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Anesthesia and Incident Dementia: A Population-Based, Nested, Case-Control Study

      Abstract

      Objective

      To test the hypothesis that exposure to procedures requiring general anesthesia during adulthood is not significantly associated with incident dementia using a retrospective, population-based, nested, case-control study design.

      Participants and Methods

      Using the Rochester Epidemiology Project and the Mayo Clinic Alzheimer's Disease Patient Registry, residents of Olmsted County, Minnesota, diagnosed as having dementia between January 1, 1985, and December 31, 1994, were identified. For each incident case, a sex- and age-matched control was randomly selected from the general pool of Olmsted County residents who were dementia free in the index year of dementia diagnosis. Medical records were reviewed to determine exposures to procedures requiring anesthesia after age 45 years and before the index year. Data were analyzed using logistic regression.

      Results

      We analyzed 877 cases of dementia, each with a corresponding control. Of the dementia cases, 615 (70%) underwent 1681 procedures requiring general anesthesia; of the controls, 636 (73%) underwent 1638 procedures. When assessed as a dichotomous variable, anesthetic exposure was not significantly associated with dementia (odds ratio, 0.89; 95% CI, 0.73-1.10; P=.27). In addition, no significant association was found when exposure was quantified as number of procedures (odds ratios, 0.87, 0.86, and 1.0 for 1, 2-3, and ≥4 exposures, respectively, compared with none; P=.51).

      Conclusion

      This study found no significant association between exposure to procedures requiring general anesthesia after age 45 years and incident dementia.

      Abbreviations and Acronyms:

      AD (Alzheimer disease), DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)), OR (odds ratio), POCD (prolonged postoperative cognitive decline), REP (Rochester Epidemiology Project)
      Some elderly patients exposed to general anesthesia and surgery may experience temporary postoperative cognitive dysfunction, although the mechanism(s) and phenotype(s) of such dysfunction remain to be fully defined.
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      Iatrogenic risk factors for Alzheimer's disease: surgery and anesthesia.
      More controversial is the possibility that exposure to anesthesia may be associated with long-term cognitive changes, including dementia.
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      Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery.
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      Does anaesthesia cause postoperative cognitive dysfunction? a randomised study of regional versus general anaesthesia in 438 elderly patients.
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      Exposure to general anesthesia and risk of Alzheimer's disease: a systematic review and meta-analysis.
      These concerns arose in part from a series of studies showing that in animals exposed to volatile anesthetic agents, neurohistopathologic lesions similar to those observed in Alzheimer disease (AD) can develop, including accumulation of β-amyloid in neural tissues and the formation of neurofibrillary tangles.
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      Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline.
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      Altered hippocampal gene expression 2 days after general anesthesia in rats.
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      Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia.
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      • et al.
      Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia.
      Several studies using a case-control design have analyzed exposure to anesthesia for surgery as a risk factor for incident dementia.
      The Canadian Study of Health and Aging: risk factors for Alzheimer's disease in Canada.
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      • Zuo Z.
      Spine surgery under general anesthesia may not increase the risk of Alzheimer's disease.
      As summarized in a recent meta-analysis, there is little evidence from these studies that exposure to general anesthesia for surgical and other procedures is an independent risk factor for dementia.
      • Seitz D.P.
      • Shah P.S.
      • Herrmann N.
      • Beyene J.
      • Siddiqui N.
      Exposure to general anesthesia and risk of Alzheimer's disease: a systematic review and meta-analysis.
      However, available studies have notable limitations, including small sample sizes that limit statistical power, selection biases in the construction of case cohorts (eg, patients studied at tertiary referral centers may not reflect the general population), selection of appropriate controls (who do not have cognitive impairment preoperatively), little to no information regarding the details of anesthesia exposure, and a lack of rigorous application of diagnostic criteria for dementia.
      The present study sought to mitigate these limitations by using the Rochester Epidemiology Project (REP),
      • Kurland L.T.
      • Molgaard C.A.
      The patient record in epidemiology.
      • Melton III, L.J.
      History of the Rochester Epidemiology Project.
      • Rocca W.A.
      • Yawn B.P.
      • St Sauver J.L.
      • Grossardt B.R.
      • Melton L.J.
      History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population.
      • St Sauver J.L.
      • Grossard B.R.
      • Yawn B.P.
      • et al.
      Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system.
      • St Sauver J.L.
      • Grossardt B.R.
      • Leibson C.L.
      • Yawn B.P.
      • Melton III, L.J.
      • Rocca W.A.
      Generalizability of epidemiological findings and public health decisions: an illustration from the Rochester Epidemiology Project.
      • St Sauver J.L.
      • Grossardt B.R.
      • Yawn B.P.
      • Melton III, L.J.
      • Rocca W.A.
      Use of a medical records linkage system to enumerate a dynamic population over time: the Rochester Epidemiology Project.
      which provides access to all the medical records of residents of Olmsted County, Minnesota; the Mayo Clinic Alzheimer's Disease Patient Registry, which includes all incident cases of dementia in Olmsted County between 1985 and 1994; and an age- and sex-matched cohort without dementia at the time of index diagnosis. Its purpose was to test the hypothesis that exposure to general anesthesia after age 45 years is not significantly associated with incident dementia using a nested case-control study design.

