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Association between diabetes and causes of dementia: Evidence from a clinicopathological study

ASSOCIAÇÃO ENTRE DIABETES E CAUSAS DE DEMÊNCIA: EVIDÊNCIA DE UM ESTUDO CLÍNICO-PATOLÓGICO

ABSTRACT.

Background:

Diabetes mellitus is a risk factor for dementia, especially for vascular dementia (VaD), but there is no consensus on diabetes as a risk factor for Alzheimer's disease (AD) and other causes of dementia.

Objective:

To explore the association between diabetes and the neuropathological etiology of dementia in a large autopsy study.

Methods:

Data were collected from the participants of the Brain Bank of the Brazilian Aging Brain Study Group between 2004 and 2015. Diagnosis of diabetes was reported by the deceased's next-of-kin. Clinical dementia was established when CDR ≥ 1 and IQCODE > 3.41. Dementia etiology was determined by neuropathological examination using immunohistochemistry. The association of diabetes with odds of dementia was investigated using multivariate logistic regression.

Results:

We included 1,037 subjects and diabetes was present in 279 participants (27%). The prevalence of dementia diagnosis was similar in diabetics (29%) and non-diabetics (27%). We found no association between diabetes and dementia (OR = 1.22; 95%CI = 0.81-1.82; p = 0.34) on the multivariate analysis. AD was the main cause of dementia in both groups, while VaD was the second-most-frequent cause in diabetics. Other mixed dementia was the second-most-common cause of dementia and more frequent among non-diabetics (p = 0.03).

Conclusion:

Diabetes was not associated with dementia in this large clinicopathological study.

Key words:
Alzheimer's disease; Diabetes mellitus; vascular dementia; neuropathology; clinicopathologic study

RESUMO.

Introdução:

Diabetes mellitus é um fator de risco para a demência, especialmente para a demência vascular (DV), mas ainda não há consenso sobre diabetes como fator de risco para a doença de Alzheimer (DA) e outras causas de demência.

Objetivo:

Verificar a associação entre diabetes e demência e sua etiologia neuropatológica em um grande estudo de autópsia. Métodos: Os dados foram coletados do Banco de Encéfalos Humanos do Grupo de Estudos em Envelhecimento Cerebral da FMUSP entre 2004 e 2015. O diagnóstico de diabetes foi relatado por pelos parentes do falecido. A demência clínica foi estabelecida quando CDR ≥ 1 e IQCODE > 3,41. A etiologia da demência foi determinada pelo exame neuropatológico com imuno-histoquímica. A associação de diabetes com probabilidades de demência foi investigada usando regressão logística multivariada.

Resultados:

Foram incluídos 1.037 sujeitos, diabetes esteve presente em 279 participantes (27%). A frequência de diagnóstico de demência foi semelhante entre diabéticos (29%) e não diabéticos (27%). Não encontramos associação entre diabetes e demência (OR = 1,22; IC 95% = 0,81-1,82; p = 0,34) na análise multivariada. DA foi a principal causa de demência em ambos os grupos, DV foi a segunda causa em diabéticos. A frequência de outra demência mista foi a segunda causa de demência e mais frequente entre os não diabéticos (p = 0,03).

Conclusão:

A diabetes não foi associada à demência neste grande estudo clínico-patológico.

Palavras-chave:
doença de Alzheimer; diabetes mellitus; demência vascular; neuropatologia; estudo clinicopatológico

INTRODUCTION

The number of people affected by diabetes mellitus has been growing worldwide.11 International Diabetes Federation, 2015. IDF Diabetes Atlas seventh edition: www.idf.org.
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In 2015, the International Diabetes Federation estimated that 415 million people aged 20-79 years had diabetes worldwide, and nearly 75% lived in low-to-middle-income countries (LMIC).11 International Diabetes Federation, 2015. IDF Diabetes Atlas seventh edition: www.idf.org.
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The number of diabetics will continue to rise with diabetes set to affect 642 million people by 2040, and this will take place especially in regions where economies are transitioning from low-income to middle-income levels.11 International Diabetes Federation, 2015. IDF Diabetes Atlas seventh edition: www.idf.org.
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The World Alzheimer Report 2015 estimated that 46.8 million people worldwide had dementia in 2015, and 58% of these lived in LMIC.22 Ali GC, Guerchet M, Wu YT, Prince M, Prina M. World Alzheimer Report 2015: The global prevalence of dementia. Chapter 2. Alzheimer´s Disease Internacional. The proportion of people with dementia living in LMIC will reach 63% in 2030 and 68% in 2050.22 Ali GC, Guerchet M, Wu YT, Prince M, Prina M. World Alzheimer Report 2015: The global prevalence of dementia. Chapter 2. Alzheimer´s Disease Internacional. Dementia and type 2 diabetes are more prevalent with aging.11 International Diabetes Federation, 2015. IDF Diabetes Atlas seventh edition: www.idf.org.
www.idf.org...
,22 Ali GC, Guerchet M, Wu YT, Prince M, Prina M. World Alzheimer Report 2015: The global prevalence of dementia. Chapter 2. Alzheimer´s Disease Internacional.

