Attribution of risk

Anaesthesia and surgery are inseparable in clinical settings. Thus, it is difficult to establish whether the increased risk of dementia development observed was attributable to anaesthesia per se, the surgical process, or both. It is noteworthy that there is a growing body of laboratory evidence suggesting that anaesthetic agents may interact with Alzheimer’s disease neuropathology at multiple levels in the involved pathways. However, human evidence has been lacking. Another plausible mechanism of dementia development after anaesthesia and surgery is the occurrence of perioperative events. To help control for this possibility, we excluded patients with vascular dementia. The association of overt perioperative stroke with dementia was beyond the scope of our study. Nevertheless, microvascular perioperative brain damages, such as white matter lesions and silent small infarctions, might influence the risk of dementia development. Alzheimer’s disease has also been linked to hypoxia and hypocapnia events. ^{Reference Futterer, Maurer, Schmitt, Feldmann, Kuschinsky and Waschke15} Deliberate or unintended hypothermia in the perioperative period might also be a risk factor. ^{Reference Baranov, Bickler, Crosby, Culley, Eckenhoff and Eckenhoff12} In animal studies, anaesthesia-induced hypothermia has been shown to produce tau hyperphosphorylation, a biochemical process that may have a role in Alzheimer’s disease pathogenesis. ^{Reference Planel, Richter, Nolan, Finley, Liu and Wen4} However, caution must be exercised in asserting causality, because surgery with anaesthesia shares some common features with dementia pathology, such as old age and involvement of inflammatory processes. The other possible explanation for the observed association between surgery under anaesthesia and subsequent dementia is that patients are more susceptible to surgical illness prior to a clinical diagnosis of dementia. Thus, some comorbidities associated with Alzheimer’s disease might cause patients to be prone to surgical intervention. ^{Reference Duthie, Chew and Soiza16} However, it is noteworthy that some illnesses, such as cancer, have been shown to have an inverse association with Alzheimer’s disease. ^{Reference Driver, Beiser, Au, Kreger, Splansky and Kurth17} Unfortunately, clinical evidence of susceptibility to surgical illness during the preclinical period of Alzheimer’s disease is scant.

The best-identified risk factor for post-operative long-term cognitive decline and Alzheimer’s disease is increasing age. ^{Reference Zuo and Zuo18} In animal studies, less effect on cognitive function attributable to the anaesthesia was noted in adolescent or middle-aged rodents. ^{Reference Culley, Baxter, Yukhananov and Crosby19} Thus, the older brain may demonstrate enhanced vulnerability to mild insults. As expected, our study showed that the incidence of dementia after anaesthesia with surgery was higher in senior patients than in middle-aged patients. However, the extent of increased risk of dementia was similar between these two groups. One previous study of patients with Alzheimer’s disease showed that age at onset was inversely related to cumulative exposure to anaesthesia before the age of 50 years. ^{Reference Bohnen, Warner, Kokmen and Kurland20} These results suggest that anaesthesia and surgery may speed up the process of neurodegeneration, and that this is not specific to older people.

Type of anaesthesia and surgery

Thus far, most studies whose results support the proposition of anaesthetic-induced neurotoxicity have examined inhaled anaesthetic agents. Limited data are available in relation to the effects of IV anaesthetic drugs, which are generally considered less neurotoxic than inhaled agents. Propofol only enhanced Aβ oligomerisation at high concentrations, ^{Reference Eckenhoff, Johansson, Wei, Carnini, Kang and Wei1} and did not impair memory in rats. ^{Reference Lee, Culley, Baxter, Xie, Tanzi and Crosby21} There has been an ongoing debate as to whether regional anaesthesia is superior to general anaesthesia in relation to the incidence of cognitive decline; previous studies have shown inconsistent results. One study demonstrated that Aβ and tau in cerebrospinal fluid changed in a manner consistent with Alzheimer’s disease 6 months after CABG, regardless of whether the patient received inhaled or IV anaesthesia. ^{Reference Palotas, Reis, Bogats, Babik, Racsmany and Engvau22} One study showed that patients exposed to general anaesthesia had a lower risk of dementia 5 years after prostate or hernia surgery than did patients given regional anaesthesia, ^{Reference Vanderweydea, Bednarb, Formanc and Wolozin7} but other studies demonstrated no significant difference between these types of anaesthesia. ^{Reference Williams-Russo, Sharrock, Mattis, Szatrowski and Charlson23,Reference Seitz, Shah, Herrmann, Beyene and Siddiqui24} In our study all three modes of anaesthesia were associated with an increased risk of dementia, and the hazard ratio for dementia development was higher in the regional anaesthesia group than in the general anaesthesia group, whereas there was no significant difference between the IV/IM group and the general anaesthesia group. It may be that anaesthetic-induced neurotoxicity does not play a key part in the onset or acceleration of Alzheimer’s disease pathogenesis after anaesthesia and surgery. Other perianaesthesia factors, such as duration and depth of anaesthesia, might also modulate Alzheimer’s disease pathogenesis. ^{Reference Farag, Chelune, Schubert and Mascha25}

There is a bidirectional link between depression and dementia. In our study the approximately fourfold increase in dementia risk associated with depression may suggest that depression is a risk factor for development of dementia after anaesthesia and surgery, especially when the diagnosis of depression occurred post-operatively. Nonetheless, this association may also suggest that depression might be a prodrome of dementia. Electroconvulsive therapy is sometimes administered with IV/IM anaesthesia to people with severe depression, and has been reported to cause cognitive decline. ^{Reference Gardner and O'Connor26} However, none of the 18 patients in our study who had received ECT developed dementia. Therefore, we can conclude that our finding of increased risk of dementia after IV/IM anaesthesia was not biased by inclusion of these patients with depression. On the other hand, given the small number of cases of ECT treatment, we cannot elaborate on the possible association of exposure to IV/IM anaesthesia during ECT with dementia development in patients with depression.

