Consortium (ADGC) Haplotype Reference Consortium (HRC) (n = 9,135). 
Sex-specific associations with AD risk were found for 11 different genes, many of which have functions that may be relevant to development of AD. These include genes related to risk only in men—MCOLN3 and CHMP2B—both of which are involved in endocytosis, a process critical to the development of AD, and genes related to risk only in females—CD1E and PTPRC—which play essential roles in immunity. 
“This research demonstrates that genetics may contribute to differences in risk and progression of Alzheimer’s disease between men and women,” said Brian Kunkle, PhD, MPH, genetic epidemiologist and associate scientist at the University of Miami. “More research is needed to understand how much these genes contribute to Alzheimer’s risk, and whether they can be used to specifically identify men and women at risk for this disease.” 

Structural Tau Network Differences
In a study using [18F]-fluortaucipir PET to model the brain as a network of tau-connected regions, it was found that women with mild cognitive impairment (MCI) had higher tau network density and increased brain-wide tau burden compared with men with MCI and both men and women without MCI. The study also showed that compared with men, women had more hubs and connections in several brain regions that could favor an accelerated, brain-wide tau spread

“The differences that we observed indicate the strong possibility that there are sex differences in the structural and functional connections in the brain, which may contribute to women’s increased risk for Alzheimer’s,” said Sepideh Shokouhi, PhD, assistant professor of psychiatry and behavioral sciences at Vanderbilt University Medical Center. “This study has implications for the possibility of creating sex-specific risk-reduction strategies and preventive interventions.”