Diabetes is a known risk factor for dementia and vascular dementia (VaD), but the association between diabetes and Alzheimer's disease (AD) needs to be better clarified.33 Prince M, Luchsinger JA, Albanese E. Dementia and Risk Reduction an Analysis of Protective and Modifiable Factors. World Alzheimer Report 2014, Chapter 5: 66-83. Several longitudinal studies have shown that diabetes was associated only with VaD, but not with AD.44 Katzman R, Aronson M, Fuld P, Kawas C, Brown T, Morgenstern H, et al. Development of dementia illnesses in an 80-year-old volunteer cohort. Ann Neurol 1989;25:317-24.

5 Luchsinger JA, Tang M-X, Stern Y, Shea S, Mayeux R. Diabetes Mellitus and Risk of Alzheimer’s Disease and Dementia with Stroke in a Multiethnic Cohort. Am J Epidemiol 2001;154:635-41.

6 MacKnight C, Rockwood K, Awalt E, McDowell I. Diabetes mellitus and the risk of dementia, Alzheimer’s disease and vascular cognitive impairment in the Canadian Study of Health and Aging. Dement Geriatr Cogn Disord 2002;14(2):77-83.

7 Hassing LB, Johansson B, Nilson SE, Berg S, Pedersen NL, Gatz M, McClearn G. Diabetes Mellitus is a risk factor for vascular dementia, but not for Alzheimer1s disease: a population-based study of the oldest old. Int Psychogeriatr 2002;14(3):239-48.

8 Raffaitin C, Gin H, Empana JP, Helmer C, Berr C, Tzourio C et al. Metabolic Syndrome and Risk for Incident Alzheimer’s Disease or Vascular Dementia. Diabetes Care 2009;32(1):169-74.
-99 Xu WL, von Strauss, Qiu CX, Winblad B, Fratiglioni L. Uncontrolled diabetes increses the risk of Alzheimer’s disease: a population-based cohort study. Diabetologia 2009;52:1031-9. Meanwhile, some studies have shown that DM is associated with increased risk of dementia and AD,1010 Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O’Brien PC, Palumbo PJ. Risk of dementia amongpersons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 1997; 145:301-8.

11 Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes Mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;53(9):1937-42.

12 Brayne C, Gill C, Huppert FA, Barkley C, Gehlhaar E, Girling DM et al. Vascular Risks and Incident Dementia: Results from a Cohort Study of the Very Old. Dement Geriatr Disord 1998;9:175-80.

13 Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes Mellitus and Risk of Alzheimer Disease and Decline in Cognitive Function. Arch Neurol 2004;61:661-6.

14 Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of Vascular Risk Factors and Risk of Incident Alzheimer’s Disease. Neurology 2005;65(4):545-51.

15 Borenstein AR, Wu Y, Mortimer JA, Schellenberg GD, McCormick WC, Bowen JD, et al. Developmental and vascular risk factors for Alzheimer’s disease. Neurobiol Aging 2005;26:325-34.

16 Cheng D, Noble J, Tang MX, Schupf N, Mayeux R, Luchsinger JA. Type 2 Diabetes and Late-Onset Alzheimer’s Disease. Dement Geriatr Cogn Disord 2011;31:424-30.
-1717 Wang KC, Woung LC, Tsai MT, Liu CC, Su YH, Li CY. Risk of Alzheimer’s disease in relation to diabetes: a population-based cohort study. Neuroepidemiology. 2012;38:237-44. while others have found a positive association only in the presence of the apolipoprotein E e4 allele (APOE e4).1818 Xu WL, Qui CX, Wahlin A, Winblad B, Fratiglioni L. Diabetes Mellitus and risk of dementia in the Kungsholmen project. Neurology 2004;63:1181-6.,1919 Irie F, Fitzpatrick AL, Lopez OL, Kuller LH, Peila R, Newman AB, Launer LJ. Enhanced Risk for Alzheimer Disease in Persons with Type 2 Diabetes and APOE e4. The Cardiovascular Health Sudy Cognition Study. Arch Neurol 2008;65(1):89-93. However, Akomolafe et al.2020 Akomolafe A, Beiser A, Meigs JB, Au R, Green RC, Farrer LA, et al. Diabetes Mellitus and Risk of Developing Alzheimer Disease. Arch Neurol 2006; 63(11):1551-4. showed diabetes was a risk factor for AD, especially when three known AD risk factors were absent: elevated plasma homocysteine level, the APOE e4 allele, or age 75 years or older.

