Risk Factors in Late Adolescence for Young-Onset Dementia in Men A Nationwide Cohort Study

Transcription

1 Risk Factors in Late Adolescence for Young-Onset Dementia in Men A Nationwide Cohort Study Peter Nordström, PhD; Anna Nordström, PhD; Marie Eriksson, PhD; Lars-Olof Wahlund, PhD; Yngve Gustafson, PhD IMPORTANCE Young-onset dementia (YOD), that is, dementia diagnosed before 65 years of age, has been related to genetic mutations in affected families. The identification of other risk factors could improve the understanding of this heterogeneous group of syndromes. Invited Commentary page 1619 Supplemental content at jamainternalmedicine.com OBJECTIVE To evaluate risk factors in late adolescence for the development of YOD later in life. DESIGN We identified the study cohort from the Swedish Military Service Conscription Register from January 1, 1969, through December 31, Potential risk factors, such as cognitive function and different physical characteristics, were assessed at conscription. We collected other risk factors, including dementia in parents, through national register linkage. PARTICIPANTS All Swedish men conscripted for mandatory military service (n = ) with a mean age of 18 years. SETTING Predominantly Swedish men born from January 1, 1950, through December 31, EXPOSURE Potential risk factors for dementia based on those found in previous studies, data available, and quality of register data. MAIN OUTCOMES AND MEASURE All forms of YOD. RESULTS During a median follow-up of 37 years, 487 men were diagnosed as having YOD at a median age of 54 years. In multivariate Cox regression analysis, significant risk factors (all P <.05) for YOD included alcohol intoxication (hazard ratio, 4.82 [95% CI, ]); population-attributable risk, 0.28), stroke (2.96 [ ]; 0.04), use of antipsychotics (2.75 [ ]; 0.12), depression (1.89 [ ]; 0.28), father s dementia (1.65 [ ]; 0.04), drug intoxication other than alcohol (1.54 [ ]; 0.03), low cognitive function at conscription (1.26 per 1-SD decrease [ ]; 0.29), low height at conscription (1.16 per 1-SD decrease [ ]; 0.16), and high systolic blood pressure at conscription (0.90 per 1-SD decrease [ ]; 0.06). The population-attributable risk associated with all 9 risk factors was 68%. Men with at least 2 of these risk factors and in the lowest third of overall cognitive function were found to have a 20-fold increased risk of YOD during follow-up (hazard ratio, [95% CI, ]). CONCLUSIONS AND RELEVANCE In this nationwide cohort, 9 independent risk factors were identified that accounted for most cases of YOD in men. These risk factors were multiplicative, most were potentially modifiable, and most could be traced to adolescence, suggesting excellent opportunities for early prevention. JAMA Intern Med. 2013;173(17): doi: /jamainternmed Published online August 12, Author Affiliations: Department of Community Medicine and Rehabilitation, Section of Geriatric Medicine, Umeå University, Umeå, Sweden (P. Nordström, Gustafson); Department of Surgical and Perioperative Sciences, Section of Sports Medicine, Umeå University, Umeå, Sweden (A. Nordström); Department of Statistics, School of Business and Economics, Umeå University, Umeå, Sweden (Eriksson); Department of Neurobiology, Care Sciences, and Society, Division of Clinical Geriatrics, Karolinska Institute, Stockholm, Sweden (Wahlund). Corresponding Author: Peter Nordström, PhD, Department of Community Medicine and Rehabilitation, Geriatric Medicine, Umeå University, Umeå, Sweden (peter.nordstrom@germed.umu.se) jamainternalmedicine.com

