Marked by acute temporary confusion, disorientation and/or agitation, postoperative delirium is the most common post-surgical complication in older adults, striking as many as half of adults older than 65 who undergo high-risk procedures such as cardiac surgery or hip replacements. Postoperative delirium is also tightly linked to Alzheimer’s disease (AD).
Although each can occur independently, Alzheimer’s is a leading risk factor for delirium, and an episode of delirium puts patients at increased risk for cognitive decline and Alzheimer’s disease.
However, the physiological mechanisms linking delirium and Alzheimer’s disease remain largely unknown.
A paper published today in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, researchers at Beth Israel Deaconess Medical Center (BIDMC) shed new light on a genetic risk factor for Alzheimer’s disease that may indirectly influence patients’ risk of postoperative delirium.
In a study of older adults without dementia undergoing major non-cardiac surgery, researchers observed that patients carrying a specific variant of a gene appeared to be much more vulnerable to delirium under certain conditions than people without this genetic variant.
The team’s findings could open the door to future interventions to prevent or mitigate postoperative delirium in at-risk patients.
“Our findings confirmed our hypothesis that patients’ risk of postoperative delirium differs by genetic predisposition,” said Sarinnapha M. Vasunilashorn, Ph.D., an Assistant Professor of Medicine in the Division of General Medicine at BIDMC.
“We observed a strong and significant association between high postoperative inflammation and delirium incidence, duration and severity among patients carrying a variant of the gene considered to be risky, while the association was weaker and non-significant among non-carriers.”
Vasunilashorn and colleagues focused on a gene called APOE (short for apolipoprotein E).
The risky version of the gene—notated as APOE ɛ4—is the strongest known genetic risk factor for late-onset Alzheimer’s disease and a widely studied genetic risk marker for delirium.
While recent studies have shown no direct relationship between APOE ɛ4 and delirium, Vasunilashorn’s team hypothesized that the gene variant might indirectly influence risk of delirium by modifying the body’s response to inflammation—part of the immune system’s natural defense system—indicated by the presence of an inflammatory marker in the blood called CRP (C-reactive protein).
Using data from the Successful Aging after Elective Surgery (SAGES) study, an ongoing prospective cohort study investigating risk factors and long-term outcomes of delirium, the scientists looked at the incidence, severity and duration of delirium in 560 patients 70 years or older who underwent major non-cardiac surgeries under general or spinal anesthesia. Patients were monitored for delirium, assessed by daily cognitive assessments of patients’ attention, memory and orientation throughout their hospital stay.
Analyzing data from patients’ blood (drawn before surgery, immediately after surgery, two days after and one month after) revealed that, among carriers of the APOE ɛ4 gene variant, patients with high levels of inflammation had an increased risk of postoperative delirium.
However, among non-carriers of the APOE ɛ4 gene variant, the scientists found no such association.
“Our findings suggest that APOE ɛ4 may be an indicator of brain vulnerability,” said Vasunilashorn, who also holds appointments at Harvard Medical School, and the Harvard T.H. Chan School of Public Health.
“This work may inform the targeting of future interventions, such as anti-inflammatory treatments, for prevention of postoperative delirium and its associated adverse long-term cognitive outcomes in patients with this genetic susceptibility.”
Dementia progressively deteriorates the quality of life through decreased functioning and cognition. Many studies have investigated factors that contribute to decline in functional and mental capabilities [1–5]. In these studies, functional and cognitive capacities have been evaluated for different dementia subtypes, and analyses have indicated that changes may vary by subtype. Interest has also extended into understanding cognitive decline in mixed dementia [5, 6]. Furthermore, studies have shown specific associations of cardiovascular risk factors to these subtypes [7, 8].
The relationship between cardiovascular disease and dementia is of particular interest as both have increased risk with age and many studies have identified associations between cardiovascular risk factors and the risk of dementia, especially for Alzheimer’s disease (AD) [9–27]. In a previous study, it was determined differential associations between late-life cardiovascular factors and neurodegenerative diseases exist for multiple dementia subtypes . The presence of cardiovascular risk factors was evaluated in individuals who had a diagnosis of probable AD, possible AD, vascular dementia (VaD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), Parkinson’s disease, progressive supranuclear palsy, or corticobasal degeneration.