There are fewer autopsy studies than epidemiological investigations. Despite the positive evidence linking diabetes and cerebrovascular neuropathology,2121 Peila R, Rodriguez BL, Launer LJ. Type 2 Diabetes, APOE Gene, and the Risk for Dementia and Related Pathologies. The Honolulu-Asia Aging Study. Diabetes 2002;51:1256-62.

22 Arvanitakis Z, Schneider JA, Wilson RS, Li Y, Arnold SE, Wang Z, Bennett DA. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 2006;67:1960-5.

23 Alafuzoff I, Aho L, Helisalmi S, Mannermaa A, Soininen H. b-Amyloid deposition in brains of subjects with diabetes. Neuropathology Applied Neurobiology 2009;35:60-8.

24 Nelson PT, Smith CD, Abner EA, Schmitt FA, Scheff SW, Davis GJ, et al. Human cerebral neuropathology of type 2 diabetes mellitus. Biochim Biophys Acta 2009;1792:454-69.

25 Sonnen JA, Larson EB, Brickell K, Crane PK, Woltjer R, Montine TJ, Craft S. Different Pattenrs of Cerebral Injury in Dementia with or without Diabetes. Arch Neurol 2009;66(3):315-22.

26 Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. diabetes, Alzheimer's disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010;75:1195-202.
-2727 Abner EL, Nelson PT, Kryscio RJ, Schmitt FA, Fardo DW, Woltjer RL et al. Diabetes is associated with cerebrovascular but no Alzheimer neuropathology. Alzheimers Dement 2016:1-8. most autopsy studies have not supported the same conclusion regarding the association between diabetes and AD neuropathology2222 Arvanitakis Z, Schneider JA, Wilson RS, Li Y, Arnold SE, Wang Z, Bennett DA. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 2006;67:1960-5.,2424 Nelson PT, Smith CD, Abner EA, Schmitt FA, Scheff SW, Davis GJ, et al. Human cerebral neuropathology of type 2 diabetes mellitus. Biochim Biophys Acta 2009;1792:454-69.,2626 Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. diabetes, Alzheimer's disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010;75:1195-202.

27 Abner EL, Nelson PT, Kryscio RJ, Schmitt FA, Fardo DW, Woltjer RL et al. Diabetes is associated with cerebrovascular but no Alzheimer neuropathology. Alzheimers Dement 2016:1-8.

28 Heitner J, Dickson D. Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects. Neurology 1997;49:1306-11.

29 Beeri MS, Silverman JM, Davis KL, Marin D, Grossman HZ, Schmeidler J, et al. Type 2 Diabetes Is Negatively Associated with Alzheimer’s Disease Neuropathology. J Gerontol A Biol Sci Med Sci. 2005;60A(4):471-5.
-3030 Matioli MNPS, Suemoto CK, Rodriguez RD, Farias DS, da Silva MM, Leite REP, et al. J Alzheimers Dis 2017;60:1035-43. and some authors described a positive association only in individuals carrying the APOE e4 allele.2121 Peila R, Rodriguez BL, Launer LJ. Type 2 Diabetes, APOE Gene, and the Risk for Dementia and Related Pathologies. The Honolulu-Asia Aging Study. Diabetes 2002;51:1256-62.,2323 Alafuzoff I, Aho L, Helisalmi S, Mannermaa A, Soininen H. b-Amyloid deposition in brains of subjects with diabetes. Neuropathology Applied Neurobiology 2009;35:60-8.,3131 Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, et al. Insulin resistance is associated with the pathology of Alzheimer disease: The Hasayama Study. Neurology 2010;75:764-70.,3232 Malek-Ahmadi M, Beach Thomas, Obradov A, Sue L, Belden C, Davis K, et al. Type 2 diabetes is associated with increased Alzheimer’s disease neuropathology in ApoE e4 Carriers. Curr Alzheiner Res 2013; 10(6): 654-9. Studies from LMIC regarding the association between diabetes and dementia are scarce.22 Ali GC, Guerchet M, Wu YT, Prince M, Prina M. World Alzheimer Report 2015: The global prevalence of dementia. Chapter 2. Alzheimer´s Disease Internacional. We recently showed that diabetes was not associated with AD-neuropathology in a large sample from Brazil.3030 Matioli MNPS, Suemoto CK, Rodriguez RD, Farias DS, da Silva MM, Leite REP, et al. J Alzheimers Dis 2017;60:1035-43. Here, we aimed to expand this finding by examining the association between diabetes and causes of dementia in a large autopsy study.

