data were obtained from the finnish national prescription register and special reimbursement register , maintained by the social insurance institution ( sii ) of finland .
the national prescription register contains records of all reimbursed drug purchases of all finnish residents living in noninstitutionalized settings .
the special reimbursement register includes information on all individuals who are entitled to reimbursement of medication for certain chronic diseases , such as ad or diabetes . to be included in the special reimbursement register
, the diagnosis must be based on explicit predefined criteria and written documentary evidence , including results of a diagnostic test , such as imaging or blood biochemistry , must be provided to the sii by a physician .
data from these registers have previously been applied in nationwide drug utilization studies ( 30 ) . in finland ( population , 5.3 million ) , all citizens are covered by a tax - supported public health system and have access to health services , regardless of age , ethnic background , or socioeconomic status , and individual - level data on purchases of reimbursed prescription medicines and hospital visits are collected and updated continuously on statutory registers ( 31 ) .
thus , these data are available on all individuals , provided that they have a social security number ( i.e. , all citizens and noncitizens living in finland for at least 2 years but excluding persons who were living abroad for > 1 year at the time of the study ) .
each resident of finland is assigned a unique social security number , and this identification number was used to track information from registers .
changes in social security numbers in the 1970s mean that reliable automated linkage without individual checking and recoding of pins is possible from 1972 onwards , and thus we included data from 1972 onwards only .
data linkage was performed by sii , and all data were de - identified before submission to the research team . no ethics committee approval was required as de - identified data were used and participants were not contacted .
all community - dwelling people with a verified ad diagnosis , residing in finland on 31 december 2005 ( n = 28,093 ) were identified from the special reimbursement register , and a single age- , sex- , and region of residence  matched control subject per ad case subject ( n of matched case - control pairs = 28,093 ) was identified .
ad diagnosis was based on the national institute of neurological and communicative disorders and stroke and the alzheimer 's disease and related disorders association ( nincds - adrda ) and the dsm - iv criteria for ad ( 32,33 ) . in brief , the main diagnostic criterion is progressive memory loss , supported by abnormal magnetic resonance imaging or cerebrospinal fluid biomarker findings .
alternative explanations for memory impairment , such as severe depression , metabolic disturbances ( including hyperglycemia per se ) , and other forms of dementia , such as vascular dementia , needed to be excluded .
the finnish current care guidelines recommend that all people with ad are treated with memantine or acetylcholinesterase inhibitors unless there is a specific contraindication ( including gastric ulcer / intestinal tract operation < 6 months previously or severe asthma ) ( 34 ) .
patients with mild or moderate ad are entitled to reimbursed ad medication , but the reimbursement is not withdrawn if / when the disease progresses .
diabetes is diagnosed on the basis of fasting capillary blood glucose concentration ( sii reimbursement criterion cutoff is 7.0 mmol / l ) or 2-h glucose concentration if an oral glucose tolerance test has been performed ( cutoff 11.1 mmol / l ) ( 35 ) .
individuals with type 1 diabetes have been entitled to reimbursed insulin since 1964 , whereas the criteria for reimbursed type 2 diabetes medication have varied over time .
type 2 diabetes was first mentioned in 1981 criteria stating that medication for those with type 2 diabetes is reimbursed if they have not benefited from lifestyle modification lasting at least 3 months . in 1994 ,
the criteria for type 2 diabetes was updated to recommend 6-month dietary intervention as a first - line therapy and requesting that the pharmacotherapy for type 2 diabetes be used for at least 6 months , including a report of outcomes , before applying for special reimbursement .
people with gestational diabetes have not been entitled to reimbursement , unless the need for pharmacotherapy is prolonged .
thus , we applied a robust age - based classification so that people who were < 40 years of age when they were diagnosed with diabetes were classified as having type 1 diabetes and those who were at least 40 years of age were classified as having type 2 diabetes .
this cutoff has been suggested as a simple and relatively reliable method for differentiating people with type 1 and type 2 diabetes ( 36 ) .