Compared to the non-demented group, body mass index (BMI) of patients with probable AD and DLB was found to be significantly lower. Other studies have also identified relationships between cardiovascular factors and various disease pathologies, such as obesity or heart failure leading to a higher risk of AD [21, 28]. Identifying these relationships are important as multiple studies have suggested pharmacological and non-pharmacological therapies can improve vascular health and delay the progression of dementia. Physical activity has been demonstrated to improve brain plasticity and increase resilience to AD  while pharmacological therapies and nutritional interventions can be used to decrease the risk of obesity and delay the onset of AD .
These findings support the differential relationship of specific diseases to cardiovascular factors and presents the question of how cardiovascular factors may be related to cognition for dementia patients. A recent study evaluated the relationship of cognitive decline (measured by the Mini-Mental State Examination (MMSE)  score and Clinical Dementia Rating Scale Sum of Boxes (CDR-SUM) [32, 33]) and cardiovascular risk factors, such as diabetes mellitus, hypertension, hypercholesterolemia, smoking, and being overweight on subjects diagnosed with AD or DLB . The analysis revealed overweight AD patients had slower cognitive decline while hypertension and being overweight were also related to slower cognitive decline for DLB patients. The study indicates that cardiovascular risk factors are associated to cognition but was limited in the diagnoses that were evaluated.
The objective of the current study was to determine whether the rate of cognitive decline was affected by late life cardiovascular risk factors, using two measures of cognition, MMSE and CDR-SUM, across multiple dementia subtypes including AD, DLB, VaD, and FTD as well as non-demented elderly individuals (normal).
In a sample of patients from the NACC UDS with diagnoses of AD, DLB, FTD, VaD, and normal, we evaluated the differential associations of cardiovascular risk factors and cognitive score, measured using MMSE and CDR-SUM. The analyses indicate select cardiovascular factors are significantly associated with cognitive decline for select dementia subtypes. Four associations between changes in cognition and cardiovascular risk factors were identified that were in agreement between both the MMSE and CDR-SUM measures.
In the AD group, recent/active hypertension and recent/active hypercholesterolemia were both found to be associated with higher cognitive functioning. For FTD patients, an increase in BMI or an increase in the number of years smoking were both associated with higher cognition. Additional associations were also identified for each cognitive measure as mentioned in the results.
Our findings are in agreement with existing studies that have found a significant association between hypertension and hypercholesterolemia and increased cognitive scores, using MMSE, for patients with AD [8, 40].
+ While Bergland’s study  shows mild significance of these two cardiovascular risk factors for AD patients, our study indicates a highly statistically significant association with the rate of change in cognition. Although a previous study found increased systolic blood pressure to be associated with a higher rate of cognitive decline in patients with AD , we found that the presence of hypertension was associated with a smaller decrease in cognitive scores for this subtype.
These differences may be due to differences in study cohorts as well as methodologies used. Furthermore, many individuals with hypertension may not be optimally treated  potentially creating distinct subgroups (treated vs. untreated). This is imperative as treatment for high blood pressure has been noted to decrease cognitive decline in patients with cerebrovascular disease ; more research is needed to understand these effects across dementia subtypes.
Our study also identifies associations between cardiovascular risk factors and changes in cognition for the FTD subtype (BMI, years smoked, and atrial fibrillation). While previous studies on the FTD dementia subtype are limited, studies have demonstrated an association between increased BMI and a lower risk of cognitive decline . We similarly found a higher BMI in late life was associated with an increase in MMSE scores or a decrease in CDR-SUM, with statistically significant associations using both measures. From a mechanistic standpoint, the association of increased BMI with less cognitive impairment may be related to glucose metabolism, which is disrupted in mild cognitive impairment and dementia [48, 49] or may be related to changes in body composition which in turn alters many physiological processes . More research is needed to develop a causal link.
