Journals of Gerontology: Medical Sciences

cite as: J Gerontol A Biol Sci Med Sci, 2021, Vol. 76, No. 11, 2062–2070
https://doi.org/10.1093/gerona/glab221
Advance Access publication July 31, 2021

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Research Article

Influence of Diabetes Duration and Glycemic Control on

Dementia: A Cohort Study
Fu-Rong  Li, PhD,1,# Hai-Lian  Yang, MD,1,# Rui  Zhou, MD,1 Jia-Zhen  Zheng, MD,1
Guo-Chong  Chen, PhD,2 Xiao-Xiang  Wu, MD,3 Meng-Chen  Zou, MD,4 Jing-Ya  Wang,
PhD,5 Qiang Fu, PhD,6 and Xian-Bo Wu, PhD1,*
1
Department of Epidemiology, School of Public Health (Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical
University, Guangzhou, China. 2Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA.
3
Department of General Surgery, 157th Hospital, General Hospital of Guangzhou Military Command, China. 4Department of Endocrinology and
Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China. 5Institute of Applied Health Research, University of Birmingham,
UK. 6Department of Epidemiology and Biostatistics, College for Public Health and Social Justice, Saint Louis University, Missouri, USA.

*Address correspondence to: Xian-Bo Wu, PhD, Department of Epidemiology, School of Public Health (Guangdong Provincial Key Laboratory of
Tropical Disease Research), Southern Medical University, Guangzhou, Guangdong, 510515, China. E-mail: wuxb1010@smu.edu.cn

These authors contributed equally to this work.

#

Received: January 20, 2021; Editorial Decision Date: July 25, 2021

Decision Editor: Lewis A. Lipsitz, MD, FGSA

Abstract
Background:  To investigate the influence of diabetes duration and glycemic control, assessed by glycated hemoglobin (HbA1c) levels, on risk
of incident dementia.
Methods:  The present study is a prospective study of 461 563 participants from the UK Biobank. The age at diabetes diagnosis was determined
by self-report. Diabetes duration was calculated as baseline age minus age at diagnosis. Cox proportional hazards regression models were used
to estimate hazard ratios (HRs) with 95% confidential intervals (CIs).
Results:  During a median follow-up of 8.1  years, 2  233 dementia cases were recorded. As compared with normoglycemic individuals,
individuals with diabetes had higher risk of all-cause dementia, and the risk increased with increasing duration of diabetes; compared with
participants with diabetes duration of <5 years, the multivariable-adjusted HRs (95% CIs) were 1.49 (1.12–1.97), 1.71 (1.21–2.41), and 2.15
(1.60–2.90) for those with diabetes durations ≥5 to < 10, ≥10 to <15, and ≥ 15 years, respectively (p for trend < .001). Among participants with
diabetes, those with both longer diabetes duration (diabetes duration ≥ 10 years) and poor glycemic control (HbA1c ≥ 8%) had the highest
risk of all-cause dementia (multivariable-adjusted HR = 2.07, 95% CI 1.45, 2.94), compared with patients with shorter duration of diabetes
and better glycemic control (diabetes duration < 10 years and HbA1c < 8%).
Conclusions:  Diabetes duration appeared to be associated with the risk of incident dementia due to factors beyond glycemic control. Clinicians
should consider not only glycemic control but also diabetes duration in dementia risk assessments for patients with diabetes.
Keywords:  Dementia, Diabetes duration, Glycemic control

