Table 1: Studies of Dyslipidaemia and Cognitive Function in Type 2 Diabetes

Supplemental Data

{2 Column Table}

Table S1. Studies of inflammation and cognitive function in type 2 diabetes

Study Sample Design Num Baseline Measuremen Cognitive measures Adjus Association with

ber mean t of tment cognitive function

age inflammation variab

les Chen et Patients with Cross-sectional, 101 Mean CRP MCI identified on the None Higher CRP in al. [9] type 2 observational 63 ± 8 basis of cognitive group with MCI

(2011) diabetes; years screening instrument compared with

China group free of MCI. Keller et Patients with 4-year 1,06 Mean Plasma Composite score from Age Higher baseline al. [45] type 2 prospective, 6 68 ± 4 fibrinogen at seven cognitive tests and fibrinogen

(2012) diabetes observational years baseline sex associated with

participating steeper cognitive

in the decline

Edinburgh Type 2

Diabetes

Study;

Scotland Keller et Patients with 4-year 1,06 Mean Plasma IL-6 Composite score from Age Higher baseline IL- al. [46] type 2 prospective, 6 68 ± 4 at baseline seven cognitive tests and 6 associated with

(2012) diabetes observational years sex steeper cognitive

participating decline.

in the

Edinburgh

Type 2

Diabetes

Study;

Scotland Marioni Patients with Cross-sectional, 1,06 Mean Plasma Composite score from Age Higher fibrinogen et al. type 2 observational 6 68 ± 4 fibrinogen seven cognitive tests and associated with

[43] diabetes years sex lower cognitive

(2011) participating function. in the

Edinburgh

Type 2

Diabetes

Study;

Scotland Marioni Patients with Cross-sectional, 1,06 Mean Plasma IL-6, Composite score from Age, Higher IL-6 et al. type 2 observational 6 68 ± 4 TNF-α, and seven cognitive tests sex, associated with

[44] diabetes years CRP and estimate of pre- educa lower cognitive

(2010) participating morbid ability tion, function and

in the cardio steeper estimated

Edinburgh vascu lifetime decline

Type 2 lar (fully adjusted

Diabetes diseas analyses).

Study; e, Association of

Scotland durati higher TNF-α with

on of lower cognitive diabet function and

es, estimated lifetime

HbA1 decline only in

c, and analyses adjusted

estim for age, sex, and

ated estimated pre-

pre- morbid ability. No

morbi consistent finding

d for CRP.

abilit

y Umegak Patients with 6-year 79 Mean Mean of Composite score from None No association. i et al. type 2 prospective, 74 ± 5 CRP MMSE, Digit Symbol

[16] diabetes; observational years measured at Coding, Stroop, and

(2014) Japan baseline and word recall. Analyses of

annual ‘decliners’ versus ‘non-

follow-ups decliners’ on bases of composite score and

individual cognitive

tests. CRP, C-reactive protein; IL-6, interleukin-6; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; TNF-α, tumor necrosis factor-alpha. {2 Column Table}

Table S2. Studies of microvascular disease and cognitive function in type 2 diabetes

Study Sample Design Numbe Baseline Measuremen Cognitive Adjustment Association

r mean age t of measures variables with

microvascul cognitive

ar disease function de Bresser et Patients with 4-year 122 Mean 66 ± 6 Ophthalmol Composite Age, sex, No al. [49] type 2 diabetes prospective, years ogist- score from and pre- association.

(2010) participating in observationa identified 11 cognitive morbid

the Utrecht l presence tests, ability for

Diabetic versus estimate of analyses of

Encephalopath absence of pre-morbid cognitive

y Study; retinopathy ability, total function.

The according to brain Age and sex

Netherlands ‘standard volume, for analyses

clinical lateral of imaging

practice’ at ventricular data. baseline volume,

white matter

hyperintensi

ty volumes,

and cerebral

infarcts de Galan Patients with 5-year trial 11,140 Mean 66 ± 6 ‘Major At baseline None Cross- et al. [35] type 2 diabetes on effects of years diabetic eye and 2-year sectional

(2009) participating in intensified disease’ intervals: analysis:

ADVANCE blood MMSE increased

arm on pressure followed by prevalence

glycemic control and clinical of major

control, intensified interview diabetic eye

receiving glycemic for patients disease in

standard target control with MMSE groups with

versus target <24 or cognitive

HbA1c ≤6.5%; suspected dysfunction. Australia dementia.