people with diabetes diagnosed at < 65 years of age were categorized as having diabetes in midlife , and those who were at least 65 years of age when diabetes was diagnosed were classified as having late - life diabetes .
statistical analyses were performed with stata 12.0 ( stata corp lp , college station , tx ) . the difference in the mean age of ad diagnosis between those with and without diabetes was compared with the student t test , and differences in the duration of diabetes and age at diabetes diagnosis between case and control subjects were compared with the kruskal - wallis test .
the association of diabetes with ad was assessed in a case - control study including all 28,093 matched pairs .
crude ors and pooled ors according to the history of cardiovascular disease groups ( no / yes ) were calculated .
information on cardiovascular conditions ( hyper-/hypotension , ischemic heart disease , familial hypercholesterolemia , embolisms and thrombosis , myocardial infarctions , heart failure and cardiac arrests , atherosclerosis , and aneurysms ) was obtained from the special reimbursement register and finnish national hospital discharge register ( details available from a .- m.t . ) .
data were obtained from the finnish national prescription register and special reimbursement register , maintained by the social insurance institution ( sii ) of finland .
the national prescription register contains records of all reimbursed drug purchases of all finnish residents living in noninstitutionalized settings .
the special reimbursement register includes information on all individuals who are entitled to reimbursement of medication for certain chronic diseases , such as ad or diabetes . to be included in the special reimbursement register
, the diagnosis must be based on explicit predefined criteria and written documentary evidence , including results of a diagnostic test , such as imaging or blood biochemistry , must be provided to the sii by a physician .
data from these registers have previously been applied in nationwide drug utilization studies ( 30 ) . in finland ( population , 5.3 million ) , all citizens are covered by a tax - supported public health system and have access to health services , regardless of age , ethnic background , or socioeconomic status , and individual - level data on purchases of reimbursed prescription medicines and hospital visits are collected and updated continuously on statutory registers ( 31 ) .
thus , these data are available on all individuals , provided that they have a social security number ( i.e. , all citizens and noncitizens living in finland for at least 2 years but excluding persons who were living abroad for > 1 year at the time of the study ) .
each resident of finland is assigned a unique social security number , and this identification number was used to track information from registers .
changes in social security numbers in the 1970s mean that reliable automated linkage without individual checking and recoding of pins is possible from 1972 onwards , and thus we included data from 1972 onwards only .
data linkage was performed by sii , and all data were de - identified before submission to the research team . no ethics committee approval was required as de - identified data were used and participants were not contacted .
all community - dwelling people with a verified ad diagnosis , residing in finland on 31 december 2005 ( n = 28,093 ) were identified from the special reimbursement register , and a single age- , sex- , and region of residence  matched control subject per ad case subject ( n of matched case - control pairs = 28,093 ) was identified .
ad diagnosis was based on the national institute of neurological and communicative disorders and stroke and the alzheimer 's disease and related disorders association ( nincds - adrda ) and the dsm - iv criteria for ad ( 32,33 ) . in brief , the main diagnostic criterion is progressive memory loss , supported by abnormal magnetic resonance imaging or cerebrospinal fluid biomarker findings .
alternative explanations for memory impairment , such as severe depression , metabolic disturbances ( including hyperglycemia per se ) , and other forms of dementia , such as vascular dementia , needed to be excluded .
the finnish current care guidelines recommend that all people with ad are treated with memantine or acetylcholinesterase inhibitors unless there is a specific contraindication ( including gastric ulcer / intestinal tract operation < 6 months previously or severe asthma ) ( 34 ) .
patients with mild or moderate ad are entitled to reimbursed ad medication , but the reimbursement is not withdrawn if / when the disease progresses .
diabetes is diagnosed on the basis of fasting capillary blood glucose concentration ( sii reimbursement criterion cutoff is 7.0 mmol / l ) or 2-h glucose concentration if an oral glucose tolerance test has been performed ( cutoff 11.1 mmol / l ) ( 35 ) .
