Unique Alzheimer Disease Risk Factors Found in Postmenopausal Women

Cardiovascular and genetic risk factors may predict decreased brain volume in and increased blood flow to Alzheimer disease-specific brain regions among sedentary postmenopausal women with asymptomatic cerebral amyloidosis, according to findings presented in a poster session at the 2022 North American Menopause Society (NAMS) Annual Meeting held October 12 to 15 in Atlanta, Georgia.¹

These findings highlight the importance of considering differences in patterns of neurodegeneration and amyloid-β burden among older men and women with preclinical Alzheimer disease (AD) when developing effective, modifiable interventions and prevention strategies, said lead author Genna Losinski, MA, who is a clinical psychology doctoral candidate at the University of Kansas.

“Cardiovascular AD risk factors explain sex-associated neuroimaging biomarker differences for sedentary older adult women,” Losinski said in an interview. “Many of the cardiovascular risk factors are modifiable. Emerging lines of evidence suggest that 1 out of every 3 cases of AD can be linked to modifiable risk factors.² Taking previous comparable studies conducted in midlife women, combined with the results of our study, these findings could suggest the importance of earlier AD risk factor modifiable behaviors for women, starting in midlife.”

Study Background and Design

Prevalence rates are higher among women for several AD risk factors, especially after the age of 60 years and postmenopause, Losinski explained. Evidence also suggests that for some risk factors, the strength of the association with AD differs by sex and gender with women often more severely affected. A potential reason for this phenomenon is the estrogen theory, which posits that estrogen is neuroprotective, but after the transition into menopause, estrogen dysfunction exacerbates the development of AD, the study authors explained.

This study, conducted by investigators from the University of Kansas sought to evaluate gender-specific AD risk factors. The study involved sedentary women (n=74; mean age, 71.38±5.24 years) and men (n=38; mean age, 71.91±4.35 years) with no evidence of cognitive decline. AD risk factors were assessed as follows in brain regions of interest based on the estrogen theory and known pathology trajectory patterns in AD:

• Amyloid-β via 18F-AV-45 florbetapir positron emission tomography (PET)
• Neurodegeneration via T1 magnetic resonance imaging (MRI) volumetrics
• Cerebral blood flow via arterial-spin labeling-MRI

The patients all had elevated global cerebral amyloid-β levels (mean, 7.27±1.05 standardized uptake value ratio [SUVR]), which is a risk factor for AD in people without cognitive symptoms, the researchers explained.

Sex Differences in Blood Flow and Brain Volume

Women had decreased brain volume in brain regions of interest the hippocampus, amygdala, parahippocampal gyrus, insula, and caudate (all P <.05) compared with men. These findings were independent of the effects of age, education, and intracranial volume.

Similarly, women had significantly increased blood flow to the amygdala, anterior cingulate cortex, hippocampus, precuneus, superior parietal lobe, parahippocampal gyrus, and temporal lobe regions (all P <.05) compared with men.

Significant predictors of these trends in brain volume and blood flow among women included higher android fat percentage, age, apolipoprotein ε4 (APOE*E4) status, education, fasting plasma glucose, and waist-to-hip ratio. Among men, only age, education, and waist-to-hip ratio were significant predictors. No sex differences in amyloid-β levels were found.

In an exploratory analysis, stratifying women by hysterectomy status revealed that women who had not undergone a hysterectomy tended to have increased blood flow to the amygdala and temporal lobe compared with women who had undergone a hysterectomy. This underpowered analysis did not reach significance (F_7,13=2.44; P =.08).

Study Limitations and Future Research

“The current study is cross-sectional in design, and therefore directionality of results cannot be determined,” Losinski said. Longitudinal studies are needed to determine if the identified sex differences are predictive of AD or suggest healthy brain aging differences over time, she added. The use of regression analysis to examine a potential relationship between neuroimaging biomarkers and cardiovascular risk factors is also problematic as the analysis did not control for other well-established risk factors for AD including other health conditions, socioeconomic considerations, and psychological factors.

“Neurodegeneration can only be measured using longitudinal study designs and it also cannot be determined whether blood flow is increasing or decreasing over time for either men or women,” Losinksi explained. “Lastly, cardiovascular risk factors and health are cumulative over time; therefore, analyses examining health outcomes should control for health and related behaviors over a lifetime in an attempt to examine potential effects in later life.”

“The current analysis was unique in that it was able to include neuroimaging techniques that considered 2 of the 3 categories as part of the A/T/N biomarker classification scheme for AD pathology,” Losinski explained.³ “However, the analysis is missing consideration of biomarkers of neurofibrillary tangle tau pathology, which is commonly measured by elevated cerebrospinal fluid phosphorylated tau and elevated neurofibrillary tangles-tau ligand uptake on PET imaging analyses. Future studies should consider examining sex differences among tau pathology in preclinical AD individuals. Further, the interaction between biomarkers in relationship to each other and including predictors, especially sex should be examined. These studies may be able to further explore whether men and women come to cognitive impairment by different mechanistic pathways.”

Furthermore, the findings are only generalizable to persons who identify as female or male and may not apply to transwomen or transmen. “Research on sex differences must better examine how being trans or elsewhere on the sex/gender spectrum would affect overall health and the experience of aging, and consider factors unique to this population such as hormone therapy,” Losinski said. 

Conclusions

The findings suggest that “genetic and cardiovascular risk factors uniquely predict lower brain volume and higher blood flow in AD-related brain regions in sedentary postmenopausal women with asymptomatic cerebral amyloidosis” compared with age-matched men, the study authors concluded.

“Future investigations with larger sample sizes should include reproductive history characteristics including hysterectomy status and hormone replacement to investigate a potential underlying sex-specific biological pathway to brain aging to explain these differences, as has was found among midlife women in previous studies,” Losinski concluded.⁴

The study was supported by the University of Kansas Alzheimer’s Disease Center and the National Institute of Aging.

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This article originally appeared on Clinical Advisor