      Participants and Methods

      This retrospective, population-based, nested, case-control study was approved by the institutional review boards of Olmsted Medical Center and Mayo Clinic, Rochester, Minnesota. Medical records were reviewed only for participants who had provided previous authorization for the use of their medical records in research (Minnesota Statute 144.335 [Subd. 3a. (d)]). Incident cases (Olmsted County residents with a diagnosis of dementia or AD) were identified between January 1, 1985, and December 31, 1994, and their corresponding controls were obtained through the medical records linkage system of the REP.
      • Melton III, L.J.
      History of the Rochester Epidemiology Project.
      Details regarding the REP and procedures used to identify cases and controls in this cohort have been detailed in several previous communications
      • Kokmen E.
      • Beard C.M.
      • Chandra V.
      • Offord K.P.
      • Schoenberg B.S.
      • Ballard D.J.
      Clinical risk factors for Alzheimer's disease: a population-based case-control study.
      • Beard C.M.
      • Kokmen E.
      • Offord K.P.
      • Kurland L.T.
      Lack of association between Alzheimer's disease and education, occupation, marital status, or living arrangement.
      • Knopman D.S.
      Dementia and cerebrovascular disease.
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      • Boeve B.F.
      • Petersen R.C.
      Essentials of the proper diagnoses of mild cognitive impairment, dementia, and major subtypes of dementia.
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      • Knopman D.S.
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      • Edland S.D.
      • Rocca W.A.
      Coronary artery bypass grafting is not a risk factor for dementia or Alzheimer disease.
      • Knopman D.S.
      • Petersen R.C.
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      Incidence and causes of nondegenerative nonvascular dementia: a population-based study.
      • Knopman D.S.
      • Petersen R.C.
      • Rocca W.A.
      • Larson E.B.
      • Ganguli M.
      Passive case-finding for Alzheimer's disease and dementia in two U.S. communities.
      • Kokmen E.
      • Beard C.M.
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      Epidemiology of dementia in Rochester, Minnesota.
      • Kokmen E.
      • Chandra V.
      • Schoenberg B.S.
      Trends in incidence of dementing illness in Rochester, Minnesota, in three quinquennial periods, 1960-1974.
      • Roberts R.O.
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      • Rocca W.A.
      Postmenopausal estrogen therapy and Alzheimer disease: overall negative findings.
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      Subjective complaints in mild cognitive impairment make a difference.
      • Rocca W.A.
      • Cha R.H.
      • Waring S.C.
      • Kokmen E.
      Incidence of dementia and Alzheimer's disease: a reanalysis of data from Rochester, Minnesota, 1975-1984.
      • Rocca W.A.
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      • et al.
      Trends in the incidence and prevalence of Alzheimer's disease, dementia, and cognitive impairment in the United States.
      and are briefly summarized herein.

      Definition of Cases

      Through the REP, all information for county residents seeking care in Olmsted County is indexed by medical diagnoses and procedures
      • Kurland L.T.
      • Molgaard C.A.
      The patient record in epidemiology.
      • Melton III, L.J.
      History of the Rochester Epidemiology Project.
      • St Sauver J.L.
      • Grossardt B.R.
      • Yawn B.P.
      • Melton III, L.J.
      • Rocca W.A.
      Use of a medical records linkage system to enumerate a dynamic population over time: the Rochester Epidemiology Project.
      so that individuals with a given condition can be identified using appropriate diagnostic codes.
      • Rocca W.A.
      • Petersen R.C.
      • Knopman D.S.
      • et al.
      Trends in the incidence and prevalence of Alzheimer's disease, dementia, and cognitive impairment in the United States.
      The method used to identify incident dementia cases has been reported in detail previously.
      • Knopman D.S.
      Dementia and cerebrovascular disease.
      • Knopman D.S.
      • Edland S.D.
      • Cha R.H.
      • Petersen R.C.
      • Rocca W.A.
      Incident dementia in women is preceded by weight loss by at least a decade.
      • Knopman D.S.
      • Petersen R.C.
      • Cha R.H.
      • Edland S.D.
      • Rocca W.A.
      Coronary artery bypass grafting is not a risk factor for dementia or Alzheimer disease.
      • Knopman D.S.
      • Petersen R.C.
      • Cha R.H.
      • Edland S.D.
      • Rocca W.A.
      Incidence and causes of nondegenerative nonvascular dementia: a population-based study.
      • Knopman D.S.
      • Petersen R.C.
      • Rocca W.A.
      • Larson E.B.
      • Ganguli M.
      Passive case-finding for Alzheimer's disease and dementia in two U.S. communities.
      In brief, information from the REP was used to identify patients with primary dementia or AD in Olmsted County during the study period through the screening use of diagnostic codes followed by abstraction of relevant information from the medical record.
      • Knopman D.S.
      • Petersen R.C.
      • Cha R.H.
      • Edland S.D.
      • Rocca W.A.
      Coronary artery bypass grafting is not a risk factor for dementia or Alzheimer disease.
      • Knopman D.S.
      • Petersen R.C.
      • Cha R.H.
      • Edland S.D.
      • Rocca W.A.
      Incidence and causes of nondegenerative nonvascular dementia: a population-based study.
      • Rocca W.A.
      • Cha R.H.
      • Waring S.C.
      • Kokmen E.
      Incidence of dementia and Alzheimer's disease: a reanalysis of data from Rochester, Minnesota, 1975-1984.
      • Edland S.D.
      • Rocca W.A.
      • Petersen R.C.
      • Cha R.H.
      • Kokmen E.
      Dementia and Alzheimer disease incidence rates do not vary by sex in Rochester, Minn.
      Using this information, 1 of 3 behavioral neurologists who had wide experience in dementia and epidemiologic research (including one of the coauthors [D.S.K.]) reviewed the abstracted information to confirm the diagnosis of dementia, classify the type of dementia, and determine the year of onset.
      • Knopman D.S.
      Dementia and cerebrovascular disease.
      • Knopman D.S.
      • Edland S.D.
      • Cha R.H.
      • Petersen R.C.
      • Rocca W.A.
      Incident dementia in women is preceded by weight loss by at least a decade.
      • Knopman D.S.
      • Petersen R.C.
      • Cha R.H.
      • Edland S.D.
      • Rocca W.A.
      Incidence and causes of nondegenerative nonvascular dementia: a population-based study.
      • Knopman D.S.
      • Petersen R.C.
      • Rocca W.A.
      • Larson E.B.
      • Ganguli M.
      Passive case-finding for Alzheimer's disease and dementia in two U.S. communities.
      • Rocca W.A.
      • Cha R.H.
      • Waring S.C.
      • Kokmen E.
      Incidence of dementia and Alzheimer's disease: a reanalysis of data from Rochester, Minnesota, 1975-1984.
      • Rocca W.A.
      • Petersen R.C.
      • Knopman D.S.
      • et al.
      Trends in the incidence and prevalence of Alzheimer's disease, dementia, and cognitive impairment in the United States.
      Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV)
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders.
      criteria were used to define dementia. Each element of the DSM-IV criteria was documented separately, and a diagnosis of dementia was made only if all 3 criteria were present. Alzheimer disease was distinguished from other types of dementia based on available clinical and laboratory data using DSM-IV criteria (dementia with gradual onset and continuing decline and absence of any other conditions that could explain the deficits)
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders.
      and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association criteria.
      • McKhann G.
      • Drachman D.
      • Folstein M.
      • Katzman R.
      • Price D.
      • Stadlan E.M.
      Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.
      Although the criteria for AD dementia have recently been revised,
      • McKhann G.M.
      • Knopman D.S.
      • Chertkow H.
      • et al.
      The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
      the fundamental features supporting the clinical diagnosis of AD dementia are still reflected in DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association criteria. Individuals with postoperative confusion who later returned to their normal mental state were not considered demented. Dementia of presumed neurodegenerative or cerebrovascular etiology (primary dementia) was defined by excluding patients with clear causes, such as multiple sclerosis, late effects of brain trauma, anoxic encephalopathy, primary and metastatic brain tumor, alcohol use, and a lifelong psychiatric disorder.
      To be included in the cohort, patients with dementia were required to reside in Rochester during the year of dementia onset and for at least 1 preceding year. Patients with dementia who moved to Rochester for the management of a preexisting dementing illness were excluded. Age at the onset of dementia was determined according to information collected in the medical record at the time of diagnosis.
      • Knopman D.S.
      • Edland S.D.
      • Cha R.H.
      • Petersen R.C.
      • Rocca W.A.
      Incident dementia in women is preceded by weight loss by at least a decade.