It has been recognized that diabetes, as an uncontrolled state of
hyperglycemia, is associated with changes in cognition, and it is
believed to be an important contributor to the development of de-
mentia (1).
With improvements in the interventions to prevent and treat
classic complications of diabetes, people with diabetes are living
longer. This trend means that novel complications associated with
© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
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aging, such as dementia, could start to emerge. Currently, diabetes
guidelines rank diabetes duration over and beyond the simple pres-
ence of diabetes (2) and recommend that the disease duration be
considered in clinical practice (3,4); as a result, many studies sug-
gest that glycemic control targets be tailored according to disease
duration (5). Indeed, the etiology of dementia in diabetic patients
is multifactorial (6), and all of the putative mechanisms underlying
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Journals of Gerontology: MEDICAL SCIENCES, 2021, Vol. 76, No. 11
the detrimental effects of diabetes require time to accrue. Prior epi-
demiological studies conducted in different populations have con-
sistently demonstrated that diabetes increases the risk of dementia
(1,7,8). There have, however, been far fewer studies examining the
independent influences of diabetes duration and glycemic control on
the development of dementia (9,10). Thus, larger prospective studies
are needed to better understand the relationship between the time
course of diabetes and dementia risk, which is of clinical importance
for stratifying high-risk participants by their glycemic control levels.
Therefore, we conducted the present analysis using a large
population-based sample of middle-aged and older men and women
with and without diabetes in the UK. We hypothesized that not only
glycemic control but also diabetes duration are associated with risk
of dementia.
Materials and Methods
Design, Study Setting, and Participants
The UK Biobank, a national long-term prospective cohort, com-
prises approximately 500 000 participants aged 40–69 years regis-
tered with the National Health Service (NHS) in the UK. Between
2006 and 2010, participants who agreed to take part in the UK
Biobank visited 1 of 22 assessment centers across England, Wales,
and Scotland for baseline assessments (11,12). The information
collected from the participants included sociodemographic data,
anthropometric measurements, lifestyle, and clinical factors. In the
present study, we excluded participants who: (i) were diabetic pa-
tients for whom data on the age at diabetes diagnosis were missing
(n  =  3  564), (ii) had missing information on glycated hemoglobin
(HbA1c) levels (n = 34 980); (iii) had a history of dementia at base-
line (n  =  224), (iv) withdrew from the study (n  =  12), or (v) were
lost to follow-up (participants who had baseline data but the health
outcome data were not available, n = 2 164). After the above exclu-
sions, the final analytic sample consisted of 461  563 participants
(Supplementary Figure S1).
The UK Biobank study was approved by the North West Multi-
Centre Research Ethics Committee, and all participants provided
written informed consent to participate in the UK Biobank cohort.
Details of the UK Biobank are available elsewhere (13).
Exposures
In the UK Biobank study, biochemical measures such as HbA1c
levels (VARIANT II TURBO Hemoglobin Testing System; Bio-Rad)
were taken at a dedicated central laboratory. Data were centrally ad-
justed by the UK Biobank before release. The blood collection sam-
pling procedures used for the study have previously been described
and validated (14).
We defined diabetes status as a composite of self-reported diag-
nosed diabetes, self-reported use of diabetes medication, or an
HbA1c level of ≥6.5% (48 mmol/mol). Self-reported age at diabetes
onset was collected by the question “What was your age when the
diabetes was first diagnosed?.” Diabetes duration was calculated as
baseline age minus age at diagnosis. Participants without known
diabetes but with an HbA1c level exceeding the threshold for dia-
betes (≥6.5%, 48  mmol/mol) at baseline were assigned a duration
of 0 year (n = 3 254); in an exploratory analysis, these participants
were grouped into a new category termed “undiagnosed diabetes.”
As HbA1c levels indicate average blood glucose concentrations over
the preceding 3  months (15), this biomarker was used as a stable
proxy for glycemic control.
2063
Covariates
The UK Biobank study used a baseline touch screen questionnaire
to collect information on the following potential confounders:
sociodemographic information (age, sex, ethnicity); area-based so-
cial deprivation (Townsend score; a higher score indicates areas with
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more material deprivation); lifestyle (smoking, physical activity); and
self-reported medical conditions (use of medications to treat high
cholesterol or hypertension and insulin use). Blood samples were
also collected and analyzed at a central laboratory, including cre-
atinine and lipids. Serum and urine creatinine were measured using
an enzymatic (creatinase), Isotope Dilution Mass Spectrometry-
traceable, method on a Beckman Coulter AU5400 instrument. Urine
microalbumin was measured by an immunoturbidimetric method
using reagents and calibrators sourced from Randox Bioscience.
Baseline microvascular disease was defined as a composite of retin-
opathy, peripheral neuropathy, and chronic kidney disease (CKD),
using the ICD definitions reported by a previous study of UK
Biobank (16). Estimated glomerular filtration rate was calculated by
CKD–epidemiology using serum creatinine, and an estimated glom-
erular filtration rate of <60 mL/min/1.73 m2, as well as albuminuria
(urinary albumin-to-creatinine ratio) ≥ 3  mg/mmol were also used
to define prevalent CKD (17). Baseline macrovascular disease was
defined as a composite of self-reported history of myocardial infarc-
tion, stroke, or angina as well as hospital diagnoses that included
ICD-10 codes I20–24, I63–64, and G45. Major lipids were quantified
using standard procedures. Body mass index (BMI) was calculated
as weight in kilograms divided by height in meters squared (kg/m2).
Type 1 diabetes was defined as a self-reported history of the disease,
or by an age at onset of diabetes of <40 years with insulin treatment
initiation within 1 year of diagnosis, and type 2 diabetes otherwise.
Single-nucleotide polymorphism data for rs429358 and rs7412 were
used to determine apolipoprotein E (APOE) genotype (18), and par-
ticipants were coded as APOE e4 carriers or noncarriers.
Outcomes
Dementia was identified as a primary/secondary diagnosis (based on
hospital records) or underlying/contributory cause of death (in the
death register) using ICD-9 and ICD-10 codes for Alzheimer’s disease,
vascular dementia, and frontotemporal dementia (Supplementary
Table S1). In our study, the primary outcome was all-cause dementia,
and the secondary outcomes were Alzheimer’s disease and vascular
dementia. We did not explore the associations for frontotemporal
dementia due to the limited number of incident cases (n  =  94).
Participants were considered at risk for dementia starting at baseline
and were followed until the date of first diagnosis, death, or the last
hospital admission date (March 31, 2017, for England, and February
10, 2017, for Scotland and Wales), whichever occurred first.
Statistical Analysis
Continuous variables are described using means and standard devi-
ations (SDs), and categorical variables are described using percent-
ages according to diabetes status, and duration of diabetes or HbA1c
levels at baseline. We applied multivariable Cox regression models to
estimate the hazard ratios (HRs) and 95% confidence intervals (CIs)
for incident dementia, adjusting for potential confounders, using age
as the underlying time scale. Missing values accounted for <2.5%
of all the covariates, except for education (18.2%). Participants
with missing values for any of the adjusted variables were assigned
to a separate “unknown” category for that variable. Two models
were used to estimate the associations. Model 1 was adjusted for
2064 Journals of Gerontology: MEDICAL SCIENCES, 2021, Vol. 76, No. 11

