The development of Alzheimer’s disease (AD) occurs over a prolonged pre-clinical period, wherein the amyloid plaques, hypo-metabolism of glucose, and neurofibrillary tangles occur about 15-20 years before symptoms onset.
Since effective disease-modifying agents for the treatment of AD are yet to be developed, significant efforts toward the delay, prevention, and progression of dementia are underway.
A spectrum of modifiable risk factors, for example – hypertension, diabetes, and cardiovascular (CV) disease have been identified for AD, throughout patients’ lifespans. Risk models linked to populations have proposed that management of said risk factors can prevent up to 1/3rd of cases of dementia.
The patient’s gender follows age in being a predisposing factor for AD; with the female sex posing a significant risk. It has been reported that the incidence of AD in women is twice as high as in men, especially in terms of gender-associated mortality rates, differences in lifespan, and age at death.
Mounting evidence supports the vulnerability of women to AD over men. Women tend to sustain greater neurofibrillary tangle-related alterations that cause an earlier onset of AD. Besides, estrogen is deemed neuroprotective against AD; declining estrogen levels in aged women could contribute to AD development and progression. Additionally, age-related decline in testosterone levels, which is more rapid in women, has also been linked to a heightened risk for AD. Furthermore, owing to fewer opportunities for educational attainment for women in the yesteryear have resulted in inherently weaker cognitive reserves in the female sex, which again could be a likely predisposing factor.
While previous studies had focused on sex-specific and hormonal risk factors, they did not examine whether individualized interventions lead to different outcomes linked to cognition and blood biomarkers for AD risk. It is essential to investigate the effectiveness of clinical interventions targeting AD-associated factors in women.
This Comparative Effectiveness Dementia & Alzheimer's Registry (CEDAR) study demonstrated how individualized clinical management making multi-domain interventions was viable in a clinical outpatient setting. Here, participants were categorized into higher compliance (those who adhered to >60% of the recommendations) and lower compliance (those who followed <60% of the recommendations).
This subgroup analysis published in The Journal of Prevention of Alzheimer's Disease, evaluated the differential effectiveness of the clinical approach, with respect to gender, among the higher compliance group of the CEDAR study.
The higher compliance cohort from the CEDAR study was classified as: a “Prevention” group – those with normal cognition, subjective cognitive decline, and preclinical AD; and an “Early Treatment” group – those with mild cognitive impairment (MCI) due to AD and mild AD.
Patients were subjected to individualized genetic counseling and education. All patients were given personalized lifestyle interventions like counseling on diet, exercise, blood pressure control, reducing stress, and sleep hygiene. To suit individual needs, medications, vitamins, and supplements were advised.
In the original study, patients with MCI who adhered to 60% of lifestyle recommendations improved their cognitive tests for memory and thinking by five points, and those following < 60% showed no cognitive improvement for 18 months.
Signs of cognitive improvement were noted in both men and women when compared to the control groups. Since almost half of the participants of the CEDAR study carry a minimum of one apolipoprotein-ε4 (APOE-e4) gene that may increase the risk for AD, this study indicated no difference in the cognitive improvements due to intervention in patients with one or two copies of the APOE gene when compared with those devoid of this gene.
Impact on women versus men
Although no significant differences were observed in the primary outcomes for cognitive benefit, secondary outcomes like CV risk scales and lipid biomarkers improved significantly in women when compared to men. This suggests that individualized management in a real-world setting may benefit males and females equally while offering better mitigation of the estimated AD and CV risks in women.
Both women and men in the prevention group had improved m-APCC (modified-Alzheimer ’s Prevention Initiative Cognitive Composite) scores in the “Prevention” group, without any significant difference. This shows that an individualized approach that accounts for gender may be effective and necessary. However, there are contrasting reports in earlier studies on the rates of cognitive decline in men and women necessitating the need for larger studies.
In the Early Treatment group, women showed better improvements for both, CAID (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) and MESA (Multi-Ethnic Study of Atherosclerosis). While, in the “Prevention” group, women gained better improvement than men, on MESA. These results indicate that women had greater reductions in their CV and AD risks than men.
Consistent with this finding, women also showed a significant improvement for various vascular biomarkers that may drive the risk reduction of CV disease.
In the “Prevention” group, women had significantly improved HDL cholesterol compared to men. Additionally, the “Early Treatment” group showed significant improvements in various lipid biomarkers in women, such as total cholesterol, LDL-P, LDL-C, and ApoB; whereas, men showed no significant changes. These findings in conjunction with the changes observed on risk scales suggest that women show more CV benefits than men further along the AD spectrum.
The estrogen levels were speculated to play a major role in the improvements observed in the women in the “Prevention” and “Early treatment” groups.
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and glycated hemoglobin (HbA1c) are effective biomarkers for insulin resistance and diagnosis of diabetes; these as major risk factors for AD dementia. Interpretation of such metabolic markers was proven to be difficult as the men from the “Prevention” group improved HOMA-IR compared to women in the same group. Whereas, “Early treatment” women had more significantly improved HbA1c than the men in this group.
Overall, the results suggested that individualized multi-domain interventions effectively improve cognition in both women and men. These interventions rendered reductions in AD and CV risks in women, compared to men. It was stated that the results require further examination in larger cohorts to properly define the gender-related variations in the clinical reduction of AD.
- N. Saif, H. Hristov1, K. Akiyoshi1, et al. (2022). Sex-Driven Differences in the Effectiveness of Individualized Clinical Management of Alzheimer’s Disease Risk. The Journal of Prevention of Alzheimer’s Disease. doi: https://doi.org/10.14283/jpad.2022.44