      Selection of Controls

      For each case, a sex- and age (±1 year)-matched control was randomly selected from the general pool of Olmsted County residents who were dementia free in the index year (year of onset of dementia in the matched case). The list of all Rochester residents from which potential controls were drawn was provided by the medical records linkage system and was based on the enumeration of all individuals in contact with the system at least once in the 3 years after the index year.
      • Melton III, L.J.
      History of the Rochester Epidemiology Project.
      Control subjects were judged to be free of dementia if review of their medical records revealed no mention of cognitive impairment or loss of function before the index year.

      Data Abstraction for Anesthesia History

      For all cases and controls, medical records were examined and data were abstracted for each episode of exposure to general anesthesia between age 45 years and the index date. This age was chosen based on (1) analogy to the 18-month-old rats who were the subjects of some of the experimental studies suggesting contributions of anesthesia to AD abnormalities,
      • Andreollo N.A.
      • Santos E.F.
      • Araujo M.R.
      • Lopes L.R.
      Rat's age versus human's age: what is the relationship?.
      • Quinn R.
      Comparing rat's to human's age: how old is my rat in people years?.

      How old is a rat in human years? Rat Behavior and Biology website. http://www.ratbehavior.org/RatYears. Accessed August 9, 2012.

      (2) the availability of medical records that included this age and the index date in most of the participants (see the “Results” section), and (3) the desire to limit the time from exposure to outcome in seeking biologically meaningful associations, recognizing that any potential window of vulnerability is unknown. For individuals whose medical records began after age 45 years, anesthetic exposure information was abstracted back to the date that their medical records started. For each exposure to anesthesia, the agents used for induction and maintenance of anesthesia, the type of procedure, and the duration of anesthesia were recorded. All abstracted data were entered manually into the Web-based Research Electronic Data Capture system (REDCap, version 3.6.7; Vanderbilt University).
      • Harris P.A.
      • Taylor R.
      • Thielke R.
      • Payne J.
      • Gonzalez N.
      • Conde J.G.
      Research electronic data capture (REDCap): a metadata-driven methodology and workflow process for providing translational research informatics support.

      Statistical Analyses

      Conditional logistic regression (taking into account the 1:1 matched-set study design) was used to assess whether the exposure to general anesthesia for procedures was associated with an increased risk of dementia. Because most incident cases had AD dementia, separate analyses were performed that included either all dementia or the subset of AD cases and controls. Analyses were performed with anesthesia exposure quantified (1) categorically as any exposure (yes vs no), (2) as number of exposures (0, 1, 2-3, and ≥4), and (3) as continuous variables (total cumulative duration of exposure in minutes and longest exposure to a single anesthetic agent).
      Supplemental analyses were performed to assess whether the use of any individual anesthetic agent was associated with dementia. For these analyses, the odds ratio (OR) for 1 or more exposures to the given agent was calculated using no exposure to any general anesthesia as the reference group. In addition, because educational level has been found to be associated with the incidence of AD in some studies,
      • Sattler C.
      • Toro P.
      • Schonknecht P.
      • Schroder J.
      Cognitive activity, education and socioeconomic status as preventive factors for mild cognitive impairment and Alzheimer's disease.
      analyses were repeated after adjusting for the highest level of formal education (less than high school, high school, or more than high school).
      Several sensitivity analyses were also performed, repeating the primary analyses (1) after excluding individuals whose first medical record occurred after age 45 years; (2) including only exposures to procedure and anesthesia that occurred within 5, 10, and 20 years of the index date; (3) excluding 72 case-control sets in which controls subsequently developed dementia; (4) including only exposures to procedures and anesthesia after age 60 years in case-control sets with an index date after age 60 years; and (5) including only exposures to procedures and anesthesia after age 70 years in case-control sets with an index date after age 70 years. Results are summarized using ORs and corresponding 95% CIs. In all cases, a 2-tailed P≤.05 was considered statistically significant. Analyses were performed using SAS, version 9.2, statistical software (SAS Institute, Inc).