age and sex. Model 2 was further adjusted for ethnicity (White or
non-White), Townsend score (in quintiles), education (college or uni-
versity degree, A/AS levels or equivalent, O levels/GCSEs or equiva-
lent, CSEs or equivalent, NVQ or HND or HNC or equivalent,
or other professional qualifications), BMI (in quintiles), smoking
(current, former, or never), macrovascular disease, microvascular
For participants with diabetes, subgroup analysis was conducted
within different stratum, based on glycemic control levels (HbA1c
<7% or ≥7%), age (<65 years or ≥65 years), sex, BMI (<30 kg/m2 or
≥30 kg/m2), ever smoker (yes or no), with macrovascular disease (yes
or no), with microvascular disease (yes or no), and with the APOE e4
allele (yes or no). To explore potential factors that may explain the

disease, antihypertensive medication use, cholesterol-lowering medi-
cation use, and APOE status. Diabetes duration and HbA1c levels
were also further mutually adjusted for in the exploratory analysis.
Participants without diabetes were categorized into normogly-
cemic (HbA1c <5.7% [39.0  mmol/mol]) and prediabetes (≥5.7 to
<6.5% [≥39.0 to <48.0 mmol/mol]) groups. Those with known dia-
betes were subdivided by diabetes duration (<5, ≥5 to <10, ≥10 to
<15, ≥15  years) or HbA1c levels (<7.0%, ≥7.0 to <7.5%, ≥7.5 to
<8.0%, and ≥ 8.0% [<53.0, ≥53.0 to <58.5, ≥58.5 to <64.0, and
≥64.0  mmol/mol]). We also explored the combined effects of dia-
betes duration and glycemic control on each outcome. Specifically,
participants with known diabetes were categorized into 4 groups
based on a combination of diabetes duration (<10 years, ≥10 years)
and glycemic control level (HbA1c < 8.0% or HbA1c ≥ 8.0%). Tests
of linear trends were conducted by treating the median values for
each category as a continuous variable. We used Cox models with
penalized splines to present the associations of diabetes duration and
HbA1c levels with dementia on a continuous scale (19). The optimal
degree of freedom (df) was determined as follows: for each outcome,
we fit models with 3, 4, 5, 6, and 7 df, and for each of these we
calculated the Akaike Information Criterion (AIC, which balances
model fit against parsimony); the number of knots resulting in the
minimum AIC was then chosen. For models with the same AIC, we
opted to use the one with the smallest df. Details of the df and AIC
values for model selection are presented in Supplementary Table S2.
The improvement in dementia risk reclassification and discrimin-
ation with HbA1c and diabetes duration was assessed by computing
change in Harrell’s C-index, continuous net reclassification improve-
ment, and integrated discrimination index. The baseline model for
these analyses consisted of covariates used in Model 2.
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associations between diabetes duration and dementia risk, a series
of sensitivity analyses were conducted for the primary outcome by
additionally adjusting for insulin use, levels of plasma C-reactive
protein, total cholesterol, and physical activity (summed metabolic
equivalents of energy per week for all activity). We also excluded
participants with missing data for covariates, those who had de-
veloped all-cause dementia within the first 5 years of follow-up, or
those who had type 1 diabetes, aiming to test the robustness of the
results.
All analyses were performed using Stata/SE 14.2 (StataCorp LP,
College Station, TX) or R software (version 4.0.1), and p values
< .05 were considered statistically significant.
Results
Baseline Characteristics
The analytic sample comprised 461  563 individuals who were
free from dementia at baseline. A total of 2 233 participants were
diagnosed with dementia during a median follow-up period of
8.1  years. Of the participants, 81.4% had normoglycemia, 13.0%
had prediabetes. A total of 25 879 (5.6%) participants had diabetes
at baseline and were included in the duration analysis: 56.4% had
a duration of <5 years, 21.3% had a duration of ≥5 to <10 years,
9.2% had a duration of ≥10 to <15 years, and 13.1% had a duration
of ≥15 years at baseline; the corresponding mean ages for the above
duration categories were 59.2, 60.6, 60.9, and 60.0, respectively.
Compared with individuals who had normoglycemia, those with
diabetes tended to be older, non-White, male, current smokers and
to have a higher Townsend score, BMI. A history of macrovascular
disease or microvascular disease was more common among