METHODS

Participants.

This cross-sectional study included subjects aged 50 years and older from the Brain Bank of the Brazilian Aging Brain Study Group of the University of São Paulo Medical School (BB-BABSG-FMUSP). Exclusion and inclusion criteria for the BB-BABSG-FMUSP were previously described.3333 Grinberg LT. Ferretti RE. Farfel JM. Leite R. Pasqualucci CA. Rosemberg S. et al. Brain bank of the Brazilian aging brain study group - a milestone reached and more than 1.600 collected brains. Cell Tissue Bank. 2007;8(2):151-62. Initially, 1,083 subjects were selected from 2004 to 2015, but incomplete interview or neuropathological data were found in 46 deceased. Therefore, the final sample comprised 1,037 deceased. Signed informed consent obtained from the deceased's next-of-kin (NOK) allowed autopsy and brain donation. The local ethics committee approved this study.

Clinical information.

A skilled team of gerontologist nurses applied the structured interview to the deceased's NOK. The NOK had to have at least weekly contact with the deceased during the six months prior to death. This structured interview provided information about demographics (age, sex, race, and education) and socioeconomic status, previous diagnosis of diseases (hypertension, dyslipidemia, heart failure, coronary artery disease, and stroke), lifestyle (alcoholism, smoking, sedentary lifestyle), medication intake, as well as cognitive and functional status.3333 Grinberg LT. Ferretti RE. Farfel JM. Leite R. Pasqualucci CA. Rosemberg S. et al. Brain bank of the Brazilian aging brain study group - a milestone reached and more than 1.600 collected brains. Cell Tissue Bank. 2007;8(2):151-62. A Brazilian scale classifying subjects into five socioeconomic strata3434 Almeida P. Wickerhauser H. O critério ABA/ABIPEME: em busca de uma atualização. Editora da Associação Brasileira dos Institutos de Pesquisa de Mercado. São Paulo. Editora ABA/ABIPEME; 1991. was applied. Stratum A is the highest income and stratum E the lowest, and this scale was grouped into high (stratum A+B), middle (stratum C) and low (stratum D+E) socioeconomic status for statistical analysis. Diabetes was defined based on the NOK report of diabetes diagnosis during life or the use of any antidiabetic medication. Cognitive status was evaluated by the Clinical Dementia Rating scale (CDR)3535 Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;43:2412-4. and the Informant Questionnaire on Cognitive Decline in the Elderly.3636 Jorm AF. Jacomb PA. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates reliability, validity and some norms. Psychol Med 1989;19:1015-22. The clinical diagnosis of dementia was established in the presence of CDR ≥ 1 and IQCODE score > 3.41.3737 Grinberg LT, Nitrini R, Suemoto CK, Ferretti-Rebustini RE, Leite REP, Farfel JM, et al. Clinics 2013;68(8):1140-5. The cause of dementia was determined following neuropathological criteria.

Neuropathological assessment.

The brain was collected within 24 hours of death. One hemisphere was coronally sectioned and snap frozen and the other hemisphere was fixed in 4% buffered paraformaldehyde. Samples from the fixed hemisphere were embedded in paraffin and sectioned to produce slides of following regions: hippocampus and parahippocampal gyrus at the level of the lateral geniculate body, amygdala at the level of mammillary bodies (including the ambiens gyrus), basal ganglia at the level of the anterior commissure, thalamus, midbrain, pons, medulla oblongata, and cerebellum, middle frontal gyrus, middle and anterior temporal gyri, angular gyrus, superior frontal gyrus and anterior cingulate gyrus, and visual cortex. Hematoxylin & eosin (H&E) staining was applied to all sampled regions. Selected sections were immunostained with antibodies against phosphorylated tau (PHF-1, dilution 1:2.000; gift of Prof. Peter Davies, NY), b-amyloid (4G8, dilution 1:10.000; Signet Pathology Systems, Dedham, MA), a-synuclein (EQV, 1:10.000, gift of Kenji Ueda, Tokyo, Japan), and transactivation response DNA-binding protein of 43 kDA (TDP-43; 1:500, Proteintech, Chicago, IL).3333 Grinberg LT. Ferretti RE. Farfel JM. Leite R. Pasqualucci CA. Rosemberg S. et al. Brain bank of the Brazilian aging brain study group - a milestone reached and more than 1.600 collected brains. Cell Tissue Bank. 2007;8(2):151-62. Internationally accepted neuropathological criteria and guidelines were used for diagnosing and staging the causes of dementia.3333 Grinberg LT. Ferretti RE. Farfel JM. Leite R. Pasqualucci CA. Rosemberg S. et al. Brain bank of the Brazilian aging brain study group - a milestone reached and more than 1.600 collected brains. Cell Tissue Bank. 2007;8(2):151-62.