‘Normal’

cognitive

function

defined as

MMSE ≥28;

‘mild

dysfunction’

as MMSE =

24-27;

‘severe

dysfunction’

as MMSE

Additional

use of

MMSE as continuous

measure. Hugenschmid Patients with 40-month 1,862 Mean 62 ± 6 Presence of Digit Age, sex, Cross- t et al. [50] type 2 diabetes prospective, years no Symbol ethnicity, sectional

(2014) participating in observationa retinopathy, Coding education, association

ACCORD-Eye l of mild non- (primary smoking, of

and ACCORD- proliferative outcome), geographic retinopathy

MIND retinopathy, MMSE, Rey region, with lower

substudies of or of Auditory duration of gray matter

ACCORD; moderate/se Verbal diabetes, volume but

North America vere Learning, HbA1c, not with

retinopathy and Stroop cholesterol, cognitive

at baseline; (secondary triglycerides function.

based on outcomes) , blood Prospective

ETDRS at baseline pressure, association

chart and 20 and anti- of

40 months. hypertensive retinopathy Total brain medication with steeper volume, use, 40-month white matter depression, (but not 20- volume, alcohol, and month) gray matter neuropathy. decline on volume, and Additional MMSE and abnormal adjustment Digit white matter for visual Symbol volume at acuity for Coding. baseline and analyses of Statistically

40 months. cognitive non-

function and significant

for total trend for

intracranial association

volume for of baseline

analyses of retinopathy

brain with greater volumes. increase in

white matter

abnormalitie

s during 40-

follow-up. Manschot et Patients with Cross- 122 Mean 66 ± 6 Presence Composite Age, sex, No al. [25] type 2 diabetes sectional, years versus score from and association

(2007) participating in observationa absence of 11 cognitive estimated of

the Utrecht l retinopathy tests, pre-morbid retinopathy

Diabetic based on estimate of ability with

Encephalopath scores on pre-morbid estimated

y Study; diabetic ability, lifetime

The retinopathy cortical decline in

Netherlands severity atrophy, and cognitive

scale white matter function.

(Wisconsin lesions Association Epidemiolog of

ic Study of retinopathy

Diabetic with

Retinopathy presence of

) at baseline cortical

atrophy

(analysis

additionally

controlling

for lipid-

lowering

drugs and

cerebral

infarcts). ACCORD, Action to Control Cardiovascular Risk in Diabetes; ACCORD-MIND, Action to Control Cardiovascular Risk in Diabetes-

Memory in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled

Evaluation; ETDRS, Early Treatment of Diabetic Retinopathy Study; MMSE, Mini-Mental State Examination.

{2 Column Table}

Table S3. Studies of markers of macrovascular disease and cognitive function in type 2 diabetes

Study Sample Design Numbe Baselin Macrovascular Cognitive Adjustme Association

r e mean disease measures nt with cognitive

age variables function Bruce et Patients with 8-year 302 Mean ‘Cerebrovascular Dementia and None Cross- al. [14] type 2 retrospectiv 76 ± 5 disease’ (stroke MCI identified sectional

(2008) diabetes e, years and TIA), ‘CHD’ from screening analyses:

participating observation (MI, angina, instruments/clinic increased

in the al coronary artery al interview prevalence of

Fremantle bypass, and cerebrovascul

Diabetes evidence of MI on ar disease

Study; ECG), and across

Australia peripheral arterial cognitive

disease at baseline groups, with

and 8 years earlier highest

prevalence in dementia group, followed by

MCI group and unimpaired group.

Increased prevalence of

PAD in group with any cognitive impairment

(in model controlling for sex, duration of diabetes, and stroke) and in group with dementia

(in model controlling for age, sex, and duration of diabetes).

Prospective analyses: cerebrovascul ar disease

(unadjusted analysis) and

PAD (model controlling for age, sex, duration of

diabetes, and

waist-hip

ratio) 8 years

earlier both

associated

with poorer

cognitive

outcome. No

findings for

CHD. Bruce et Patients with 8-year 205 Mean Cerebrovascular Dementia and None No al. [21] type 2 retrospectiv 75 ± 4 disease and MCI identified association.