Table 1.  Baseline Characteristics of Participants According to Diabetes Status and Diabetes Duration

Without Diabetes Diabetes, by Duration (y)

Baseline Characteristics Normoglycemic Prediabetes <5 y ≥5 to <10 y ≥10 to <15 y ≥15 y

No. of participants 375 545 60 139 14 601 5 507 2 382 3 389

HbA1c, mmol/mol 34.0 (3.0) 41.1 (1.9) 52.1 (14.7) 54.2 (13.5) 57.5 (15.0) 59.2 (14.7)
Age, y 55.8 (8.2) 59.6 (7.0) 59.2 (7.1) 60.6 (6.7) 60.9 (6.7) 60.0 (7.6)
Age at diabetes onset, y NA NA 57.3 (7.2) 52.8 (6.8) 48.2 (6.8) 30.2 (14.6)
Men, % 44.7 45.4 61.6 66.5 67.5 64.7
White, % 95.9 90.0 87.9 87.6 86.0 86.5
Townsend score −1.5 (3.0) −1.0 (3.2) −0.5 (3.4) −0.6 (3.4) −0.4 (3.4) −0.3 (3.4)
Education level (college or university), % 34.0 25.7 22.9 23.1 23.6 25.6
Body mass index, kg/m2 26.9 (4.4) 28.9 (5.2) 31.7 (5.8) 31.7 (5.7) 31.6 (6.0) 29.8 (5.9)
Current smoker, % 9.6 15.6 12.1 10.5 10.4 10.5
Macrovascular disease, % 4.2 10.2 15.9 20.6 21.9 22.7
Microvascular disease, % 8.1 15.1 25.6 32.3 37.8 43.2
Type 1 diabetes, % NA NA 0.5 1.7 4.9 37.5
Insulin use, % NA NA 3.3 11.3 22.7 60.8
Hypertensive medication use, % 16.4 30.3 55.0 69.3 70.8 34.5
Cholesterol-lowering medication use, % 12.0 27.3 63.5 80.5 80.4 76.3
APOE carrier, % 22.1 20.8 19.9 20.2 21.0 19.7