AD-type pathology was scored using the Braak and Braak staging system3838 Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82:239-59. and the Consortium to Establish a Registry for AD (CERAD)3939 Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991;41:479-86. criteria. Diagnosis of AD dementia was made in cases that had at least Braak stage III and CERAD moderate score.4040 Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P. Epidemiological pathology of dementia: attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med. 2009;6(11):e1000180.

The presence of diffuse small-vessel disease in the white matter, of hippocampal sclerosis, and of lacunae, microinfarcts, and infarcts were analyzed semi-quantitatively by H&E staining. Cerebral amyloid angiopathy was investigated using anti b-amyloid immunostaining. The diagnosis of VaD was defined in cases with one large chronic infarct (> 1 cm) or three lacunae in strategic areas (thalamus, frontocingular cortex, basal forebrain and caudate, medial temporal area, and angular gyrus).3737 Grinberg LT, Nitrini R, Suemoto CK, Ferretti-Rebustini RE, Leite REP, Farfel JM, et al. Clinics 2013;68(8):1140-5. AD plus VaD was considered as mixed dementia only when the criteria for AD and VaD were concomitantly present.

Lewy body disease was diagnosed based on criteria described by McKeith et al.4141 McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H et al. Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65:1863-72. To define dementia secondary to Parkinson's disease, a criterion described by Braak et al.4242 Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197-211. was applied. The diagnosis of Frontotemporal lobar degeneration was established using the criteria of Mackenzie et al.4343 Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 2010;119:1-4. The diagnosis of argyrophilic grain disease was established according to Saito et al.4444 Saito Y, Ruberu NN, Sawabe M, Arai T, Tanaka N, Kakuta Y, et al. Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol. 2004;63:911-8. Undefined cause was defined when there was no agreement between the clinical diagnosis of dementia and the neuropathological findings. Other mixed dementia was considered in presence of two or more neuropathologies of dementia, except when AD + VaD were present.

Statistical analysis.

We used the unpaired t-test or Mann-Whitney test for quantitative variables, and the Chi-square or Fisher's exact tests for categorical variables, to investigate the association of demographic and clinical variables with dementia stratified by diabetes status. The association between diabetes and dementia was investigated using multivariate ordinal logistic regression with results adjusted for age, sex, education, hypertension, dyslipidemia, smoking, alcohol use and physical inactivity. We also described the frequency of neuropathological diagnosis by diabetes status among participants with dementia, and compared these frequencies using Chi-square or Fisher's exact tests. Stata 13.0 (College Station, TX: StataCorp LP) was employed for statistical analyses. The significance level was set at 0.05 in two-tailed tests.

RESULTS

We analyzed data from 1,037 subjects, of which 758 (72%) were non-diabetics and 279 (27%) diabetics. Dementia was determined in 80 diabetics (29%) and 205 (27%) non-diabetics, and no difference was found regarding dementia frequency between these groups (p = 0.24). First, the total sample were stratified by diabetes status, and compared for frequency of dementia diagnosis regarding sociodemographic and clinical variables (Table 1). Participants with dementia, with and without diabetes, were mostly female, had lower educational level, and were older compared to non-demented groups. Black and admixed races were more frequent in diabetics with dementia than diabetics without dementia. A higher frequency of stroke and physical inactivity were found in both demented groups. Hypertension and current smoking were more frequent in non-diabetics without dementia compared to non-diabetics with dementia.

Table 1
Sociodemographic and clinical data from diabetics and non-diabetics with and without dementia (n=1,037).