2 Risk Factors for Young-Onset Dementia in Men Original Investigation Dementia is a major public health concern currently affecting an estimated 35.6 million people worldwide. 1 With the increasing number of elderly individuals, the disability and cost associated with dementia are expected to rapidly increase in the next 40 years, affecting more than 115 million people by Young-onset dementia (YOD) is usually defined as that occurring before 65 years of age. Because affected individuals are young, YOD is associated with severe consequences related to employment, social life, and even patients roles as parents and guardians. The diagnosis of YOD is very challenging because its initial symptoms are quite heterogeneous and often atypical; its pathological features differ from those of dementia in older individuals. 2,3 Early-onset Alzheimer dementia (AD) has also been suggested to have an inherited cause more often than lateonset AD, and mutations in several genes have been identified. 4-7 The identification of more generally applicable risk factors for YOD would be important for several reasons. First, identification might aid in the construction of preventive measures for the general population. Second, identification could increase understanding of the mechanism underlying this complex group of syndromes. Studies of late-onset dementia have identified lower cognitive performance as a risk factor, 8,9 whereas other studies have suggested that higher levels of education, physical activity, and engagement in social activities are associated with a reduced risk of dementia. 10,11 Whether these risk factors apply to the different subtypes of YOD is not known. In this study, we evaluated premorbid cognitive performance, physical characteristics, socioeconomic factors, various diagnoses, use of medication, and the influence of heritable factors in young adulthood in relation to the risk of developing different YOD syndromes in a nationwide cohort of Swedish men. Methods Study Population The cohort considered for inclusion consisted of all Swedish men conscripted for mandatory military service from September 15, 1969, through December 31, 1979 (N = ). Of these men, 9360 (1.9%) were excluded; 9352 had unknown or extreme body weight (<40 or >170 kg) or height (<140 or >215 cm), and registry data were not useful for the remaining 8. Thus, men were included in the present analyses. The Swedish Military Service Conscription Register has been described in detail previously. 12 During the years of conscription investigated in the present study (1969 to 1979), exemptions from conscription (2% to 3% of all Swedish men) were granted only to incarcerated men and those with severe chronic medical conditions or disabilities documented by a medical certificate. Baseline Examination and Data Collection During a 2-day baseline examination, all men in the cohort underwent standardized cognitive and physical examinations at 6 conscription centers in Sweden before being assigned to service in the Swedish armed forces. All men also underwent a physician-administered medical examination; medical disorders were diagnosed according to the Swedish version of the International Classification of Disease, Eighth Revision (ICD- 8). Isometric knee extension strength was measured in the right leg using a dynamometer. Four tests were used to assess cognitive performance; they have been described in detail and evaluated previously Briefly, a logical test assessed the ability to understand written instructions; a word recollection test, the ability to determine which of 4 alternatives was the synonym of a given word; a visuospatial test, the capacity to identify a 3-dimensional object correctly using a series of 2-dimensional drawings; and a technical test, problem-solving capacity. Results of these tests were used to estimate overall cognitive performance by summing the normalized z scores of each test, expressed as a score ranging from 1 to 40 points. Detailed information about drinking habits and smoking (yes/no) was available for a subcohort of men. Follow-up Data Collection Information about diagnoses of dementia through December 31, 2011, was obtained from the Swedish National Hospital Discharge Patient Register (NPR). The NPR covered about 90% of all specialist inpatient care since 1971 and all outpatient specialist care since Potential risk factors for dementia were selected based on risk factors found in previous studies, data available, and quality of register data. 16 The following ICD codes (from ICD-8, International Classification of Disease, Ninth Revision, and International Statistical Classification of Disease, Tenth Revision [ICD-10]) were used: F00.x, G30.x, and 290.x for the subjects parents (AD); F01.x (vascular dementia); F10.7A (alcohol