Notes: Continuous variables are described as means (standard deviations), and categorical variables are described as percentages. The summary of the baseline
characteristics are provided in the Results section. APOE = apolipoprotein E; HbA1c = glycated hemoglobin.
Journals of Gerontology: MEDICAL SCIENCES, 2021, Vol. 76, No. 11
participants with diabetes than among those without diabetes; those
with diabetes were more likely to be taking antihypertensive medi-
cation and cholesterol-lowering medication. In addition, among
participants with diabetes, a longer duration of diabetes was not
associated with older age but was associated with younger age
at diabetes onset, worse glycemic control (higher HbA1c level)
(Table 1) and a higher prevalence of insulin use, type 1 diabetes,
macrovascular disease, and microvascular disease. Characteristics by
diabetes status, HbA1c levels and participants’ inclusion status are
also presented in Supplementary Tables S3 and S4.
Diabetes Duration and Dementia
Compared with those with normoglycemia, participants with
prediabetes did not have a higher risk of all-cause dementia, whereas
those with long-standing diabetes had an elevated risk of all-cause de-
mentia (Table 2). Compared with participants with a diabetes duration
of <5 years, the fully adjusted HR (95% CI) for dementia associated
with diabetes duration was 1.49 (1.12, 1.98) for a diabetes duration of
≥5 to < 10 years, 1.72 (1.22, 2.43) for ≥10 to <15 years, and 2.18 (1.63,
2.92) for ≥15 years (p-trend < .001). These associations remained when
baseline HbA1c levels were further adjusted for (p-trend < .001). We
also observed that longer diabetes duration was significantly associ-
ated with higher risks of Alzheimer’s disease and especially vascular
dementia (both p-trend < .05; Table 2). When diabetes duration was
modeled continuously, the all-cause dementia risk increased steeply ini-
tially and then plateaued (Figure 1); these patterns were also seen for
Alzheimer’s disease and vascular dementia (Supplementary Figure S2).
Glycemic Control and Dementia
Participants with higher levels of HbA1c had a greater all-cause
dementia risk than their normoglycemic counterparts (Table 3).
Among participants with diabetes, the adjusted HRs (95% CI)
for incident all-cause dementia were 1.05 (0.77, 1.43) for ≥7.0 to
<7.5%, 1.13 (0.78, 1.64) for ≥7.5% to <8.0%, and 1.26 (1.01,
1.69) for ≥8.0% (p-trend = .043), compared with those with HbA1c
levels of <7.0%. Of note, HbA1c levels were no longer signifi-
cantly associated with incident all-cause dementia after adjustment
for diabetes duration (HRhighest versus lowest = 1.18; 95% CI 0.88, 1.59;
p-trend = .230). Regarding dementia subtypes, similar trends were
also noted (p-trend = .046 for Alzheimer’s disease, p-trend = .004 for
vascular dementia; Table 3). Further adjustment for diabetes dur-
ation yielded a borderline significant result for Alzheimer’s disease
(p-trend  =  .080), while the association for vascular dementia re-
mained significant (p-trend = .015), although the magnitude of the
associations was attenuated. Among participants with diabetes, the
associations between HbA1c and dementia were generally linear
when plotted them on a continuous scale (Supplementary Figure S3).
We also found that the relationship between HbA1c and dementia
risk was graded across the range of HbA1c levels observed when
HbA1c level was defined merely as normal, prediabetic, or diabetic;
namely, dementia risk increased over the entire range of HbA1c.
Evaluating the risk for each 10 mmol/mol increase in HbA1c yielded
adjusted HRs (95%) of 1.11 (1.08, 1.14), 1.12 (1.06, 1.18), and 1.14
(1.10, 1.18) for all-cause dementia, Alzheimer’s disease, and vascular
dementia, respectively (Supplementary Figure S4).
Exploratory Analysis, Subgroup Analysis, and
Sensitivity Analysis
In an exploratory analysis, participants without known diabetes but
with an HbA1c level exceeding the threshold for diabetes (≥6.5%,
2065