(2008) diabetes e, 2-year years peripheral arterial from screening

participating prospective, disease assessed 8 instruments/clinic

in the observation years prior to al interview at

Fremantle al baseline cognitive baseline and at 2- Diabetes assessment year follow-up.

Study; ‘Cognitive

Australia decline’ defined

as downward

conversion

between

‘normal’, MCI,

and dementia. Chen et al. Patients with Cross- 101 Mean ABI and cIMT MCI identified on None Lower ABI

[9] (2011) type 2 sectional, 63 ± 8 the basis of and higher

diabetes; observation years screening cIMT in

China al instrument group with

compared

with group

free of MCI. Chen et al. Patients with Cross- 157 Mean cIMT MCI identified on None Higher cIMT

[11] type 2 sectional, 55 ± 7 the basis of in group with (2012) diabetes; observation years cognitive MCI

China al screening compared

instrument with group

free of MCI.

Inverse

correlation

between

cognitive

scores and

cIMT. Cukierma Patients with Cross- 2,977 Mean Stroke, ‘CVD’ Digit Symbol Age Association of n-Yaffe type 2 sectional 63 ± 6 (stroke, MI, angina Coding (primary stroke with et al. [13] diabetes analysis of years with ischemic outcome), lower

(2009) participating trial on changes, and MMSE, Rey cognitive

in ACCORD- blood coronary Auditory Verbal function.

MIND; pressure, procedure) Learning, and Association of

North lipids, and Stroop CVD (without America glycemic (secondary stroke) with

control outcomes) lower verbal

memory but

higher MMSE

scores. de Galan Patients with 5-year 11,140 Mean Stroke, MI, major At baseline and Age, sex, Cross- et al. [35] type 2 prospective 66 ± 6 coronary event 2-year intervals: education, sectional,

(2009) diabetes trial on years (non-fatal MI, MMSE followed and unadjusted

participating effects of death from by clinical treatment analyses:

in ADVANCE intensified coronary event), interview for allocation association of

arm on blood and major CVD patients with stroke and

glycemic pressure event (MI, stroke, MMSE <24 or major CVD

control; control and and cardiovascular suspected event with

Australia intensified death) during dementia. lower

glycemic follow-up ‘Normal’ cognitive

control cognitive function. No

function defined finding for as MMSE ≥28; MI.

‘mild Prospective dysfunction’ as analyses

MMSE = 24-27; (adjusted):

‘severe baseline mild dysfunction’ as and severe

MMSE <24. impairment

Additional use of (versus

MMSE as unimpaired) continuous associated measure. with increased

risk of major

CVD event,

stroke, and

coronary

event during follow-up.

Lower MMSE

at baseline

associated

with increased

risk of major

CVD event. Feinkohl Patients with 4-year 1,066 Mean MI, stroke, angina, MMSE, Age, sex, Cross- et al. [51] type 2 prospective, 68 ± 4 ABI, and cIMT at composite score cholestero sectional

(2013) diabetes observation years baseline from seven l, blood analyses:

participating al cognitive tests, pressure, stroke,

in the and estimate of smoking, angina, and

Edinburgh pre-morbid and MI associated

Type 2 ability estimated with lower

Diabetes pre- cognitive

Study; morbid function.

Scotland ability Prospective analyses:

stroke, higher

cIMT, and

lower ABI

associated

with increased

late-life

cognitive

decline and

increased

estimated

lifetime

decline. Manschot Patients with Cross- 122 Mean ‘Any Composite scores Age, sex, Association of et al. [20] type 2 sectional, 66 ± 6 macrovascular on five cognitive and infarcts with

(2006) diabetes observation years event’ defined as domains from 11 estimated steeper

participating al MI, stroke, or cognitive tests, pre- estimated in the Utrecht surgery/endovascul estimate of pre- morbid lifetime

Diabetic ar treatment for morbid ability, ability decline in

Encephalopat coronary, carotid cortical atrophy, processing

hy Study; or peripheral and white matter speed.