Second, only diabetics and non-diabetics with dementia data were compared. Similar frequencies were found between them regarding age (p = 0.12), sex (p = 0.79), education (p = 0.88), race (p = 0.17), socioeconomic status (p = 0.70), coronary artery disease (p = 0.72), stroke (p = 0.52), heart failure (p = 0.83), physical inactivity (p = 0.90), current smoking (p = 0.60), and alcohol use (p = 0.90). Hypertension (p < 0.01) and dyslipidemia (p < 0.01) were more frequent in demented diabetics than in non-diabetics with dementia. There was a higher frequency of individuals with severe dementia (CDR = 3) among non-diabetics (p = 0.03), and with mild (CDR = 1) and moderate dementia (CDR = 2) among diabetics. Non-diabetics with dementia died with highest mean IQCODE scores (4.43; SD:0.48; p = 0.04) (Table 2).

Table 2
CDR and IQCODE in diabetics and non-diabetics with dementia (n = 285).

Diabetes was not associated with dementia (OR:1.22; 95%CI:0.81-1.82; p = 0.34) on multivariate ordinal logistic regression adjusted for age, sex, race, education, hypertension, dyslipidemia, smoking, physical inactivity and alcohol use (Table 3).

Table 3
Association between clinical dementia and diabetes mellitus status (n = 1,037).

Among participants with dementia, AD was the main neuropathological cause of dementia in both groups (Table 4). Only other mixed dementia was more frequent in non-diabetics with dementia (p = 0.03). The distribution of causes of dementia differed between diabetics and non-diabetics. The second-most-common cause of dementia in diabetics was VaD, but in non-diabetics was other mixed dementia. Undefined cause of dementia was similar between diabetics and non-diabetics (Table 4).

Table 4
Neuropathological causes of dementia in diabetics and non-diabetics (n = 285).

DISCUSSION

This study did not find an association between diabetes and dementia in a large sample of subjects submitted to autopsy. All diabetics and non-diabetics with dementia were older, predominantly women, had lower education, and a higher frequency of stroke and physical inactivity. Older age, low education, female sex, physical inactivity and stroke have been considered risk factors for dementia.22 Ali GC, Guerchet M, Wu YT, Prince M, Prina M. World Alzheimer Report 2015: The global prevalence of dementia. Chapter 2. Alzheimer´s Disease Internacional.,4545 Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:2672-713.

46 Ferri C, Piovezan RD, Padilla I, Prince M, Albanese E, Prine M. Lyfestile. World Alzheimer Report 2014, Chapter 4: 9-10.

47 Pender R, Guerchet M, Prince M. Developmental and early-life risk factors. World Alzheimer Report 2014, Chapter 2: 12-24.
-4848 Chenê G, Beiser A, Au R, Preis SR, Wolf PA, Dufouil C, Seshadri S. Gender and incidence of dementia in the Framingham Heart Study from mid-adult life. Alzheimers Dement 2015;11(3):310-20. Participants with diabetes died at mild and moderate stages of dementia. They had more comorbidities, exhibiting more hypertension and dyslipidemia; therefore, they might have died before dementia had reached more advanced clinical stages.

The prevalence of dementia among non-diabetics (27%) and diabetics (29%) was lower in our study compared with other reports.2222 Arvanitakis Z, Schneider JA, Wilson RS, Li Y, Arnold SE, Wang Z, Bennett DA. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 2006;67:1960-5.,2626 Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. diabetes, Alzheimer's disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010;75:1195-202.,2727 Abner EL, Nelson PT, Kryscio RJ, Schmitt FA, Fardo DW, Woltjer RL et al. Diabetes is associated with cerebrovascular but no Alzheimer neuropathology. Alzheimers Dement 2016:1-8. Arvanitakis et al.2222 Arvanitakis Z, Schneider JA, Wilson RS, Li Y, Arnold SE, Wang Z, Bennett DA. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 2006;67:1960-5. found dementia in 44.2% of non-diabetics and in 50% of diabetics (p = 0.52). Ahtiluoto et al.2626 Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. diabetes, Alzheimer's disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010;75:1195-202. reported a very high frequency of dementia, present in 65.9% of non-diabetics and 60.0% of diabetics (p = 0.381) with mean age of 88 years. Abner et al.2727 Abner EL, Nelson PT, Kryscio RJ, Schmitt FA, Fardo DW, Woltjer RL et al. Diabetes is associated with cerebrovascular but no Alzheimer neuropathology. Alzheimers Dement 2016:1-8. reported dementia in 38.2% of non-diabetics and 39.1% of diabetics (p = 0.69), also with a mean sample age of 88.7 years. However, the study by Alafuzoff et al.2323 Alafuzoff I, Aho L, Helisalmi S, Mannermaa A, Soininen H. b-Amyloid deposition in brains of subjects with diabetes. Neuropathology Applied Neurobiology 2009;35:60-8. found a higher frequency of dementia in the non-diabetic group (p < 0.01) of 31% in non-diabetics and 21% in diabetics, but with a mean age similar to the present study. Peila et al.2121 Peila R, Rodriguez BL, Launer LJ. Type 2 Diabetes, APOE Gene, and the Risk for Dementia and Related Pathologies. The Honolulu-Asia Aging Study. Diabetes 2002;51:1256-62. described an increased risk for the development of dementia in diabetics, whereas the study by Ahtiluoto et al.2626 Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. diabetes, Alzheimer's disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010;75:1195-202. reported double the incidence of dementia in this group.