      Results

      A total of 908 dementia cases and 908 age- and sex-matched controls were identified in the initial ascertainment. After excluding 28 matched sets in which either the case or control denied authorization for the use of their medical records in research and 3 matched sets in which the age at dementia onset was younger than 45 years, the analytic data set included 877 matched case-control sets. Each control was followed up for at least 5 years after the index date (unless they died or moved out of the county). Of those initially included as controls, 72 individuals had development of dementia before 1994. Thus, in addition to being included as controls for the originally identified cases, these individuals were also included as cases along with additional appropriate age- and sex-matched controls.
      Most cases (n=732; 83.5%) met the criteria for AD, with the remainder meeting the criteria for dementia (Table 1). The median (25th-75th percentile) age at the time of the first medical record entry was 31 years (21-49 years) for cases and 32 years (21-49 years) for controls, and the median length of the medical record after age 45 years and before the index date was similar for cases (34.3 years) and controls (34.4 years). Among the 877 cases, 615 (70.1%) were identified who underwent 1681 operations or procedures performed under general anesthesia after age 45 years and before their formal diagnosis of dementia. For these 1681 operations, the median (25th-75th percentile) duration of anesthesia was 90 minutes (45-150 minutes). In the matched control group, 636 individuals (72.5%) were identified who underwent 1638 operations with median (25th-75th percentile) duration of anesthesia of 90 minutes (50-150 minutes). Most procedures (2542, 77%) included the use of a halogenated inhalational anesthetic, with the specific agent used reflective of the era when the procedure was conducted (Figure). For most operations, anesthesia induction was performed with sodium thiopental (3090, 93%), and the maintenance anesthetic included nitrous oxide (2985, 90%). The categories of procedures received were similar in cases and controls (Table 2).
      Table 1Demographic Characteristics
      Data are presented as No. (percentage) except where indicated otherwise.
      CharacteristicDementia due to all causes
      Dementia due to all causes includes any etiology, including Alzheimer disease dementia.
      Dementia due to Alzheimer disease
      Controls (N=877)Cases (N=877)Controls (N=732)Cases (N=732)
      Age at index date (y), mean ± SD81.7±8.081.7±8.081.3±7.981.3±7.9
      Sex
       Male241 (27.5)241 (27.5)203 (27.7)203 (27.7)
       Female636 (72.5)636 (72.5)529 (72.3)529 (72.3)
      White race868 (99.0)870 (99.2)723 (98.8)726 (99.2)
      Education (y)
       <12298 (34.0)291 (33.2)240 (32.8)228 (31.2)
       12225 (25.7)214 (24.4)187 (25.6)184 (25.1)
       >12331 (37.7)351 (40.0)288 (39.3)304 (41.5)
       Unknown23 (2.6)21 (2.4)17 (2.3)16 (2.2)
      a Data are presented as No. (percentage) except where indicated otherwise.
      b Dementia due to all causes includes any etiology, including Alzheimer disease dementia.
      Figure thumbnail gr1
      FigureRelative distribution of inhalational anesthetic agents used during the study period among patients receiving these agents. The use of cyclopropane and nitrous oxide is not shown.
      Table 2Procedures Performed Under General Anesthesia
      Among cases, 615 individuals underwent 1681 procedures under general anesthesia; in the control group, 636 individuals underwent 1638 procedures. The data presented correspond to individuals who received at least one procedure in the given category (ie, patients who underwent multiple procedures of the same type are counted only once). For this reason, the sum across categories does not equal the total number of procedures performed.
      Type of surgery/procedureNo. (%) of controls (N=877)No. (%) of cases (N=877)
      Orthopedic214 (24)244 (28)
      Obstetrics/gynecology208 (24)189 (22)
      General (hernia, appendectomy, etc)177 (20)148 (17)
      Breast84 (10)87 (10)
      Hepatobiliary84 (10)86 (10)
      Urologic76 (9)77 (9)
      Colorectal78 (9)72 (8)
      Oral and maxillofacial61 (7)67 (8)
      Vascular47 (5)51 (6)
      Major cardiac40 (5)31 (4)
      Endocrine37 (4)26 (3)
      Ear, nose, and throat26 (3)30 (3)
      Ophthalmologic18 (2)20 (2)
      Neurosurgery16 (2)16 (2)
      Thoracic13 (1)12 (1)
      Dermatologic12 (1)9 (1)
      Plastic and reconstructive10 (1)8 (1)
      Electroconvulsive therapy2 (<1)4 (<1)
      Other12 (1)12 (1)
      a Among cases, 615 individuals underwent 1681 procedures under general anesthesia; in the control group, 636 individuals underwent 1638 procedures. The data presented correspond to individuals who received at least one procedure in the given category (ie, patients who underwent multiple procedures of the same type are counted only once). For this reason, the sum across categories does not equal the total number of procedures performed.
      The results of analyses performed to assess whether exposure to general anesthesia after age 45 years was associated with dementia and AD dementia specifically are shown in Table 3. When exposure to general anesthesia was assessed as a dichotomous variable (any vs none), anesthesia was not associated with dementia (OR, 0.89; 95% CI, 0.73-1.10; P=.27). In addition, no association was found when anesthetic was quantified as the number of procedures (ORs, 0.87, 0.86, and 1.0 for 1, 2-3, and ≥4 exposures, respectively, compared with no exposure as the reference; P=.51) or when total cumulative duration of exposure was assessed as a continuous variable (OR, 1.00; 95% CI, 0.99-1.01 per 30-minute increase; P=.86). When the analysis was limited to only cases of AD, exposure to general anesthesia (any vs none) was not associated with AD dementia (OR, 0.88; 95% CI, 0.71-1.1; P=.28). In addition, no significant association was found when anesthetic exposure was quantified as number of procedures (ORs, 0.85, 0.86, and 1.02 for 1, 2-3, and ≥4 exposures, respectively; P=.46) or when total cumulative duration of exposure was assessed as a continuous variable (OR, 1.00; 95% CI, 0.99-1.01 per 30-minute increase; P=.78). Analysis of risk according to individual anesthetic agent also did not reveal any association with incident dementia (Table 4). Similar findings were obtained in analyses performed using a model that included the highest level of formal education as a covariate (Supplemental Table 1 [available online at http://www.mayoclinicproceedings.org]); in this model, exposure to general anesthesia (any vs none) was not associated with dementia (OR, 0.88; 95% CI, 0.71-1.09; P=.24).