The arterial disease. lesions Association of

Netherlands Cerebral infarcts any

on MRI. macrovascular

event with

steeper

estimated

lifetime

decline in

processing

speed and

memory. Manschot Patients with Cross- 122 Mean ‘Any Composite score Age, sex, ‘Any et al. [25] type 2 sectional, 66 ± 6 macrovascular from 11 cognitive and macrovascular (2007) diabetes observation years event’ (MI, stroke, tests, estimate of estimated event’ and

participating al and pre-morbid pre- infarcts both

in the Utrecht surgery/endovascul ability, cortical morbid associated

Diabetic ar treatment for atrophy, and ability with steeper

Encephalopat coronary, carotid, white matter estimated

hy Study; or peripheral lesions lifetime

The arterial disease) cognitive

Netherlands and cerebral decline.

infarcts on MRI. Finding on

Measurement of ‘any vascular

cIMT. event’

attenuated

following

exclusion of

patients with

stroke. For

‘any vascular event’, but not

infarcts,

association

persisted in

final model

adjusting for

age, estimated

pre-morbid

ability,

hypertension,

smoking, and

lipid-lowering

drugs. No

finding for

cIMT. ABI, ankle brachial index; ACCORD-MIND, Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes; ADVANCE,

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; CHD, coronary heart disease; cIMT, carotid intima-media thickness; CVD, cardiovascular disease; ECG, electrocardiogram; MCI, mild cognitive impairment; MI, myocardial infarction; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; PAD, peripheral arterial disease; TIA, transient ischemic attack. {2 Column Table}

Table S4. Studies of natriuretic peptides and cognitive function in the general population and in type 2 diabetes

Study Sample Design Number Baseli Natriuretic Cognitiv Adjustment Association

ne peptide e variables with

mean measures cognitive

age function Daniels et Rancho Cross-sectional, 950 Mean NT-proBNP, MMSE, Age, sex, ‘High’ NT- al. [52] Bernardo observational 77 ± 8 categorized as Trail- education, proBNP

(2011) Study; USA years ‘high’ (≥450 Making hypertension, group likely

pg/mL) versus Test, and body mass to score low

‘low’ (<450 Category index, exercise, on MMSE

pg/mL) and Fluency. alcohol, and Trail-

additionally as ‘Low’ smoking, Making

quartiles of the performa cholesterol, and compared

distribution nce on creatinine with ‘low’

each group.

defined Findings as similar when

MMSE excluding

≤24, participants

Trail- with stroke

Making and

≥300 cardiovascul seconds, ar disease. and Findings for

Category Category

Fluency Fluency

≤12 restricted to words. largely

Cognitiv unadjusted e tests analyses. additiona Additionally lly used increased as prevalence quartiles of scoring in

of lower

respectiv quartiles of

e cognitive

distributi scores with

on. increasing

quartiles of

NT-proBNP

(unadjusted

analyses). Feinkohl et Patients with 4-year 1,066 Mean NT-proBNP at MMSE, Age, sex, Association al. [51] type 2 prospective, 68 ± 4 baseline composit cholesterol, of higher

(2013) diabetes observational years e score blood pressure, baseline NT-

participating from and smoking proBNP

in the seven with steeper

Edinburgh cognitive late-life

Type 2 tests, and cognitive Diabetes estimate decline and

Study; of pre- steeper

Scotland morbid estimated

ability lifetime

decline.

Finding on

4-year

decline lost

statistical

significance

controlled

estimated

pre-morbid

ability or for

stroke, cIMT, and

ABI. Kerola et Kuopio 75+ 5-year 464 Mean BNP at baseline Diagnosi Age, education, Association al. cohort; prospective, 80 ± 4 s of AD, and of higher

[53] (2010) Finland observational years VaD, and hypertension BNP with

MMSE lower

MMSE and

with steeper

decline on

(unadjusted

analyses).

Association

of higher

BNP and

increased

risk of AD and VaD

diagnosis

during

follow-up

(adjusted

analyses). Hiltunen et Kuopio 75+ 5-year 601 Range BNP at baseline Diagnosi Cross-sectional Presence of al. cohort; prospective, 75-96 s of analyses: age, any

[54] (2013) Finland observational years dementia sex, dementia

medication, associated

heart failure, with higher

and blood BNP in

pressure. youngest

Prospective tertile and

analyses: age, lower BNP

education, and in oldest

hypertension. tertile. Higher

baseline

associated

increased

risk of

dementia

during

follow-up in

youngest

tertile only. Tynkkynen National 14-year 7,158 Mean NT-proBNP at Medical Age, sex, Higher et al. [56] FINRISK prospective, 48 ± baseline records cholesterol, baseline NT-

(2015) Study; observational 13 for body mass proBNP

Finland years diagnosis index, ischemic associated

(range with any heart disease, with 25 to dementia and diabetes increased

74) or AD, or risk of any

dementia incident

medicati dementia

on across all

participants.