AD was the main cause of dementia in both groups, showing the importance of this neurodegenerative disease in older people even in the presence of vascular risk factors. VaD was the second-most-common cause only in diabetics. Other mixed neuropathology of dementia was more frequent and the second-most-frequent cause of dementia in non-diabetics. The difference in cause of dementia distribution can probably be explained by diabetics being a group with more vascular risk factors, showing the important role of diabetes in cerebrovascular disease. DM was not associated with increased frequency of any particular type of dementia in the present study, unlike cohort studies that have shown an increased risk for AD,1010 Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O’Brien PC, Palumbo PJ. Risk of dementia amongpersons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 1997; 145:301-8.

11 Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes Mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;53(9):1937-42.

12 Brayne C, Gill C, Huppert FA, Barkley C, Gehlhaar E, Girling DM et al. Vascular Risks and Incident Dementia: Results from a Cohort Study of the Very Old. Dement Geriatr Disord 1998;9:175-80.

13 Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes Mellitus and Risk of Alzheimer Disease and Decline in Cognitive Function. Arch Neurol 2004;61:661-6.

14 Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of Vascular Risk Factors and Risk of Incident Alzheimer’s Disease. Neurology 2005;65(4):545-51.

15 Borenstein AR, Wu Y, Mortimer JA, Schellenberg GD, McCormick WC, Bowen JD, et al. Developmental and vascular risk factors for Alzheimer’s disease. Neurobiol Aging 2005;26:325-34.

16 Cheng D, Noble J, Tang MX, Schupf N, Mayeux R, Luchsinger JA. Type 2 Diabetes and Late-Onset Alzheimer’s Disease. Dement Geriatr Cogn Disord 2011;31:424-30.
-1717 Wang KC, Woung LC, Tsai MT, Liu CC, Su YH, Li CY. Risk of Alzheimer’s disease in relation to diabetes: a population-based cohort study. Neuroepidemiology. 2012;38:237-44.,1919 Irie F, Fitzpatrick AL, Lopez OL, Kuller LH, Peila R, Newman AB, Launer LJ. Enhanced Risk for Alzheimer Disease in Persons with Type 2 Diabetes and APOE e4. The Cardiovascular Health Sudy Cognition Study. Arch Neurol 2008;65(1):89-93.,4949 Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, Kanba S, Kiyohara Y. Glucose tolerance status and risk of dementia in community: the Hisayama Study. Neurology. 2011;77:1126-34. VaD,55 Luchsinger JA, Tang M-X, Stern Y, Shea S, Mayeux R. Diabetes Mellitus and Risk of Alzheimer’s Disease and Dementia with Stroke in a Multiethnic Cohort. Am J Epidemiol 2001;154:635-41.

6 MacKnight C, Rockwood K, Awalt E, McDowell I. Diabetes mellitus and the risk of dementia, Alzheimer’s disease and vascular cognitive impairment in the Canadian Study of Health and Aging. Dement Geriatr Cogn Disord 2002;14(2):77-83.

7 Hassing LB, Johansson B, Nilson SE, Berg S, Pedersen NL, Gatz M, McClearn G. Diabetes Mellitus is a risk factor for vascular dementia, but not for Alzheimer1s disease: a population-based study of the oldest old. Int Psychogeriatr 2002;14(3):239-48.