48 mmol/mol) were grouped into a new category termed “undiag-
nosed diabetes”; compared with participants with normoglycemia,
those with undiagnosed diabetes did not have higher risks of all out-
comes (Supplementary Table S5). Among participants with diabetes,
those who had both longer diabetes duration (diabetes duration ≥
10 years) and poor glycemic control (HbA1c ≥ 8%) had the highest
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risks of all outcomes (all-cause dementia: HR = 2.07, 95% CI 1.45,
2.94; Alzheimer’s disease: HR = 2.53, 95% CI 1.43, 4.46; vascular
dementia: HR = 3.07, 95% CI 1.78, 5.31), compared with patients
with shorter duration of diabetes and better glycemic control (dia-
betes duration < 10 years and HbA1c < 8%) (Figure 2). For partici-
pants with diabetes, the addition of diabetes duration yielded better
improvement of the C-index than the addition of HbA1c did for
all-cause dementia. This pattern of improvement was also found for
vascular dementia but not for Alzheimer’s disease (Supplementary
Figure S5). Adding diabetes duration but not HbA1c resulted in in-
creases in overall net reclassification improvement and integrated
discrimination index for both all-cause dementia and vascular de-
mentia, yet no significant results were found for Alzheimer’s disease
(Supplementary Table S6). We conducted subgroup analyses of the
associations of each 5-year increase in diabetes duration with all-
cause dementia based on predefined subgroups; all of the interaction
terms had p values > .05 (Supplementary Figure S6). Supplementary
Table S7 shows the sensitivity analyses for the adjusted HRs of in-
cident all-cause dementia risk associated with diabetes duration
among participants with diabetes. Specifically, further adjustment
for insulin use, plasma levels of C-reactive protein, total cholesterol,
physical activity, and age at diabetes onset did not materially change
the results; we also found similar results after excluding individuals
with missing covariates, had type 1 diabetes, or those who developed
dementia during the first 5 years of follow-up.
Discussion
In this prospective study of 461  563 UK participants with and
without diabetes, we found that diabetes duration was associated
with the risk of dementia, and that diabetes duration had a linear re-
lationship with all-cause dementia risk. In addition, regardless of gly-
cemic control status (HbA1c levels), a longer diabetes duration was
consistently associated with a higher dementia risk; notably, individ-
uals with both longer diabetes duration and poorer glycemic control
had the highest risks of all the outcomes, compared with those with
shorter disease duration and better glycemic control. Among partici-
pants with diabetes, the associations between diabetes duration and
all-cause dementia did not differ across different subgroups, and the
results were unchanged after a series of sensitivity analyses.
Previous studies have demonstrated that diabetes predicts an
increased incidence of dementia. For example, a meta-analysis of
144 prospective studies found that diabetes conferred a 1.91-fold
excess risk for dementia (8). Another Canadian study of 225  045
older adults showed that those with diabetes had a 16% increased
risk of dementia (20) relative to those without diabetes. However,
less attention has been given to the role of diabetes duration in
previous publications. A  small prospective study of 5  099 partici-
pants from the Atherosclerosis Risk in Communities study found
that longer diabetes durations were associated with dementia risk
among diabetic individuals (n = 1 675) during a 5-year follow-up
(9). Unfortunately, that study did not examine whether the link be-
tween diabetes duration and dementia was affected by glycemic con-
trol level, and further exploration by dementia subtype was lacking,
partly due to the relatively small sample size. In a twin study of
Table 2.  Hazard Ratios and 95% CIs for the Associations Between Diabetes Duration and Risk of Incident Dementia
2066