      Table 3Association Between Exposure to Anesthesia and Subsequent Dementia
      Data are No. (percentage) or median (25th-75th percentile).
      ExposureControlsCasesOdds ratio95% CIP value
      Dementia (including Alzheimer dementia) (N=877)
       Any anesthetic636 (72.5)615 (70.1)0.890.73-1.10.27
       Anesthetic exposure.51
      0241 (27.5)262 (29.9)1.00Reference
      1224 (25.5)211 (24.1)0.870.68-1.12
      2-3282 (32.2)263 (30.0)0.860.67-1.10
      ≥4130 (14.8)141 (16.1)1.000.74-1.35
       Cumulative duration of anesthesia (min)
      Cumulative duration of anesthesia is the total time an individual was exposed to general anesthesia after age 45 years and before their index date. The odds ratio for total anesthesia duration reflects increased risk per 30 minutes of anesthesia. In all cases, odds ratios were obtained using conditional logistic regression taking into account the matched study design.
      140 (0-305)135 (0-307.5)1.000.99-1.01.86
       Cumulative duration of anesthesia (min).58
      0241 (27.5)262 (29.9)1.00Reference
      1-120163 (18.6)159 (18.1)0.900.69-1.19
      121-240195 (22.2)175 (20.0)0.830.64-1.08
      ≥241278 (31.7)281 (32.0)0.930.73-1.19
       Duration of longest single exposure (min)105 (0-165)100 (0-170)0.990.96-1.02.49
       Duration of longest single exposure (min).54
      0241 (27.5)262 (29.9)1.00Reference
      1-120268 (30.6)249 (28.4)0.860.67-1.10
      121-240280 (31.9)269 (30.7)0.890.70-1.14
      ≥24188 (10.0)97 (11.1)1.020.72-1.44
      Alzheimer disease (excluding other forms of dementia) (N=732)
       Any anesthetic535 (73.1)516 (70.5)0.880.71-1.11.28
       Anesthetic exposure.46
      0197 (26.9)216 (29.5)1.00Reference
      1191 (26.1)176 (24.0)0.850.64-1.11
      2-3235 (32.1)219 (29.9)0.860.66-1.12
      ≥4109 (14.9)121 (16.5)1.020.74-1.40
       Cumulative duration of anesthesia (min)
      Cumulative duration of anesthesia is the total time an individual was exposed to general anesthesia after age 45 years and before their index date. The odds ratio for total anesthesia duration reflects increased risk per 30 minutes of anesthesia. In all cases, odds ratios were obtained using conditional logistic regression taking into account the matched study design.
      145 (0-300)135 (0-305)1.000.99-1.01.78
       Cumulative duration of anesthesia (min).69
      0197 (26.9)216 (29.5)1.00Reference
      1-120137 (18.7)134 (18.3)0.900.67-1.21
      121-240167 (22.8)153 (20.9)0.840.63-1.12
      241 or more231 (31.6)229 (31.3)0.910.69-1.19
       Duration of longest single exposure (min)
      Cumulative duration of anesthesia is the total time an individual was exposed to general anesthesia after age 45 years and before their index date. The odds ratio for total anesthesia duration reflects increased risk per 30 minutes of anesthesia. In all cases, odds ratios were obtained using conditional logistic regression taking into account the matched study design.
      105 (0-165)100 (0-167.5)0.980.95-1.01.28
       Duration of longest single exposure (min).62
      0197 (26.9)216 (29.5)1.00Reference
      1-120226 (30.9)216 (29.5)0.880.67-1.14
      121-240236 (32.2)221 (30.2)0.860.66-1.12
      241 or more73 (10.0)79 (10.8)0.990.68-1.45
      a Data are No. (percentage) or median (25th-75th percentile).
      b Cumulative duration of anesthesia is the total time an individual was exposed to general anesthesia after age 45 years and before their index date. The odds ratio for total anesthesia duration reflects increased risk per 30 minutes of anesthesia. In all cases, odds ratios were obtained using conditional logistic regression taking into account the matched study design.
      Table 4Association Between Exposure to Individual Anesthetic Agents and Subsequent Dementia
      Odds ratios and corresponding 95% CIs are presented using no exposure to any general anesthesia as the reference group. In all cases, odds ratios were obtained using conditional logistic regression taking into account the matched study design. Among cases, 615 individuals underwent 1681 procedures under general anesthesia; in the control group, 636 individuals underwent 1638 procedures. Patients may be exposed to multiple inhalational and intravenous agents in the same procedure.
      Anesthetic agentNo. (%) of controls (N=877)No. (%) of cases (N=877)Odds ratio95% CIP value
      Inhalational agents
       Ether149 (17)152 (17)0.940.71-1.26.69
       Methoxyflurane36 (4)42 (5)1.080.67-1.74.75
       Cyclopropane9 (1)7 (1)0.730.27-1.98.54
       Halothane255 (29)249 (28)0.900.70-1.15.40
       Enflurane276 (31)292 (33)0.970.77-1.23.82
       Isoflurane223 (25)191 (22)0.780.60-1.02.07
       Nitrous oxide616 (70)607 (69)0.910.74-1.12.38
      Intravenous drugs
       Benzodiazepines186 (21)174 (20)0.860.65-1.13.28
       Sodium thiopental612 (70)596 (68)0.900.73-1.10.30
       Ketamine9 (1)7 (1)0.720.27-1.95.52
       Propofol6 (1)4 (<1)0.620.18-2.22.47
       Intraoperative opioids595 (68)571 (65)0.880.72-1.09.24
      a Odds ratios and corresponding 95% CIs are presented using no exposure to any general anesthesia as the reference group. In all cases, odds ratios were obtained using conditional logistic regression taking into account the matched study design. Among cases, 615 individuals underwent 1681 procedures under general anesthesia; in the control group, 636 individuals underwent 1638 procedures. Patients may be exposed to multiple inhalational and intravenous agents in the same procedure.
      In the planned sensitivity analyses, a similar lack of association between exposure and dementia was found (1) when the analysis included only individuals with complete medical records available after age 45 years (Supplemental Table 2 [available online at http://www.mayoclinicproceedings.org]); (2) when exposure was defined as occurring within 5, 10, or 20 years of the index date (Supplemental Table 3 [available online at http://www.mayoclinicproceedings.org]); (3) when the 72 case-control sets in which controls had development of dementia before 1994 were excluded from the analysis (Supplemental Table 4 [available online at http://www.mayoclinicproceedings.org]); (4) when analyzing only exposures to procedures and anesthesia after age 60 years in case-control sets with an index date after age 60 years (Supplemental Table 5 [available online at http://www.mayoclinicproceedings.org]), and; (5) when analyzing only exposures to procedures and anesthesia after age 70 years in case-control sets with an index date after age 70 years (Supplemental Table 6 [available online at http://www.mayoclinicproceedings.org]).