dementia); F03.9 (dementia of unspecified type); F02.3 (dementia associated with Parkinson disease); G31.8A (Lewy body dementia); and F06.7 (mild cognitive impairment [MCI]). For all diagnoses of dementia except MCI, the diagnosis at each subject s last clinical examination was used in further analysis. Subjects with MCI were excluded. Other diagnoses of interest included ICD codes 303 and F10.x, excluding F10.7A (alcohol intoxication); F11.x and 304 (other drug intoxication); F32.x and 311 (depression); I63.x, 433, and 434 (ischemic stroke); and I21.x and 410.x (myocardial infarction). The NPR has been validated previously with a positive predictive value of 85% to 95% for most diagnoses. 16 We obtained information about drugs prescribed and expedited in Sweden since July 2005 through the National Drug Register using the Anatomical Therapeutic Chemical Classification codes N06A (antidepressants), N05A (neuroleptics), and A10 (antidiabetics). In later analyses, the presence of depression will include diagnosed depression or any drug therapy expedited for depression. Information about total income and highest achieved educational level was collected 15 years after the conscription tests from the Statistics Sweden database. Highest achieved educational level was classified into the following 4 groups: elementary school only, 2 and 3 years of secondary school, and education at the university level. Subjects biological parents were tracked through the Statistics Sweden database, and information about diagnoses of dementia in parents was obtained using the ICD codes specified above. Information about deaths, immigration, and emigration occurring during the study period was obtained through record linkage with the National Cause of jamainternalmedicine.com JAMA Internal Medicine September 23, 2013 Volume 173, Number

3 Risk Factors for Young-Onset Dementia in Men Table 1. Characteristics at Conscription and Follow-up According to YOD Diagnosed During Follow-up a Characteristic No Dementia (n = ) All Cases of YOD (n = 487) Prevalence per men 91.7 Age at dementia diagnosis, y 53.6 (4.5) Characteristics at conscription Age, y 18.5 (0.8) 18.7 (0.7) b Weight, kg 68.2 (9.8) 67.1 (10.3) b Height, cm 179 (6) 177 (6) b Knee strength, N 533 (102) 525 (109) Blood pressure, mm Hg Systolic 128 (11) 128 (12) Diastolic 71 (9) 72 (9) b Cognitive function, score Overall function 21.1 (4.7) 19.0 (4.9) b Logical function 24.8 (5.5) 22.7 (5.9) b Word recollection 23.1 (6.1) 20.8 (6.4) b Visuospatial function 14.1 (4.0) 12.7 (4.2) b Technical function 32.1 (8.2) 29.2 (8.7) b Dementia in father, No. (%) (6.3) 48 (9.9) b Dementia in mother, No. (%) (7.5) 43 (8.8) Educational level assessed 15 y after conscription, No. (%) c Elementary school only (23.1) 155 (32.2) Secondary school, 2 y (37.2) 193 (40.0) Secondary school, 3 y (11.9) 38 (7.9) University (27.8) 96 (19.9) b Total annual income assessed 15 y after conscription, 1000 Sk 162 (87) 137 (102) b Diagnoses during follow-up, No. (%) c Alcohol intoxication (5.5) 165 (33.9) b Other drug intoxication 6283 (1.3) 37 (7.6) b Depression or use of antidepressants (13.8) 192 (39.4) b Myocardial infarction (2.4) 19 (3.9) Stroke 5055 (1.0) 31 (6.4) b Medication during follow-up, No. (%) d Neuroleptics (2.5) 110 (22.6) b Antidiabetics (5.8) 38 (7.8) Abbreviation: YOD, young-onset dementia. a Unless otherwise indicated, data are expressed as mean (SD). b Indicates P <.05 vs subjects with no dementia. c Data were missing for subjects in the cohort with no dementia during follow-up and 5 subjects in the YOD cohort. d Diagnoses and medication were included only until the diagnosis of YOD for the cases. Death Register and the Statistics Sweden database. All information was then linked to subjects using the unique social security numbers assigned to all Swedish citizens. The study protocol was approved by the regional ethics board in Umeå and the National Board of Health and Welfare in Sweden. Validation of Dementia Diagnoses Two authors (P.N. and L.