Without Diabetes Diabetes, by Duration

Normoglycemic Prediabetes <5 y ≥5 to <10 y ≥10 to <15 y ≥15 y

All-cause dementia
  No. of events 1 520 377 122 84 47 83
 Person-years 3 028 622 477 577 114 872 42 903 18 322 25 903
  All participants
  Model 1 Reference (1.00) 1.07 (0.95, 1.20) 1.46 (1.21, 1.75) 2.26 (1.81, 2.82) 2.87 (2.15, 3.84) 3.89 (3.12, 4.86)
  Model 2 Reference (1.00) 0.97 (0.86, 1.09) 1.23 (1.01, 1.49) 1.79 (1.42, 2.25) 2.09 (1.55, 2.83) 2.67 (2.11, 3.38)
  Participants with diabetes p for trend
  Model 1 NA NA Reference (1.00) 1.58 (1.20, 2.09) 2.02 (1.44, 2.83) 2.76 (2.08, 3.65) <.001
  Model 2 NA NA Reference (1.00) 1.49 (1.12, 1.98) 1.72 (1.22, 2.43) 2.18 (1.63, 2.92) <.001
   Model 2 + HbA1c NA NA Reference (1.00) 1.48 (1.12, 1.97) 1.71 (1.21, 2.41) 2.15 (1.60, 2.90) <.001
Alzheimer’s disease
  No. of events 588 137 36 29 14 24
 Person-years 3 285 497 518 693 124 769 46 528 19 881 28 121
  All participants
  Model 1 Reference (1.00) 0.98 (0.81, 1.18) 1.27 (0.93, 1.75) 2.01 (1.38, 2.93) 2.22 (1.30, 3.77) 2.91 (1.93, 4.38)
  Model 2 Reference (1.00) 0.94 (0.79, 1.14) 1.20 (0.86, 1.67) 1.80 (1.22, 2.66) 1.80 (1.04, 3.10) 2.26 (1.47, 3.47)
  Participants with diabetes p for trend
  Model 1 NA NA Reference (1.00) 1.64 (1.02, 2.64) 1.82 (0.99, 3.34) 2.39 (1.44, 3.97) .001
  Model 2 NA NA Reference (1.00) 1.52 (0.94, 2.47) 1.43 (0.77, 2.67) 1.72 (1.09, 2.91) .009
   Model 2 + HbA1c NA NA Reference (1.00) 1.49 (0.92, 2.42) 1.37 (0.73, 2.55) 1.59 (1.02, 2.11) .020
Vascular dementia
  No. of events 266 88 34 27 21 33
 Person-years 3 309 400 521 874 125 438 46 797 19 964 28 250
  All participants
  Model 1 Reference (1.00) 1.40 (1.10, 1.78) 2.46 (1.75, 3.46) 3.79 (2.55, 5.65) 6.69 (4.28, 10.46) 8.05 (5.59, 11.59)
  Model 2 Reference (1.00) 1.15 (0.89, 1.47) 1.70 (1.19, 2.44) 2.42 (1.59, 3.68) 3.78 (2.36, 6.07) 4.42 (2.98, 6.55)
  Participants with diabetes p for trend
  Model 1 NA NA Reference (1.00) 1.59 (0.97, 2.61) 2.81 (1.65, 4.80) 3.39 (2.12, 5.42) <.001
  Model 2 NA NA Reference (1.00) 1.46 (0.88, 2.40) 2.30 (1.33, 3.97) 2.58 (1.59, 4.21) <.001
   Model 2 + HbA1c NA NA Reference (1.00) 1.44 (0.88, 2.38) 2.25 (1.30, 3.89) 2.50 (1.53, 4.09) <.001