      Discussion

      The main finding of this study was that receiving general anesthesia for procedures after age 45 years is not a risk factor for incident dementia. Concerns regarding the potential effect of anesthesia and surgery on postoperative cognition have arisen from 2 primary sources. First, although it is accepted that cognition may be affected in the immediate postoperative period, some authors have also suggested that more prolonged postoperative cognitive decline (POCD) may be relatively common and is a serious public health concern.
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      ISPOCD Investigators
      Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study: International Study of Post-Operative Cognitive Dysfunction.
      • Vanderweyde T.
      • Bednar M.M.
      • Forman S.A.
      • Wolozin B.
      Iatrogenic risk factors for Alzheimer's disease: surgery and anesthesia.
      As recently reviewed,
      • Avidan M.S.
      • Evers A.S.
      Review of clinical evidence for persistent cognitive decline or incident dementia attributable to surgery or general anesthesia.
      considerable controversy surrounds the concept of POCD, including the existence of persistent POCD. The authors of this review concluded that the current evidence is not persuasive that anesthesia and surgery are associated with persistent POCD or dementia and highlighted several challenges in studying this area, including lack of diagnostic criteria for POCD; separation of any independent effects of anesthesia from those of illness, surgical stress, and aging; the potential role of preexisting cognitive impairment; and multiple potential confounding factors that make the selection of appropriate controls in studies critically important.
      • Ghoneim M.M.
      • Block R.I.
      Clinical, methodological and theoretical issues in the assessment of cognition after anaesthesia and surgery: a review.
      Second, preclinical studies have shown that volatile anesthetics can induce caspase activation and apoptosis and increase β-amyloid protein oligomerization and accumulation in vivo (rodent models) and in vitro.
      • Bianchi S.L.
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      Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics.
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      Isoflurane-induced apoptosis: a potential pathogenic link between delirium and dementia.
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      The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid β-protein accumulation.
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      Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline.
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      Altered hippocampal gene expression 2 days after general anesthesia in rats.
      • Planel E.
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      Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia.
      • Planel E.
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      • Nolan C.E.
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      Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia.
      • Xie Z.
      • Culley D.J.
      • Dong Y.
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      The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid β-protein level in vivo.
      • Xie Z.
      • Tanzi R.E.
      Alzheimer's disease and post-operative cognitive dysfunction.
      Although many of these studies were performed in older rodents (analogous to the age selected in the present study to evaluate anesthetic exposure), such changes can also be observed in younger animals.
      • Culley D.J.
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      • Tanzi R.E.
      • Crosby G.
      Altered hippocampal gene expression 2 days after general anesthesia in rats.
      • Culley D.J.
      • Baxter M.
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      • Crosby G.
      The memory effects of general anesthesia persist for weeks in young and aged rats.
      • Crosby C.
      • Culley D.J.
      • Baxter M.G.
      • Yukhananov R.
      • Crosby G.
      Spatial memory performance 2 weeks after general anesthesia in adult rats.
      These findings have prompted speculation that anesthetics may initiate or accelerate processes that lead to AD or its progression.
      The case-control study design is a useful method to seek associations between risk factors and disease and has been useful in exploring the association between exposure to anesthesia and surgery in infants and later learning and behavioral problems.
      • Sprung J.
      • Flick R.P.
      • Katusic S.K.
      • et al.
      Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia.
      • Wilder R.T.
      • Flick R.P.
      • Sprung J.
      • et al.
      Early exposure to anesthesia and learning disabilities in a population-based birth cohort.
      Several studies have used this design to examine the association between general anesthesia and AD dementia.
      • Heyman A.
      • Wilkinson W.E.
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      • Helms M.J.
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      Risk factors for clinically diagnosed Alzheimer's disease: a case-control study of an Italian population.
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      Alzheimer's disease and cumulative exposure to anesthesia: a case-control study.
      • Broe G.A.
      • Henderson A.S.
      • Creasey H.
      • et al.
      A case-control study of Alzheimer's disease in Australia.
      • French L.R.
      • Schuman L.M.
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      A case-control study of dementia of the Alzheimer type.
      • Gasparini M.
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      • et al.
      A case-control study on Alzheimer's disease and exposure to anesthesia.