-O.W.) retrieved total journal records of all specialized care, including radiographic examinations and laboratory tests, in 79 men diagnosed with YOD. Personal history, including first symptoms of the disease and radiographic examination results, was obtained in all cases; a Mini- Mental State Examination was administered in all but 1 case; and more extensive neuropsychological examinations were performed in 56 cases. In 51 cases, markers of dementia (tau and amyloid protein) were measured in cerebrospinal fluid. On the basis of information provided in the journal records, misdiagnosis was identified for 4 patients in a nonblinded comparison using the ICD-10 criteria. The remaining 75 diagnoses (95%) were judged to be valid, which is higher than the percentages reported for most other diagnoses in a previous evaluation of the NPR. 16 Statistical Analysis Differences at baseline based on the diagnosis of dementia during the follow-up period were examined using analysis of variance with a Bonferroni post hoc test. Cox proportional hazards regression models were used to evaluate independent risk factors for YOD and death. For the outcome of YOD of any subtype, or death, all covariates in Table 1 were included in the models. For the outcome of YOD of each subtype, only covariates that were significant in univariate analysis according to Table 1 were included. The study end point for models evaluating risk factors for YOD was the first date of a registered dementia diagnosis, date of emigration, date of death, or December 31, 2011, whichever came first. The study end point for the outcome of death was date of emigration, date of death, or December 31, 2011, whichever came first. The proportional hazards assumption was checked graphically using Kaplan- Meier curves and log minus log plots. Populationattributable risk (PAR) was calculated from a Cox proportional hazards regression model including continuous variables entered as above/below the median using the PAR macro of Spiegelman et al 17 for SAS (version 9.3 for Windows; SAS Institute, Inc). We used SPSS software (version 20.0 for PC; SPSS, Inc) for all other statistical analyses. P <.05 was considered significant. Results Prevalence and Forms of YOD Diagnosed During Follow-up The study cohort included men with a mean age of 18 years who were followed up for a median of 37 (range, 0-41) years. During the follow-up, 506 men were diagnosed as having some type of YOD and 36 men were diagnosed as having MCI during a total of 1808 (per-subject mean, 3.3; median, 3; range, 1-30) hospital visits (median age at diagnosis, 54 years). In addition to cases of MCI, 19 cases of dementia associated with Parkinson disease (n = 13) and Lewy body dementia (n = 6) were excluded, leaving 487 cases of YOD analyzed in the present study. At the study end point (December 31, 2011), the prevalence of all cases of YOD per men was Subjects baseline characteristics are presented in Table 1 according to a diagnosis of YOD during follow-up and in the Supplement (etable 1) according to the subtype of YOD. The cumulative incidence of different forms of YOD during follow-up is illustrated in Figure JAMA Internal Medicine September 23, 2013 Volume 173, Number 17 jamainternalmedicine.com

4 Risk Factors for Young-Onset Dementia in Men Original Investigation Figure 1. The Cumulative Incidence of Different Types of Young-Onset Dementia With Increasing Age in the Study Cohort Cumulative Incidence per Men Age, y AD indicates Alzheimer dementia; NUD, dementia of unspecified type; VD, vascular dementia. AD VD Alcohol dementia Frontal lobe dementia NUD Risk Factors Associated With YOD During Follow-up Nine independent risk factors for YOD (n = 487) were identified (Table 2), including alcohol intoxication (hazard ratio [HR], 4.82 [95% CI, ]; PAR, 0.28), stroke (2.96 [ ]; PAR, 0.04), use of antipsychotic drugs (2.75 [ ]; PAR, 0.12), depression (1.89 [ ]; PAR, 0.28), father s dementia (1.65 [ ]; PAR, 0.04), drug intoxication other than alcohol (1.54 [ ]; PAR, 0.03), low cognitive function at conscription (1.26 per 1-SD decrease [ ]; PAR, 0.29), high systolic blood pressure at conscription (0.90 per 1-SD decrease [ ]; PAR, 0.06), and low height at conscription (1.16 per 1-SD decrease [ ]; PAR, 0.16). The PAR associated with these 9 independent risk factors was 68% (95% CI, 