individuals with type 1 diabetes have been entitled to reimbursed insulin since 1964 , whereas the criteria for reimbursed type 2 diabetes medication have varied over time .
type 2 diabetes was first mentioned in 1981 criteria stating that medication for those with type 2 diabetes is reimbursed if they have not benefited from lifestyle modification lasting at least 3 months . in 1994 , the criteria for type 2 diabetes was updated to recommend 6-month dietary intervention as a first - line therapy and requesting that the pharmacotherapy for type 2 diabetes be used for at least 6 months , including a report of outcomes , before applying for special reimbursement .
people with gestational diabetes have not been entitled to reimbursement , unless the need for pharmacotherapy is prolonged .
thus , we applied a robust age - based classification so that people who were < 40 years of age when they were diagnosed with diabetes were classified as having type 1 diabetes and those who were at least 40 years of age were classified as having type 2 diabetes . this cutoff has been suggested as a simple and relatively reliable method for differentiating people with type 1 and type 2 diabetes ( 36 ) .
people with diabetes diagnosed at < 65 years of age were categorized as having diabetes in midlife , and those who were at least 65 years of age when diabetes was diagnosed were classified as having late - life diabetes .
statistical analyses were performed with stata 12.0 ( stata corp lp , college station , tx ) . the difference in the mean age of ad diagnosis between those with and without diabetes
was compared with the student t test , and differences in the duration of diabetes and age at diabetes diagnosis between case and control subjects were compared with the kruskal - wallis test .
the association of diabetes with ad was assessed in a case - control study including all 28,093 matched pairs .
crude ors and pooled ors according to the history of cardiovascular disease groups ( no / yes ) were calculated .
information on cardiovascular conditions ( hyper-/hypotension , ischemic heart disease , familial hypercholesterolemia , embolisms and thrombosis , myocardial infarctions , heart failure and cardiac arrests , atherosclerosis , and aneurysms ) was obtained from the special reimbursement register and finnish national hospital discharge register ( details available from a .- m.t . ) .
the prevalence of diabetes with reimbursed medication in 2005 was 11.4% in the whole study population , 10.7% ( n = 3,012 ) among control subjects ( i.e. , those without ad ) , and 12.0% ( n = 3,372 ) among ad cases .
a history of cardiovascular diseases was more common among those with diabetes than those who did not have diabetes ( or 2.91 [ 95% ci 2.663.18 ] , n = 5,159 , 80.8% , and n = 27,941 , 56.1% , respectively , including those with and without ad ) .
people with ad were more likely to have a history of clinically verified and medically treated diabetes ( either type 1 or type 2 diabetes ) in the unadjusted analysis ( or 1.14 [ 95% ci 1.081.20 ] ) , and the association was strengthened after adjusting for cardiovascular diseases ( adjusted or 1.31 [ 1.221.41 ] ) .
the association between diabetes and ad was similar in individuals with no history of cardiovascular diseases ( n = 23,086 , or 1.39 [ 1.231.57 ] ) and those with cardiovascular diseases ( n = 33,100 , or 1.29 [ 1.211.37 ] ) .
the associations were similar in both sexes ( adjusted or 1.27 [ 1.171.39 ] and 1.40 [ 1.231.59 ] in women and men , respectively ) .
association between diabetes and incident ad in the whole study population , according to previous cardiovascular disease ( cvd ) , sex , and onset age of diabetes . * adjusted for cardiovascular diseases .
both midlife and late - life diabetes were more common among those with ad ( table 1 and fig .
midlife diabetes was more strongly associated with ad than diabetes diagnosed in late life ( crude or 1.42 [ 95% ci 1.281.60 ] and 1.05 [ 1.001.12 ] for midlife and late - life diabetes , respectively ) .
the associations were strengthened after adjusting for cardiovascular diseases ( pooled or 1.60 [ 1.341.84 ] and 1.25 [ 1.161.36 ] for midlife and late life , respectively ) .
