In a recent review published in Alzheimer’s & Dementia, researchers investigated sex-related and gender-specific resistance and resilience factors in Alzheimer’s disease (AD).

Background

Sex and gender have a crucial role in determining protective and risk factors for AD. Understanding these characteristics is critical to improving our understanding of the resilience and resistance mechanisms that sustain cognitive function while reducing pathology buildup in aging and AD. Inter-individual diversity exists in the response to AD pathology, with a few older individuals staying cognitively intact. A sex- and gender-aware resilience paradigm in AD should go beyond defining differences to gain full knowledge of cognitive decline and dementia prevention.

About the review

In the present review, researchers discussed sex- and gender-specific determinants of resistance and resilience in AD.

Resilience and resistance to Alzheimer’s disease

AD researchers are reaching an agreement on the difference between managing and preventing AD diseases. Researchers use the words resistance (avoiding) and resilience (coping) to distinguish between characteristics that might help prevent AD development from neurodegeneration and clinical manifestations of the illness.

In AD, the term resilience indicates the capability of mitigating the negative impact of risk and pathology on cognitive function. Resistance against pathologies in AD indicates the premise that particular individuals may exhibit a low to negligible pathological load despite increased risk. This hypothesis assumes that while advanced age and hereditary variables may cause AD-associated pathologies and cognitive decay, a few individuals minimize or avoid the impact of contributing factors, resulting in no or fewer pathologies than predicted.

Researchers considered two pathways that result in preserved cognition in disease and aging: lower risk of pathologies (resistance against pathologies due to elevated tau or amyloid levels) and highly reserved brain function and structure with effective neural resources, compensating for pathologies (brain resilience).

Gender and sex variations in cognitive resistance and resilience to AD

Women with mild cognitive impairment (MCI) experience more cognitive deterioration than men throughout pathological aging, as indicated by the AD Assessment Scale-Cognitive subscale. Studies consistently show that women advance quicker to a clinical diagnosis of MCI and dementia, with women with AD dementia outperforming men in a variety of areas. Women with the apolipoprotein ε4 (APOE ε4) allele have a greater incidence of dementia than males; however, this lately limits to the age range of 65–75 years. Women initially exhibit stronger cognitive resistance to hippocampus volume loss, but this tends to erode with time, particularly following cognitive impairment diagnosis, and most likely at advanced stages of AD-related neurodegeneration.

Research shows that females have worse cognitive resistance to AD pathology than males. At the brain level, AD pathology may have a different influence on brain function and structure in women than in males. Women with reduced cerebrospinal fluid (CSF) Aβ42 and greater CSF tau revealed more rapid hippocampus shrinkage, indicating weaker brain resistance to AD diseases over time in women.

Studies show that women are more susceptible to amyloid and tau pathology, especially those with MCI or dementia. Women with APOE ε4 have higher levels of total tau and p-tau compared to male carriers and non-carriers. APOE ε4 affects tau resistance and cognitive resilience in women. Higher plasma p-tau levels are linked to increased amyloid and entorhinal cortex tau buildup, decreased brain glucose metabolism, and quicker cognitive decline. Previous hormone treatments may have reduced tau accumulation in women.

Older women have superior cognitive abilities due to biological and societal factors. Education helps them lower their dementia risk and enhance cognitive resilience. Women over 60 have more potent immune responses, quicker wound healing, and a higher susceptibility to autoimmune disorders.

They also have greater arterial stiffness, type 2 diabetes prevalence, and a stronger association between hemoglobin A1c and brain capacity. However, the initial memory advantage in women provides cognitive resilience during aging, but this diminishes over time.

Gender variations in sedentary behavior and physical exercise also contribute to cognitive decline. Women exhibit better memory function and performance despite hippocampal atrophy, but beyond a certain threshold, they experience accelerated cognitive decline. They have greater brain resilience to amyloid burden, with a smaller effect of amyloid on hippocampal volume compared to men.

Conclusions

The review reveals that sex variations in resistance to cognitive loss vary with age and cognition levels. Initial data indicates sex-specific variations in brain disease, suggesting that pathology affects cognition differently. During clinical phases, resilience shifts sex-specifically.

Age-related hormonal changes, menopause, genetics, and glial response alterations may lead to proteinopathies, lowering cognitive performance. APOE status, risk factors, physical activity, cardiovascular risks, and pregnancy can alter brain structure and function, lowering cognitive levels. X-chromosomes, immunological pathways, and education status can also increase cognitive impairment risk. Researchers recommend a sex- and gender-aware approach to studying biological and social variables and the function of the X chromosome in resilience.