For the DLB subtype, we found that number of years smoked was associated with a significant increase in MMSE score per month although we did not identify an association between years smoked and CDR-SUM. This result agrees with a previous study which also investigated both cognitive measures and only found a statistically significant association between smoking and change in MMSE . Many previous studies have indicated that smoking may have a protective effect from Parkinson’s disease [50–54], which is consistent with the association between smoking and the cognitive rate of change measured using MMSE. This association may be explained by select underlying physiological processes as mentioned in previous interpretations of similar findings including reduction of the enzyme monoamine B oxidase, interaction with glutathione S-transferases, or induction of cytochrome P-450 .
For the VaD subgroup, diabetes was identified to be significantly associated to an increase in the change of CDR-SUM over time, although other associations between cardiovascular risk factors and cognitive decline were not identified. While the VaD group had a small sample size (n=13) and should be assessed carefully, there are several factors that could contribute to a lack of associations between cardiovascular risk factors and cognitive decline for VaD patients. By definition, VaD patients have been previously diagnosed with cardiovascular risk factors and over time the factors may fall within the remote/inactive category. Moreover, VaD is not a progressive disease, unlike AD, DLB, and FTD and studies have noted less of a cognitive decline in VaD when compared to AD .
Recent studies have also shown that VaD patients often have mixed dementia , which the current study excluded. In addition, individual cardiovascular risk factors may not contribute to cognitive decline in VaD patients as these factors define a VaD diagnosis.
Since cardiovascular disease is very common in VaD patients, it is difficult to identify the impact of individual cardiovascular risk factors. In this study, 85.7 percent of patients had recent/active hypertension and 64.3 percent of patients had recent/active hypercholesterolemia (Table 1). Since patients with VaD often have these cardiovascular risk factors, we do not suspect changes should have a significant impact on cognitive decline but due to limitations in our sample size, this should be further investigated.
Although MMSE and CDR-SUM are both measures of cognition, the differing associations between cardiovascular risk factors and each measure can be expected. A study evaluating 19 different cognitive tests to assess a range of cognitive abilities was performed and it was found that the rates of change in cognitive score varied depending on the test . MMSE is considered more of a cognitive assessment, while CDR-SUM is more of a global measure as it assesses skills other than memory and cognition. The scales for both measures vary greatly as well. Previous comparisons between the two measures found that while MMSE and CDR-SUM can generally capture similar levels of dementia severity, CDR-SUM is more precise in measuring cognitive decline [58, 59].
In this study, we identify several associations between cardiovascular risk factors and the rate of cognitive decline. While we examine each factor independently to identify cardiovascular risk factors that may have the most influence, co-occurrences of risk factors can have varying impacts on the rate of decline. For patients in our study, recent or active hypertension and hypercholesterolemia most frequently co-occurred at baseline for all dementia diagnoses and the normal subgroup, as shown in Table 4.
In the NACC data, hypertension and hypercholesterolemia were both associated with a smaller decline in cognition for AD patients, while the two cardiovascular risk factors had opposing effects for other disease diagnoses. For patients with both hypertension and hypercholesterolemia, the predicted monthly rate of change would be a net decline for diagnoses of DLB, VaD and normal.
In our study, the change in cognition for FTD patients with both of these cardiovascular risk factors had conflicting results between MMSE and CDR-SUM. As co-occurrences of cardiovascular risk factors are common and other studies have determined that the aggregation of vascular risk factors can be associated with a higher risk of disease , we recommend future studies investigate the impact of aggregated risk factors should be further investigated on cognitive change.
As clinical diagnosis accuracy rates can vary, one might evaluate post-mortem data to understand the underlying pathology and the corresponding associations. Autopsy data was available for 692 patients in the longitudinal sample (approximately 12.1 percent of patients). Of these subjects, a primary diagnosis was determined for 416 patients. Using the post mortem diagnosis, nearly 67 percent of the 416 patients corresponded directly to the clinical diagnosis. Of the patients with conflicting primary diagnoses, most had been classified as AD or normal in the NACC data but during the autopsy had been diagnosed with a disease other than those evaluated in this study, including mixed diagnoses.