the median age at diabetes diagnosis was 71.4 years ( interquartile range 64.677.0 years ) , ranging from 15.4 to 98.9 years .
those with ad were younger when diabetes was diagnosed ( table 1 ) and thus the duration of diabetes was longer in case subjects than control subjects ( fig .
only 54 people were < 40 years of age when they were diagnosed with diabetes , suggesting that the majority had type 2 diabetes .
the exclusion of these 54 people who putatively had type 1 diabetes had no effect on the association ( data not shown ) .
age at ad diagnosis between those with and without diabetes was similar ( mean age 78.0 years , sd 0.1 for both groups ) .
individual dots represent observations outside the 95% cis . altogether , 757 ( 22.4% ) of those with ad and diabetes received the entitlement of reimbursed diabetes medication after ad diagnosis .
the median time interval was 2.0 years ( interquartile range 0.73.9 years ) , and 35.9% ( n = 272 ) of ad cases with diabetes received the decision on reimbursed medication within 1 year of ad diagnosis .
in this nationwide case - control study , people with clinically verified ad were more likely to have a history of clinically verified and medically treated diabetes than the general aged population .
the association between diabetes and ad was similar in individuals with or without a history of cardiovascular disease , and adjustment for cardiovascular diseases strengthened the association .
our findings also showed that in finland , ad patients who receive a diagnosis of diabetes often do so within 12 years of ad diagnosis .
this is likely due to the exclusion of alternative diagnoses , which is required before receiving reimbursed ad medication .
our findings and estimates are consistent with a previous meta - analysis on type 2 diabetes and ad ( 1 ) .
people with type 1 diabetes have also been suggested to have an increased risk of cognitive dysfunction ( 9 ) . in our study , the mean age at diabetes diagnosis was 70 years , and only 52 of all 6,384 people with diabetes were < 40 years of age when they were diagnosed , suggesting that the majority had type 2 diabetes .
considering the high average age ( 79.7 years ) , it is not surprising that only a small minority of the sample were < 40 years of age when diagnosed with diabetes .
mortality among people with type 1 diabetes in finland was significantly higher in the 1970s ( 37 ) , so these individuals were less likely to survive to an older age than they would be today .
according to the hypothesis that midlife vascular risk may be more strongly associated with ad than late - life risk factors ( 20 ) , we found a stronger association with midlife diabetes than late - life diabetes .
this is in line with previous studies showing that long - term diabetes is more strongly associated with cognitive impairment and dementia ( 38 ) and that diabetes in midlife increases the risk of ad ( 29 ) .
although this previous study found no association between late - life diabetes and ad ( 29 ) , another recent study investigating the midlife and late - life vascular risk factors concluded that the association of diabetes was of similar magnitude in both age groups ( 39 ) .
the age - dependent effect may be due to smaller effects of the ad disease process on midlife factors than on factors assessed in late life .
midlife vascular risk factors may also be a more accurate reflection of the vascular load during adulthood ( 40 ) .
the estimates from our study ( unadjusted 95% ci 1.081.20 ) are comparable , although lower than in the meta - analysis by profenno et al .
( 1 ) ( 95% ci 1.331.79 ) , although our adjusted estimates ( 1.221.41 ) are consistent with the previous findings .
this could be due to differences in the definition of diabetes . in half of the studies included in that meta - analysis ,
the diabetes diagnosis was based on self - report or use of diabetes medication ( 2123,25 ) , whereas in our study , all diabetes diagnoses were performed in healthcare settings and based on the assessment of blood glucose concentrations , which is mandatory for reimbursed diabetes medication in finland . there were also differences in sample size : the conclusions of profenno et al .