Finding

driven by

males. No

finding on

incident AD. Vaes et al. Leiden 85+ Cross-sectional, 274 All 90 NT-proBNP MMSE. Height, weight, No

[55] (2009) cohort; observational years categorized ‘Poor renal function, association.

The old according to sex- cognitive hemoglobin,

Netherlands specific tertiles of function’ and

distribution defined cardiovascular

as medication MMSE

<19. ABI, ankle-brachial index; AD, Alzheimer’s disease; BNP, brain natriuretic peptide; cIMT, carotid intima-media thickness; FINRISK,

Finland Cardiovascular Risk Study; MMSE, Mini-Mental State Examination; NT-proBNP, N-terminal pro-brain natriuretic peptide;

VaD, vascular dementia. {2 Column Table}

Table S5. Studies of depression and cognitive function in type 2 diabetes

Study Sample Design Nu Baselin Measuremen Cognitive measures Adjust Association with

m e mean t of ment cognitive function

be age depression variabl

r es Cukierma Patients Cross-sectional 2, Mean Scores ≥10 Digit Symbol Coding Age Association of n-Yaffe with type 2 analysis of trial 97 63 ± 6 on 9-item (primary outcome), depression with et al. [13] diabetes on blood 7 years Patient MMSE, Rey Auditory lower MMSE

(2009) participatin pressure, lipids, Health Verbal Learning, and scores. No

g in and glycemic Questionnair Stroop (secondary findings for other

ACCORD- control e or self- outcomes) cognitive tests.

MIND; reported

North depression

America Katon et Patients 3- to 5-year 19 Range ICD codes ICD codes for dementia in Sociod Co-morbid al. [60] with type 2 retrospective, ,0 30-75 for diagnosis hospital records, restricted emogra depression/diabet

(2012) diabetes observational 00 years of to incident cases occurring phic es associated with participatin depression/u 3 to 5 years after baseline factors, increased risk of

g in the se of anti- clinical dementia

Diabetes depressants risk diagnosis

and Aging in hospital factors, compared with

Study; records health diabetes alone.

USA risk

factors,

health

use Sullivan Patients 40-month trial 2, Mean Scores ≥10 Digit Symbol Coding Age, Association of et al. [61] with type 2 on blood 97 age 63 on 9-item (primary outcome), sex, depression at

(2013) diabetes pressure, lipids, 7 ± 6 Patient MMSE, Rey Auditory ethnicit baseline with

participatin and glycemic years Health Verbal Learning, and y, steeper cognitive

g in control Questionnair Stroop (secondary educati decline across

ACCORD- e at baseline outcomes) at baseline and on, cognitive tests.

MIND; 20 and 40 months glycem North ia

America treatme

nt arm,

pressur

versus

treatme

nt arm,

pressur

treatme

treatme nt, clinical center, cardiov ascular event, body mass index,

, cholest erol, smokin g, alcohol

, and insulin

use Trento et Patients Cross-sectional, 49 Mean Zung Self- MMSE Age, Statistically non- al. [58] with 2 observational 8 68 ± 7 Rating sex, significant trend

(2012) diabetes; years Depression duratio for association of

Italy Questionnair n of higher depression

e diabete scores with lower

s, MMSE scores

insulin

use Watari et Patients Cross-sectional, 40 Range Clinical MMSE, 12 cognitive tests Age, Statistically non- al. [59] with type 2 observational 30-80 interview to resulting in composite sex, significant trend

(2006) diabetes; years. diagnose scores of and for lower overall

USA Mean depression attention/processing speed, educati cognitive function

60 ± 12 memory, executive on and statistically

years. function, verbal memory, significant lower and non-verbal memory attention/processi

ng speed in co-

morbid

depression/diabet

es group than in

depression/diabet

es group. ACCORD, Action to Control Cardiovascular Risk in Diabetes; ACCORD-MIND, ACCORD-MIND, Action to Control

Cardiovascular Risk in Diabetes-Memory in Diabetes; ICD, International Classification of Diseases; MMSE, Mini-Mental State

Examination.