      • Graves A.B.
      • White E.
      • Koepsell T.D.
      • et al.
      A case-control study of Alzheimer's disease.
      • Harmanci H.
      • Emre M.
      • Gurvit H.
      • et al.
      Risk factors for Alzheimer disease: a population-based case-control study in Istanbul. Turkey.
      • Kokmen E.
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      • Chandra V.
      • Offord K.P.
      • Schoenberg B.S.
      • Ballard D.J.
      Clinical risk factors for Alzheimer's disease: a population-based case-control study.
      • Li G.
      • Shen Y.C.
      • Li Y.T.
      • Chen C.H.
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      • Silverman J.M.
      A case-control study of Alzheimer's disease in China.
      • Yip A.G.
      • Brayne C.
      • Matthews F.E.
      Risk factors for incident dementia in England and Wales: the Medical Research Council Cognitive Function and Ageing Study: a population-based nested case-control study.
      A recent meta-analysis summarized 15 such case-control studies, including 2 previous analyses of data from Olmsted County (obtained between 1960 and 1974
      • Kokmen E.
      • Chandra V.
      • Schoenberg B.S.
      Trends in incidence of dementing illness in Rochester, Minnesota, in three quinquennial periods, 1960-1974.
      and between 1975 and 198423) and found no significant association (pooled OR, 1.05; 95% CI, 0.93-1.19; P=.43).
      • Seitz D.P.
      • Shah P.S.
      • Herrmann N.
      • Beyene J.
      • Siddiqui N.
      Exposure to general anesthesia and risk of Alzheimer's disease: a systematic review and meta-analysis.
      These authors also noted the limitations of these studies, including relatively small sample sizes (a total of approximately 2000 cases among the 15 studies), wide variation in criteria used to select controls (which included in some cases patients receiving regional anesthesia), lack of information regarding anesthetic exposure (which was ascertained in many instances only by proxy report), and inconsistently applied diagnostic criteria for AD dementia.
      • Seitz D.P.
      • Shah P.S.
      • Herrmann N.
      • Beyene J.
      • Siddiqui N.
      Exposure to general anesthesia and risk of Alzheimer's disease: a systematic review and meta-analysis.
      Most of these limitations tend to bias toward finding no association. However, studies using other designs (including longitudinal
      • Tyas S.L.
      • Manfreda J.
      • Strain L.A.
      • Montgomery P.R.
      Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada.
      and cross-sectional
      • Dijkstra J.B.
      • Van Boxtel M.P.
      • Houx P.J.
      • Jolles J.
      An operation under general anesthesia as a risk factor for age-related cognitive decline: results from a large cross-sectional population study.
      cohort studies) have also found no association between exposure to anesthesia and accelerated cognitive decline.
      The present results are consistent with this previous body of work. This study design has several features that further strengthen the conclusion of a lack of association between incident dementia and exposure to anesthesia. First, the present study was based on a geographically defined population, reducing the potential for sampling bias at tertiary referral centers.
      • Melton III, L.J.
      History of the Rochester Epidemiology Project.
      • Rocca W.A.
      • Yawn B.P.
      • St Sauver J.L.
      • Grossardt B.R.
      • Melton L.J.
      History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population.
      • St Sauver J.L.
      • Grossard B.R.
      • Yawn B.P.
      • et al.
      Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system.
      • St Sauver J.L.
      • Grossardt B.R.
      • Leibson C.L.
      • Yawn B.P.
      • Melton III, L.J.
      • Rocca W.A.
      Generalizability of epidemiological findings and public health decisions: an illustration from the Rochester Epidemiology Project.
      • St Sauver J.L.
      • Grossardt B.R.
      • Yawn B.P.
      • Melton III, L.J.
      • Rocca W.A.
      Use of a medical records linkage system to enumerate a dynamic population over time: the Rochester Epidemiology Project.
      Second, recall bias was attenuated through full access to medical records for a relatively long period before diagnosis (a median of 32 years) so that the full details of anesthetic exposure were available. Third, strict criteria were applied to diagnose dementia by experienced behavioral neurologists who made full use of the detailed medical records. Finally, there was a relatively large sample size (approaching half the cumulative total of all previous case-control studies
      • Seitz D.P.
      • Shah P.S.
      • Herrmann N.
      • Beyene J.
      • Siddiqui N.
      Exposure to general anesthesia and risk of Alzheimer's disease: a systematic review and meta-analysis.
      ), increasing the power to detect associations. The present results are consistent with a previous report using a subset of the present cohort that underwent coronary artery bypass grafting between 1990 and 1994
      • Knopman D.S.
      • Petersen R.C.
      • Cha R.H.
      • Edland S.D.
      • Rocca W.A.
      Coronary artery bypass grafting is not a risk factor for dementia or Alzheimer disease.
      and found no increased risk of dementia associated with this procedure. We also found that the lack of association between exposure and dementia was quite robust in several sensitivity analyses that explored factors such as the timing of anesthetic exposure before the index date and age at the time of anesthetic exposure.
      This study has several limitations, some of which are related to the inherent limitations of the retrospective, nested, case-control design. Although a valuable tool in epidemiologic studies, enumeration of cases of dementia by passive medical record review has potential sources of error, as recently reviewed.