On average, the patients with post mortem diagnoses (n=416) died 19.2 months after their last visit to the ADC (min = 0 months, max = 71 months). It is possible that patients who were considered part of the normal group during the study later developed dementia due to the length of time between the last visit and death.
Using the NACC UDS as the source of data provides multiple strengths for this study, including standardized protocols for data collection across the ADCs as well as a large number of patients, which results in reliable statistical models and estimates.
In addition, the study design is longitudinal, across 34 ADCs in the United States, which includes many different patients with mean follow-up times of 36 months (for the DLB group) or longer. The evaluation of cardiovascular factors across multiple dementia subtypes allows for flexibility as vascular risk factors may be associated with only select neurodegenerative diseases.
The present study does have some limitations. We had very stringent inclusion criteria, including having only one consistent dementia diagnosis over the course of all visits to reduce confounding variables.
The authors are aware that most dementias are that of a mixed etiology which is revealed at the time of a post-mortem neuropathological evaluation [61, 62]. Furthermore, while the NACC database overall contains many patients, most patients in the subset of data selected for the study had a diagnosis of AD or normal. The DLB, FTD, and VaD subtypes had much smaller sample sizes and should be further analyzed in subsequent analyses. In addition, some visits were missing the MMSE value or contained invalid values and were excluded.
These missing datapoints may obscure important changes in the MMSE value or associations with the cognitive score and can create bias. Categorical cardiovascular risk factors evaluated, including atrial fibrillation, diabetes, hypertension, and hypercholesterolemia, varied for some of the patients as cardiovascular diseases developed or became inactive during the study. Of the sample evaluated, 5.8 percent of patients had a change in atrial fibrillation status, 4.1 percent had a change in diabetes status, 16.2 percent had a change in hypertension status, and 21.7 percent had a change in hypercholesterolemia status during the study. Some patients had multiple changes in status for these variables.
Across the four categorical cardiovascular risk factors, 42.2 percent of the statuses switched from absent to recent/active and 17.4 percent switched from remote/inactive to recent/active, which is expected as the population ages over the duration of the study and develops cardiovascular diseases. In 5.3 percent of status changes, the cardiovascular risk factor status switched from absent to remote/inactive. In 35.0 percent of cases, patients had a cardiovascular risk factor change from recent/active to remote/inactive.
There was one case of a patient changing from remote/inactive atrial fibrillation to the status absent, although this is likely an error in the data. Although we accounted for changing statuses rather than assigning each patient one cardiovascular risk factor status at the beginning of study, follow up studies should be performed to understand the impact on cognition when a cardiovascular risk factor becomes present after the onset of dementia. Moreover, cardiovascular risk factors may affect cognition differently based on the length of time and the age the patient acquired the condition [10, 63–66].
In addition, this study focuses on a select subset of cardiovascular risk factors. A recent study has suggested that autonomic dysfunction, measured using heart rate variability, may also be associated with dementia and cognitive impairment . Follow up investigations should further evaluate this condition as well as other cardiovascular risk factors.
This study investigated multiple dementia subtypes, as well as a non-demented group, and enhanced previous studies of this type. We identified clear associations between cardiovascular risk factors and the rate of cognitive decline for patients with diagnoses of AD, DLB, FTD and normal. This study indicates the necessity of evaluating cardiovascular risk factors to understand dementia patient outcomes and identified other potential risk factors including demographic characteristics such as age, sex, race, and education that should be further investigated in future studies.
More information: Sarinnapha M. Vasunilashorn et al, Apolipoprotein E genotype and the association between C-reactive protein and postoperative delirium: Importance of gene-protein interactions, Alzheimer’s & Dementia (2019). DOI: 10.1016/j.jalz.2019.09.080