39%-85%). Independent risk factors for the subtypes of YOD are presented in the Supplement (etable 2). The risk of alcohol intoxication during follow-up was strongly associated with subjects drinking habits at conscription in a subcohort of men (eg, 6-fold higher in men who drank beer daily than in men who never drank beer) (Table 3). In the same subcohort, smoking at conscription was higher (74.6% vs 59.4% [P =.01]) in those later diagnosed with YOD (n = 59). Joint Effects of the Independent Risk Factors We analyzed the joint effects of the 9 independent risk factors identified (Table 2) using men in the highest tertile of overall cognitive function with no risk factor as a reference (Figure 2). Height and systolic blood pressure were analyzed using the lowest and highest deciles, respectively, as risk factors. Men in the lowest tertile of overall cognitive function and with at least 2 risk factors were found to have a 20-fold increased risk of YOD during follow-up (HR, [95% CI, ]). Furthermore, the effects of an increased number of risk factors on the risk of YOD were significant for all 3 strata of overall cognitive function (P <.001 for trend for all), and the effects of increased overall cognitive function were significant for all 3 strata of risk factors (P <.01 for trend for all). Table 2. Results of Cox Proportional Hazards Regression Analyses to Identify Independent Risk Factors for YOD a All Cases of YOD, HR (95% CI) (n = 487) Year of conscription 1.05 (1.00 to 1.10) Age b 0.88 (0.79 to 0.99) Weight b 0.95 (0.85 to 1.07) YOD and the Risk of Death During follow-up a total of men died. After including all covariates according to Table 1, a diagnosis of YOD was associated with the second highest risk for death (HR, 3.54 [95% CI, ]), whereas alcohol intoxication was associated with the highest risk (HR, 5.95 [95% CI, ]). Other strong independent risk factors (P <.001 for all) for death included myocardial infarction (HR, 2.88), stroke (HR, 3.44), and other drug intoxication (HR, 1.86). Discussion PAR Estimate (95% CI) Height b 1.16 (1.04 to 1.29) 0.16 (0.05 to 0.26) c Knee muscle strength b 1.02 (0.92 to 1.12) Systolic blood pressure b 0.90 (0.82 to 0.99) 0.06 (0.02 to 0.14) d Dementia in father b 1.65 (1.22 to 2.24) 0.04 (0.01 to 0.06) Dementia in mother b 1.09 (0.79 to 1.50) Overall cognitive function b 1.26 (1.14 to 1.40) 0.29 (0.18 to 0.40) e Elementary school 1.02 (0.83 to 1.25) education only f Total income per year f 1.03 (0.93 to 1.15) Diagnoses g Alcohol intoxication 4.82 (3.83 to 6.05) 0.28 (0.16 to 0.39) Other drug intoxication 1.54 (1.06 to 2.24) 0.03 ( 0.01 to 0.07) Depression or use of antidepressants 1.89 (1.53 to 2.34) 0.28 (0.09 to 0.28) Myocardial infarction 0.99 (0.61 to 1.59) Stroke 2.96 (2.02 to 4.35) 0.04 (0.01 to 0.07) Medication g Neuroleptics 2.75 (2.09 to 3.60) 0.12 (0.04 to 0.20) Antidiabetics 0.77 (0.55 to 1.09) Abbreviations: HR, hazard ratio; PAR, population-attributable risk; YOD, young-onset dementia. a Hazard ratios (95% CIs) are presented per 1-SD decrease for interval variables. The PAR is presented for all cases of YOD. We included in the PAR analysis only variables that were independently associated with the risk of YOD and excluded age and year at conscription. b Assessed at conscription. c For height less than 180 cm. d For systolic blood pressure less than 128 mm Hg. e For overall cognitive function below f Assessed 15 years after conscription. g Included only until the diagnosis of YOD for the cases. In the present nationwide cohort study, the following 9 independent risk factors for YOD were identified in young men: alcohol and other drug intoxication, stroke, high blood pressure, low overall cognitive function, low height, dementia in the father, depression, and use of neuroleptics. These factors jamainternalmedicine.com JAMA Internal Medicine September 23, 2013 Volume 173, Number