      • Knopman D.S.
      • Petersen R.C.
      • Rocca W.A.
      • Larson E.B.
      • Ganguli M.
      Passive case-finding for Alzheimer's disease and dementia in two U.S. communities.
      However, because the record review process was performed a minimum of 6 years after the last year in which incidence was tabulated, the presence and dating of dementia onset could be more accurately determined, as the duration of symptoms at the time of diagnosis was consistently noted in the medical record. This minimized the potential for incomplete ascertainment, recognizing that mild dementia could have been missed if patients died before development of more severe symptoms that could prompt diagnosis. Another limitation is that controls may have included patients with subclinical cognitive impairment at their index date. Indeed, 72 individuals initially included as controls eventually developed dementia before 1994, although sensitivity analysis demonstrated that excluding these matched pairs did not affect the results. We also cannot exclude that at their index date some controls may have had mild cognitive impairment,
      • Petersen R.C.
      Clinical practice: mild cognitive impairment.
      a diagnosis that was not applied by Mayo Clinic neurologists until after 1994,
      • Petersen R.C.
      • Smith G.E.
      • Ivnik R.J.
      • et al.
      Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals.
      although, again, the relatively long follow-up available for each patient makes this less likely. In addition, we cannot exclude that any cognitive impairment may have influenced decisions to schedule surgical procedures. Another limitation is that some exposures included anesthetic agents such as ether and methoxyflurane, which are no longer in clinical use and have not been studied in animal models. However, most exposures were to anesthetic agents that are still in clinical use, and supplemental analyses performed according to exposure to individual agents (Table 4) found no evidence that results differed according to agent. Some individuals migrated into the geographic region (Olmsted County) after age 45 years, and, therefore, a complete medical history was not available back to age 45 years in these individuals. However, the duration of the available medical records was similar for cases and controls. In addition, a sensitivity analysis including only individuals who had their first medical record available before age 45 years yielded similar results. During the study period, the race and ethnicity of Olmsted County residents (almost exclusively white) were not representative of the overall US population, which could limit the generalizability of the results. Finally, several other factors may be associated with the risk of dementia, although there is considerable variability among studies that attempt to identify such factors.
      The Canadian Study of Health and Aging: risk factors for Alzheimer's disease in Canada.
      • Broe G.A.
      • Henderson A.S.
      • Creasey H.
      • et al.
      A case-control study of Alzheimer's disease in Australia.
      • Harmanci H.
      • Emre M.
      • Gurvit H.
      • et al.
      Risk factors for Alzheimer disease: a population-based case-control study in Istanbul. Turkey.
      • Kokmen E.
      • Beard C.M.
      • Chandra V.
      • Offord K.P.
      • Schoenberg B.S.
      • Ballard D.J.
      Clinical risk factors for Alzheimer's disease: a population-based case-control study.
      • Li G.
      • Shen Y.C.
      • Li Y.T.
      • Chen C.H.
      • Zhau Y.W.
      • Silverman J.M.
      A case-control study of Alzheimer's disease in China.
      • Byers A.L.
      • Yaffe K.
      Depression and risk of developing dementia.
      • Saczynski J.S.
      • Beiser A.
      • Seshadri S.
      • Auerbach S.
      • Wolf P.A.
      • Au R.
      Depressive symptoms and risk of dementia: the Framingham Heart Study.
      We did not attempt to control for these factors except for the exploratory inclusion of educational attainment (shown in some but not all previous studies to be associated with dementia),
      • Vanderweyde T.
      • Bednar M.M.
      • Forman S.A.
      • Wolozin B.
      Iatrogenic risk factors for Alzheimer's disease: surgery and anesthesia.
      • Tyas S.L.
      • Manfreda J.
      • Strain L.A.
      • Montgomery P.R.
      Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada.
      • Knopman D.S.
      • Petersen R.C.
      • Cha R.H.
      • Edland S.D.
      • Rocca W.A.
      Coronary artery bypass grafting is not a risk factor for dementia or Alzheimer disease.
      • Sattler C.
      • Toro P.
      • Schonknecht P.
      • Schroder J.
      Cognitive activity, education and socioeconomic status as preventive factors for mild cognitive impairment and Alzheimer's disease.
      which did not affect the results. Given the lack of association between anesthetic exposure and incident dementia, it is unlikely that the inclusion of other factors would significantly change our conclusions.

      Conclusion

      This population-based study did not find an association between exposure to procedures under general anesthesia after age 45 years and an increased risk of dementia. These findings add to the body of evidence that fails to support such a link and may provide further reassurance to patients and clinicians who care for elderly patients.

      Acknowledgments

      We acknowledge the late Leonard T. Kurland, MD (epidemiologist, Mayo Clinic), for his vision in initiating the REP and the late Emre Kokmen, MD (neurologist, Mayo Clinic), for his past work on the Mayo Clinic Alzheimer's Disease Patient Registry. We also thank our research coordinator Ms Shonie Buenvenida.
      The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

      Supplemental Online Material

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