Sex differences in postoperative cognitive functioning in older patients

Elderly adults are known to be at higher risk of cognitive dysfunction following surgical procedures, and there are known sex differences in cognitive decline rates in Alzheimer's disease, but no studies have really examined how sex as a biological variable may contribute to post-operative cognitive dysfunction. This blog, written by the authors of a recently published study in Biology of Sex Differences, explain their recent study which sought to address this question.

Cognitive dysfunction after surgery in older adults

Credit: Petty Officer 1st Class Michael DiMestico

Initial reports of cognitive changes after surgery and anesthesia date back more than 100 years, and it is not uncommon to hear anecdotal reports of older patients who were “never the same” after surgery. Individuals aged 65 years and older receive more than 1/3 of the over 40 million anesthetics delivered yearly in the United States, and this group of patients are at highest risk for developing perioperative neurocognitive disorders.

The most common perioperative neurocognitive disorder, is postoperative delirium, which typically lasts hours to days after surgery. In contrast, postoperative cognitive dysfunction (POCD) refers to a decline that persists beyond the perioperative recovery period that can last for months or even a year after surgery and anesthesia. POCD is typically characterized by cognitive deficits including impairments in attention, memory, concentration and/or executive function. Not surprisingly, cognitive recovery is a concerning issue for many geriatric patients and caregivers.

Because not everyone with a history of exposure to surgery and anesthesia develops POCD, there are likely major biological risk factors involved, which is what we hoped to learn more about by performing our study. We wanted to determine whether biological sex and/or genetic factors increased the risk of developing POCD in a group of older adults. We specifically chose to study the gene APOE4 because it is the strongest Alzheimer’s genetic risk factor known to-date.

While Alzheimer’s disease is caused by an interplay between environmental and genetic risk factors, it is unclear whether exposure to surgery and anesthesia is one such risk factor. In our prior research study of a group of over 500 older adults, we found that there was a synergistic effect of anesthesia/surgery exposure and the presence of the APOE4 allele in the rate of decline in multiple cognitive measures.

Linking age, genetics, and sex to post-operative cognitive functioning

In an effort to expand on our prior study mentioned above, we broadened our study group to include several more longitudinal aging studies conducted in the Layton Alzheimer’s Disease Center. Unlike many other longitudinal aging studies, these records are unique in that information regarding participants’ surgical history was collected and updated semi-annually.

In our recently published article in the Biology of Sex Differences, we analyzed data on over 1,000 participants. With this larger cohort, we had enough data to investigate the role of sex and genetic differences and the potential contribution of these biological factors to postoperative cognitive dysfunction. We were particularly interested in teasing out whether there was a sex-difference in cognitive decline after surgery in older adults who are APOE4+ (i.e., having at least one copy of the APOE4 allele/APOE4 positive).

We were surprised to find that the APOE4+ men demonstrated worse cognitive decline than the women.

It is known that the APOE4 allele confers an increased risk of Alzheimer’s in a sex-dependent manner, disproportionately affecting women in both prevalence and severity; almost 2/3 of American seniors living with Alzheimer’s are women. On the other hand, several studies have shown that older men are more likely to develop postoperative delirium as compared to older women.

Confirming the results of our prior study, our data indicate that older adults exposed to surgery and general anesthesia had a more rapid rate of cognitive decline compared to older adults who did not undergo surgery and anesthesia. We found that APOE4+ men were at higher risk of postoperative cognitive decline than women who were APOE4+. Because Alzheimer’s research literature has typically shown that APOE+ women are at greater risk for developing Alzheimer’s disease than APOE4+ men, we were surprised to find that the APOE4+ men demonstrated worse cognitive decline than the women.

More research is needed to determine why APOE4+ men might have a more rapid rate of cognitive decline after surgery than APOE4+ women. At advanced ages such as those under study in this cohort, a much greater proportion of women are demented compared to men. We speculate that these factors create a “ceiling effect” in women such that the effects of additional brain insults in APOE4+ females are not very potent, whereas in men there is more potential for surgery/anesthesia to influence the rate of cognitive decline.

Credit: Wellcome Collection gallery (2018-03-22): https://wellcomecollection.org/works/v4dpeevj CC-BY-4.0

What does this mean for hospitals and care providers?

Building knowledge regarding the potential impact of sex and APOE4 genotype in older adults facing decisions regarding surgery is important for several reasons. First, if health care providers knew who was at higher risk for postoperative cognitive decline, they would be able to more accurately counsel these individuals and their families regarding surgical risks and benefits, potentially leading to a decision to forego an elective surgical procedure.

Second, this information would also inform key postoperative care and appropriate discharge planning. Many studies have shown that multidisciplinary, proactive, personalized discharge planning contributes to increased patient satisfaction, decreased hospital length of stay, and reduced readmission to the hospital.

Future, prospective studies could consider sex-genetic risk factor interactions in the development of perioperative neurocognitive disorders, such as delirium and POCD.

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