5 Risk Factors for Young-Onset Dementia in Men Table 3. Drinking Habits at Conscription in Relation to the Risk of Alcohol Intoxication During Follow-up in a Subcohort of Men No. of Men No. of Intoxication Incidents Alcohol Intoxication, OR (95% CI) a Beer Frequency of consumption Never [Reference] <Weekly ( ) Once weekly ( ) Almost daily ( ) Amount consumed b,c None [Reference] 1 Glass ( ) 1 Can ( ) 2 Cans ( ) Wine Frequency of consumption Never [Reference] <Weekly ( ) About once weekly ( ) Amount consumed b,d None [Reference] 1 Glass ( ) Half to 1 bottle ( ) 1 Bottle ( ) Liquor Amount consumed b None [Reference] <5 cl ( ) 5-14 cl ( ) cl ( ) >35 cl ( ) a Adjusted for age and year and place of conscription. The category with the lowest intake was used as a reference. b Indicates amount consumed each time the subject consumed alcohol. c The amount of beer in 1 glass varies; 1 can of beer is equal to 50 cl. d The amount of wine in 1 glass varies; 1 bottle of wine is equal to 75 cl. accounted for most of the YOD cases identified (68%). The effects of these risk factors were multiplicative. Most could be traced to adolescence and were potentially modifiable, suggesting excellent opportunities to identify subjects at risk for YOD early in life. Such efforts would be of great importance, given the consequences of YOD for the patient, family, and society, including a high risk of early death as demonstrated in the present study. Based on risk estimates and PAR, hospital-treated alcohol intoxication was the single most important risk factor for YOD identified. Alcohol intoxication was not only associated with alcohol dementia but also an independent risk factor for vascular dementia and dementia of unspecified type. This increased risk could be traced to behaviors in adolescence because drinking habits at conscription were strongly linked to the risk of alcohol intoxication later in life. The impact of alcohol abuse was clearly not reflected in the number of cases diagnosed with alcohol dementia in the present study, which represented about 15% of all YOD cases, as in other studies This finding may have several explanations. One important issue is the lack of uniform diagnostic criteria for alcohol dementia. 21,22 The diagnosis of alcohol dementia is also controversial, partly owing to the potential reversal of neurologic and cognitive symptoms. Furthermore, whether alcohol dementia is caused directly by the toxic effects of alcohol 23 or is predominantly related to secondary thiamine deficiency resulting in Wernicke encephalopathy 24 is not clear. Altogether, our data suggest that the effect of alcohol abuse on the overall risk of YOD in men is at present severely underestimated. Other risk factors that increased the overall risk of YOD independently included drug intoxication other than alcohol, depression and neuroleptic use, stroke, high systolic blood pressure, low cognitive function, low height, and dementia in the father. The risk for YOD increased steeply with increasing number of independent risk factors. Thus, men in the lowest tertile of cognitive function and with at least 2 other risk factors had a 20 times higher risk of YOD than did men in the highest tertile of cognitive function with no other risk factors. Many of the most important risk factors, such as alcohol abuse and cognitive function, could be traced to subjects characteristics in adolescence. Thus, the results of the present study suggest that men at high risk for YOD could be identified already in young adulthood based on the risk factors identified in the present study. The diagnoses of dementia were retrieved from registers, and we were able to validate complete journal records 1616 JAMA Internal Medicine September 23, 2013 Volume 173, Number 17 jamainternalmedicine.com

6 Risk Factors for Young-Onset Dementia in Men Original Investigation Figure 2. Joint Effects of Overall Cognitive Function and Other Independent Risk Factors for Overall Risk of Young-Onset Dementia (YOD) in 487 Men 0 Risk factors (n= ) 1 Risk factor (n= ) 2 Risk factors (n=45 932) Risk of YOD, HR No. of Risk Factors Cognitive function, tertile Highest Middle Lowest Highest Middle Overall Cognitive Function, Tertile Lowest HR (95% CI) Incidence of YOD per Men HR (95% CI) Incidence of YOD per Men HR (95% CI) Incidence of YOD per Men 1.13 [Reference] ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) The bar graph depicts the number of risk factors present in each