Our data do not support the hypothesis that two or more exposures to anaesthesia within a year increase the risk of Alzheimer’s disease development beyond that occurring as a result of a single exposure within a year. Our data are consistent with a prior case-control study showing that neither exposure to six or more episodes of general anaesthesia, nor cumulative exposure to 600 min or more of general anaesthesia, was associated with an increased risk of Alzheimer’s disease. ^{Reference Bohnen, Warner, Kokmen, Beard and Kurland27} In contrast, cell culture and animal studies have suggested that inhaled anaesthetic agents induce neuronal apoptosis in a dose- and time-dependent manner. ^{Reference Eckenhoff, Johansson, Wei, Carnini, Kang and Wei1,Reference Wei and Xie6} An epidemiological study found that age at onset of Alzheimer’s disease was inversely related to cumulative exposure to anaesthesia in earlier life. ^{Reference Bohnen, Warner, Kokmen and Kurland20} The inconsistency between previous studies and our findings may be due to different study designs and different methods of statistical analysis.

With the exception of studies related to cardiac surgery, there is a dearth of research reports providing information about the possible relationship between surgery type and dementia development. ^{Reference Lee, Wolozin, Weiss and Bednar8,Reference Knopman, Petersen, Cha, Edland and Rocca10} In our analysis cardiovascular surgery was not associated with an increased risk of Alzheimer’s disease; however, it should be noted that our cohort included only 17 patients who underwent cardiovascular surgery, which limits interpretations of this result. The small number of patients in this subgroup was most probably due to our exclusion of patients with a diagnosis of stroke. A study of non-cardiac surgery reported that the incidence of cognitive dysfunction 1-2 years following major abdominal, thoracic or orthopaedic surgery was similar to that in the control group. ^{Reference Abildstrom, Rasmussen, Rentowl, Hanning, Rasmussen and Kristensen28} However, the number of participants in the control group might have been inadequate. Another group did not detect long-term cognitive decline attributable to non-cardiac surgery, but their analysis did not consider surgery type. ^{Reference Avidan, Searleman, Storandt, Barnett, Vannucci and Saager29} In our study, patients undergoing digestive, genitourinary or musculoskeletal surgery showed an increased risk of dementia. Eye and dermatological surgery were also associated with increased risk of dementia, but the case numbers in these subgroups were small. The effect of the surgery itself on cognitive decline remains unclear. Indeed, in animals, surgery combined with anaesthesia produced greater cognitive dysfunction than anaesthesia alone. ^{Reference Wan, Xu, Ma, Zeng, Cibelli and Maze30} In addition, inflammatory cascades and microglial activation, which are strongly implicated in neurodegeneration, are triggered by surgery. Thus, surgery may initiate a pro-inflammatory event in the brain in both humans and other animals. ^{Reference Tang, Baranov, Hammond, Shaw, Eckenhoff and Eckenhoff31,Reference Cibelli, Fidalgo, Terrando, Ma, Monaco and Feldmann32} Moreover, enhanced neuro-inflammation is hypothesised to accelerate Alzheimer’s disease neuropathology. ^{Reference Tang, Baranov, Hammond, Shaw, Eckenhoff and Eckenhoff31}

Limitations of the study

Several caveats merit attention in the interpretation of our results. Because we drew our source data from the NHIRD claims database of Taiwan, we were unable to investigate non-modifiable (Apo-E genotype) and modifiable risk factors (such as smoking or level of education). Age, prevalence of comorbidity and Charlson index were higher in the anaesthesia group than in the control group. Although we adjusted the Cox regression model for these factors, adjusting solely for these confounding factors might not have fully controlled for group differences. Additionally, it is possible that patients who underwent surgery were followed up more frequently than individuals in the control group, which could have allowed more opportunities for dementia diagnosis. The possible occurrence of post-operative cognitive decline after surgery could also lead to early awareness and initiation of a diagnostic evaluation for dementia. Moreover, we included patients who underwent anaesthesia for the first time since 1995, and the people in both anaesthesia and control groups might have been exposed to anaesthesia and surgery earlier in life. However, the variability in these exposures is unlikely to differ between these two groups.

Future research

In conclusion, this nationwide, population-based study showed a significant association between anaesthesia with surgery and dementia. Our findings support the view that patients who undergo anaesthesia and surgery may be at increased risk of dementia. Although anaesthesia and surgery have provided immeasurable health and social benefits, our observations highlight the need for further studies to understand the association and causality between anaesthesia with surgery and subsequent dementia.