( 1 ) were based on 21,560 individuals , including 1,306 ad case subjects , whereas our sample included 28,093 ad case subjects . however , our study is limited in the sense that individuals with type 2 diabetes are underrepresented , as approximately one - third of type 2 diabetes is treated by lifestyle modifications only ( 36 ) .
our sample would cover all individuals with type 1 diabetes ( who were able to survive to their 70s or 80s ) , as the insulin replacement therapy is necessary , and the majority of people with advanced type 2 diabetes or those who did not benefit from lifestyle modification .
we were not able to adjust for lifestyle or socioeconomic confounders , such as obesity , smoking , or education as these data were not available from the registers we used .
however , we attempted to capture some variation in these factors by adjusting for cardiovascular diseases .
since there was no data on glycosylated hemoglobin concentrations or glucose concentrations after the reimbursement was accepted by sii , we could not assess whether those with better control of blood glucose concentrations had a different risk of ad .
diabetes is commonly undiagnosed , especially among older individuals ( 41 ) , so the misclassification of people with undetected diabetes or diabetes treated with lifestyle modifications as not having diabetes is likely .
this has implications for the interpretation of the results : our findings are not as informative on the association of all stages of diabetes as they are on the association of clinically verified and medically treated diabetes . due to the lack of a systematic cognitive assessment of each person included in this study , it is likely that people with cognitive impairment and ad or other dementias were included in the control group .
thus , our results are likely an underestimation of the true association between diabetes and ad , although they are consistent with previous studies that were able to adjust for confounders or systematically assess the blood glucose concentrations of participants ( 1 ) .
the strengths of the study are sample size , representativeness , length of follow - up , and verified diagnosis of ad .
the study sample includes all community - dwelling individuals with ad residing in finland in 2005 .
we included only noninstitutionalized people , but it is unlikely that the association between diabetes and ad would be different among institutionalized individuals .
we had access to data collected over 30 years , whereas previous studies on type 2 diabetes ( 2126 ) , apart from a few exceptions ( 2729 ) , have included < 10 years of follow - up .
since the information on diabetes medication , age at diabetes diagnosis , ad , and cardiovascular diseases was extracted from the registries , the results are not affected by recall bias . although the register - based diagnoses of ad likely underestimate the true prevalence , these diagnoses are more reliable than ad diagnoses extracted from other sources of routine healthcare data , e.g. , national hospital discharge register , as the diagnoses in the special reimbursement register are based on dsm - iv and nincds - adrda criteria whereas the accuracy of diagnoses from the national hospital discharge register may vary considerably , depending on the facility ( e.g. , specialized geriatrics unit vs. general healthcare visit ) . in conclusion ,
results from this unique nationwide case - control study show that individuals with ad are more likely to have a history of medically treated diabetes than the older population in general and that the association is independent of cardiovascular diseases .
 objectivetype 2 diabetes in midlife or late life increases the risk of alzheimer disease ( ad ) , and type 1 diabetes has been associated with a higher risk of detrimental cognitive outcomes , although studies from older adults are lacking . 
 we investigated whether individuals with ad were more likely to have a history of diabetes than matched controls from the general aged population.research design and methodsinformation on reimbursed diabetes medication ( including both type 1 and 2 diabetes ) of all finnish individuals with reimbursed ad medication in 2005 ( n = 28,093 ) and their ad - free control subjects during 19722005 was obtained from a special reimbursement register maintained by the social insurance institute of finland.resultsthe prevalence of diabetes was 11.4% in the whole study population , 10.7% ( n = 3,012 ) among control subjects , and 12.0% 
 ( n = 3,372 ) among ad case subjects . 
 people with ad were more likely to have diabetes than matched control subjects ( unadjusted or 1.14 [ 95% ci 1.081.20 ] ) , even after adjusting for cardiovascular diseases ( or 1.31 [ 1.221.41 ] ) . 
 the associations were stronger with diabetes diagnosed at midlife ( adjusted or 1.60 [ 1.341.84 ] and 1.25 [ 1.161.36 ] for midlife and late - life diabetes , respectively).conclusionsindividuals with clinically verified ad are more likely to have a history of clinically verified and medically treated diabetes than the general aged population , although the difference is small . 