tertile of cognitive function, with hazard ratios (HRs) in the tabular material. Men in the highest tertile with no independent risk factor (alcohol or other drug intoxication, depression, neuroleptic use, stroke, lowest decile of height, highest decile of systolic blood pressure, and father s dementia) were used as a reference. Hazard ratios were adjusted for age and year of conscription. for 79 patients in a nonblinded fashion with a high positive predictive value. This result was expected because all diagnoses were made at specialist departments and patients with diagnoses underwent a median of 3 investigations, suggesting proper follow-up in most cases. Recent studies have suggested that the initial symptoms of early-onset AD are often atypical and that its neuropathological characteristics differ from those of late-onset AD, increasing the diagnostic challenge. 3,25 The results of the present study may support these findings because many cases of YOD were diagnosed as dementia of unspecified type. However, the risk factors of these men were similar to those of subjects diagnosed with vascular and alcohol dementias, including frequent diagnoses of alcohol and other drug intoxication, cerebrovascular disease, and low cognitive function in young adulthood. Thus, the results of the present study suggest that typical cases of AD may represent a lower proportion of YOD compared with dementia diagnosed in later life. Only a few risk factors were found for AD and frontotemporal lobe degeneration. Based on the findings of previous studies suggesting that early-onset AD and frontotemporal lobe degeneration have strong genetic components, 4,5,7,26,27 we hypothesized that these conditions would be linked to dementia in the parents more often than would other YOD subtypes. This hypothesis could not be confirmed in the present cohort, and the risk associated with dementia in the parents was generally low. For all cases of YOD, the PAR associated with dementia in the father was only 4%, and we found no association with dementia in the mother. Given the high PAR associated with the remaining 8 independent risk factors identified, our results support the view that heritable factors have a small influence on YOD. Given that the present cohort included only men, our findings are not applicable to women, whose risk profiles (eg, early cerebrovascular disease and substance abuse) likely differ. Most likely other risk factors that might contribute to the risk of YOD are not captured in the present study, for example, traumatic brain injuries and physical activity. Furthermore, given the observational study design, we cannot disentangle whether certain covariates, such as depression, represent early symptoms of YOD or a true risk factor. The incidence of YOD seems to correspond to those of previous reports, bearing in mind that men who were excluded from conscription (2%-3%), might be at higher risk for YOD owing to genetic disorders, such as Down syndrome. The strengths of the study include a nationwide cohort of men consisting of almost 500 cases of YOD; the extensive evaluation of risk factors, including any dementia diagnosis in the parents; and the use of national registers, resulting in no loss to follow-up, all of which increased the study s external validity. In summary, we identified 9 independent risk factors for YOD in a nationwide cohort of men. Collectively, these factors accounted for 68% of the YOD cases identified. The effects of these risk factors were multiplicative, and most were potentially modifiable and could be traced to adolescence, suggesting the existence of excellent opportunities for prevention. Such efforts would be of importance given the consequences of YOD for the patients, family, and society. The results of the present study also suggest that YOD may include a lower proportion of typical AD cases compared with later-onset dementia. ARTICLE INFORMATION Accepted for Publication: May 22, Published Online: August 12, doi: /jamainternmed Author Contributions: Dr P. Nordström had full access to all the data in the study and takes jamainternalmedicine.com JAMA Internal Medicine September 23, 2013 Volume 173, Number