8 Raffaitin C, Gin H, Empana JP, Helmer C, Berr C, Tzourio C et al. Metabolic Syndrome and Risk for Incident Alzheimer’s Disease or Vascular Dementia. Diabetes Care 2009;32(1):169-74.
-99 Xu WL, von Strauss, Qiu CX, Winblad B, Fratiglioni L. Uncontrolled diabetes increses the risk of Alzheimer’s disease: a population-based cohort study. Diabetologia 2009;52:1031-9.,1818 Xu WL, Qui CX, Wahlin A, Winblad B, Fratiglioni L. Diabetes Mellitus and risk of dementia in the Kungsholmen project. Neurology 2004;63:1181-6. AD and VaD,1111 Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes Mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;53(9):1937-42.,2121 Peila R, Rodriguez BL, Launer LJ. Type 2 Diabetes, APOE Gene, and the Risk for Dementia and Related Pathologies. The Honolulu-Asia Aging Study. Diabetes 2002;51:1256-62.,2626 Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. diabetes, Alzheimer's disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010;75:1195-202.,5050 Kimm H, Lee PH, Shin YJ, Park KS, Jo J, Lee Y, Kang HC, Jee SH. Mid-life late-life vascular risk factors and dementia in Korean men and women. Arch Gerontol Geriatr. 2011;52:e117-22. or for mixed AD and VaD1111 Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes Mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;53(9):1937-42.,2121 Peila R, Rodriguez BL, Launer LJ. Type 2 Diabetes, APOE Gene, and the Risk for Dementia and Related Pathologies. The Honolulu-Asia Aging Study. Diabetes 2002;51:1256-62. in diabetic patients Diabetes increases the risk for cerebral small-vessel disease, cerebral infarcts, vascular cognitive decline and VaD.33 Prince M, Luchsinger JA, Albanese E. Dementia and Risk Reduction an Analysis of Protective and Modifiable Factors. World Alzheimer Report 2014, Chapter 5: 66-83.,5151 Chui HC, Zheng L, Reed BR, Vinters HV, Mack WJ. Vascuar risk factors and Alzheimer’s disease: are these risck factors for plaques and tangles or concomitant vascular pathology that increses the likehood of dementia? An evidenced-based review. Alzheimers Res Ther. 2012;4:1.,5252 Richardson K, Stephan BCM, Ince PG, Brayne C, Matthews FE, Esiri MM. The Neuropathology of Vascular Disease in the Medical Research Council Cognitive Function and Aging Study (MRC CFAS). Curr Alzheimer Res. 2012;9:687-96. The role of diabetes with regard to AD remains controversial, where cerebrovascular disease is likely the main mechanism involved and diabetes possibly decreases brain resilience, but does not directly cause AD.33 Prince M, Luchsinger JA, Albanese E. Dementia and Risk Reduction an Analysis of Protective and Modifiable Factors. World Alzheimer Report 2014, Chapter 5: 66-83.

The present study has several strengths: a) the large sample size from a LMIC with low educational level among subjects, in contrast with other studies; b) autopsy studies allow for the direct measurement of neuropathological lesions, untangling the pure association between DM and dementia neuropathology; c) neuropathologists were blinded to clinical information. However, our study has some limitations: a) this is a cross-sectional study and therefore limited in determining causality of diabetes for dementia; b) all clinical data, including diabetes diagnoses, were obtained in NOK; c) the clinical diagnosis of dementia was established only after death based on NOK information. However, the accuracy of our clinical interview was tested previously and showed good reliability.5353 Ferretti REL, Damin AE, Brucki, SMD, Morillo LS, Perroco TR, Campora F et al. Post-Mortem diagnosis of dementia by informant interview. Dement Neuropsycol 2010; 2(4):138-44.

In conclusion, we did not find an association between diabetes and dementia frequency or any neuropathological cause in a large sample with low educational level in a LMIC. Further studies are necessary to better clarify these questions, especially longitudinal autopsy studies in LMIC.

  • This study was conducted at the Department of Neurology, University of São Paulo Medical School, São Paulo, SP, Brazil.
  • Study funding.
    Support for this work was provided by grants the from Fundação de Apoio a Pesquisa do Estado de São Paulo – FAPESP (grant 2009/01934-4 and scholarship to R.E.P.L.), LIM22 of the Department of Pathology of the University of São Paulo Medical School, Albert Einstein Education and Research Institute, São Paulo (grant 240/07), and the Coordenadoria de Apoio ao Pessoal de Nivel Superior – CAPES, Brazil (scholarship to students of the BABSG).

Acknowledgements/Funding.

The authors are grateful to the families of the brain donors and to the São Paulo City Autopsy Service physicians and staff for their unconditional support, and to the Brazilian Aging Brain Study Group participants.

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Publication Dates

  • Publication in this collection
    Oct-Dec 2017

History

  • Received
    11 Oct 2017
  • Accepted
    16 Nov 2017
Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: revistadementia@abneuro.org.br | demneuropsy@uol.com.br