7 Risk Factors for Young-Onset Dementia in Men responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: P. Nordström, A. Nordström. Acquisition of data: P. Nordström, A. Nordström, Wahlund. Analysis and interpretation of data: All authors. Drafting of the manuscript: P. Nordström, A. Nordström. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: P. Nordström, A. Nordström, Eriksson. Obtained funding: P. Nordström, A. Nordström. Administrative, technical, and material support: P. Nordström, A. Nordström, Gustafson. Study supervision: P. Nordström, A. Nordström, Wahlund. Conflict of Interest Disclosures: None reported. Funding/Support: The study was supported by grants from the Swedish Research Council and the Swedish Dementia Foundation. REFERENCES 1. World Health Organization; Alzheimer s Disease International. Dementia: a public health priority /dementia_report_2012/en/. Accessed January Rossor MN, Fox NC, Mummery CJ, Schott JM, Warren JD. The diagnosis of young-onset dementia. Lancet Neurol. 2010;9(8): Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011;10(9): Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer s disease. Nature. 1991;349(6311): Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer s disease locus. Science. 1995;269(5226): Rogaev EI, Sherrington R, Rogaeva EA, et al. Familial Alzheimer s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer s disease type 3 gene. Nature. 1995;376(6543): Finckh U, Müller-Thomsen T, Mann U, et al. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000;66(1): Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. Linguistic ability in early life and cognitive function and Alzheimer s disease in late life: findings from the Nun Study. JAMA. 1996;275(7): Whalley LJ, Deary IJ. Longitudinal cohort study of childhood IQ and survival up to age 76. BMJ. 2001;322(7290):819. doi: bmj Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol. 2004;3(6): Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol. 2006;5(9): Andreasson S, Allebeck P, Romelsjö A. Alcohol and mortality among young men: longitudinal study of Swedish conscripts. BMJ (Clin Res Ed). 1988;296(6628): Carlstedt B, Mårdberg B. Construct validity of the Swedish Enlistment Battery. Scand J Psychol. 1993;34: Carlstedt B. Cognitive Abilities: Aspects of Structure, Process and Measurement. Gothenburg, Sweden: University of Gothenburg; Carlstedt B, Gustafsson JE. Construct validation of the Swedish Scholastic Aptitude Test by means of the Swedish Enlistment Battery. Scand J Psychol. 2005;46(1): Ludvigsson JF, Andersson E, Ekbom A, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450. doi: / Spiegelman D, Hertzmark E, Wand HC. Point and interval estimates of partial population attributable risks in cohort studies: examples and software. Cancer Causes Control.2007;18(5): Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry. 2003;74(9): Panegyres PK, Frencham K. Course and causes of suspected dementia in young adults: a longitudinal study. Am J Alzheimers Dis Other Demen. 2007;22(1): Ikejima C, Yasuno F, Mizukami K, Sasaki M, Tanimukai S, Asada T. Prevalence and causes of early-onset dementia in Japan: a population-based study. Stroke. 2009;40(8): Oslin D, Atkinson RM, Smith DM, Hendrie H. Alcohol related dementia: proposed clinical criteria. Int J Geriatr Psychiatry. 1998;13(4): Gupta S, Warner J. Alcohol-related dementia: a 21st-century silent epidemic? Br J Psychiatry. 2008;193(5): Harper C. The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain? J Neuropathol Exp Neurol. 1998;57(2): Sechi G, Serra A. Wernicke s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol. 2007;6(5): van der Flier WM, Pijnenburg YA, Fox NC, Scheltens P. Early-onset versus late-onset Alzheimer s disease: the case of the missing APOE ε4 allele. Lancet Neurol. 2011;10(3): D Souza I, Poorkaj P, Hong M, et al. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad SciUSA. 1999;96(10): Rosso SM, van Swieten JC. New developments in frontotemporal dementia and parkinsonism linked to chromosome 17. Curr Opin Neurol. 2002;15(4): JAMA Internal Medicine September 23, 2013 Volume 173, Number 17 jamainternalmedicine.com