Notes: Model 1: adjusted for age and sex. Model 2: further adjusted for ethnicity, Townsend score, education level, body mass index, smoking, macrovascular disease, microvascular disease, antihypertensive medica-
tion use, cholesterol-lowering medication use, and APOE status. Table 2 indicated that a longer diabetes duration was associated with higher risk of all the outcomes among all participants and participants with diabetes.
APOE = apolipoprotein E; CI = confidential interval; HbA1c = glycated hemoglobin.
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Journals of Gerontology: MEDICAL SCIENCES, 2021, Vol. 76, No. 11
Figure 1.  Association between duration of diabetes and risk of incident all-cause
dementia among participants with diabetes. Multivariate analyses were adjusted
for age, sex, ethnicity, Townsend score, education level, body mass index,
smoking, macrovascular disease, microvascular disease, antihypertensive
medication use, and cholesterol-lowering medication use, and APOE status.
The solid red line represents HR, and the dashed black lines represent 95% CIs.
The blue areas indicate the distributions of HbA1c levels. APOE = apolipoprotein
E; CI = confidential interval; HbA1c = glycated hemoglobin; HR = hazard ratio.
Full color version is available within the online issue.
13 693 individuals aged ≥65 years, Xu et al reported that diabetes
was a risk factor for prevalent Alzheimer’s disease and vascular de-
mentia, and the risks were stronger when diabetes occurred at mid-
life than in late life (10). However, because of the cross-sectional
nature of the study, the temporal association could not be assessed,
and information on glycemic control levels was not available. Our
study was able to show that diabetes duration was prospectively
associated with dementia risk independent of glycemic control.
Furthermore, we also extended the analysis to show that the pre-
dictive value of diabetes duration was superior to that of a trad-
itional glycemic control marker (HbA1c).
The overall association between diabetes and dementia has been
well described, but the importance of monitoring glycemic con-
trol remains less clear. Rawlings et  al found a null association be-
tween HbA1c levels and dementia risk in the Atherosclerosis Risk
in Communities study (9). Additionally, in the ADDITION study, no
association between HbA1c and dementia was found (21). Similarly,
a meta-analysis of 7 randomized controlled trials found no evidence
that any specific treatment or treatment strategy for intensive gly-
cemic control in diabetic patients can prevent or delay cognitive im-
pairment (22). In the present study, although we observed a higher
dementia risk among those with higher HbA1c levels, the magnitude
of the association was weaker than the magnitude of the association
with diabetes duration, and these HbA1c–dementia links became
nonsignificant when diabetes duration was taken into account. These
findings may suggest that diabetes duration rather than glycemic
status at a single point can predict long-term dementia risk. Indeed,
previous studies have pointed out that the duration of diabetes is
not only a component of total glycemic load but also a proxy for
cumulative exposure to glycemic variability (23,24). Using a sample
of 13 000 participants, Rawlings et al reported that glucose peaks
in midlife are a risk factor for cognitive decline and dementia in late
life (25). Another prospective study of 2 246 community-living older
diabetic patients also found that a large reduction in HbA1c levels
could be a predictor of dementia (26). Indeed, an increasing body
of evidence reported that not only hyperglycemia but also hypogly-
cemia play important roles in diabetes–dementia associations during
disease progression (27–31), that is, excessively strict glycemic con-
trol may also be deleterious and a single measurement of baseline
glycemic control markers cannot capture disease severity or the
2067
cumulative harm caused by the variability in glycemic status. Taken
together, our data may have implications for future guidelines by
suggesting that participants with diabetes, regardless of their gly-
cemic control levels, may need to be screened for dementia based on
disease duration to facilitate early detection of the cognitive decline
before the clinical manifestation of dementia.
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Studies investigating diabetes duration and dementia subtypes
have been more limited. A study of older Chinese adults found that
diabetes duration was correlated with prevalent Alzheimer’s disease
and vascular dementia (32). However, these findings were based on
cross-sectional data and included only a modest number of partici-
pants (n = 1 109). In the present study, we found that longer diabetes
duration was linked to a higher risk of Alzheimer’s disease and vas-
cular dementia, and the association was stronger for the latter. It
has been reported that failure of the clearance of beta-amyloid are
caused by impaired insulin signaling, and that insulin resistance me-
diates the dysregulation of bioenergetics and progress to Alzheimer’s
disease (33). Thus not surprisingly, longer duration of diabetes, an
important maker of longer-term insulin resistance, would lead to
a higher risk of Alzheimer’s disease. Regarding vascular dementia,
diabetes has previously been linked to a higher risk of atheroscler-
otic changes (34), and a longer duration of the disease would in-
crease the possibility of developing vascular complications (35,36);
this relationship highlights the cumulative effects of dysglycemia on
vascular dysfunction which may underlie the stronger association
with vascular dementia risk among those with long-standing dia-
betes or high HbA1c levels. Of note is that, a large autopsy-based
neuropathological study (n = 5 715) reported that 80% of patients
diagnosed with Alzheimer’s disease and no evidence of mixed (vas-
cular) dementia, however, had vascular pathology including cortical
infarcts, lacunes, cerebral microbleeds, and multiple microinfarcts
(37), supporting the concept that cerebrovascular dysfunction is
prominent in Alzheimer’s disease. Indeed, in an additional sensitivity
analysis (Supplementary Table S8), we excluded participants with
microvascular disease and macrovascular disease, and found that the
results turned to be insignificant, providing further evidence that the
association between diabetes and dementia might have been driven
by vascular etiology. Therefore, acknowledging and characterizing
vascular contributions to the Alzheimer’s disease may be particularly
important among participants with longer-term diabetes, as these
participants are at greater risk for cardiovascular disease and cere-
brovascular disease (5,38).
Strengths and Limitations
The large sample size and wealth of information in the UK Biobank
enabled comprehensive analyses of subgroups and dementia sub-
types. Some limitations should be considered. First, the UK Biobank
is not representative of the UK general population, and as most of
the included participants were White (>90%), the results should be
interpreted with caution when generalizing to the general popula-
tion; also, there is evidence of a “healthy volunteer” selection bias in
the UK Biobank; thus, the prevalence of health conditions was lower
than that in the common population at baseline. Further studies of
diverse populations are needed to corroborate our findings. Second,
we used a single measurement of HbA1c at baseline as a marker of
glycemic control; thus, we were not able to explore the associations
between HbA1c variability and dementia risk. Third, as this study
was observational, the presence of residual confounding cannot be
excluded. Fourth, diabetes duration was calculated based on the par-
ticipants’ self-reported age at onset and is vulnerable to inaccuracy
Table 3.  Hazard Ratios and 95% CIs for the Associations Between Glycemic Control and Risk of Incident Dementia
2068

Without Diabetes Diabetes, by HbA1c Levels (%)

Normoglycemic Prediabetes <7.0% ≥7.0 to <7.5% ≥7.5 to <8.0% ≥8.0%

All-cause dementia
  No. of events 1 520 377 189 51 33 63
 Person-years 3 028 622 477 577 116 500 30 553 18 690 36 257
  All participants
  Model 1 Reference (1.00) 1.07 (0.95, 1.20) 1.94 (1.66, 2.26) 2.04 (1.54, 2.70) 2.39 (1.69, 3.38) 2.76 (2.15, 3.56)
  Model 2 Reference (1.00) 0.97 (0.86, 1.09) 1.57 (1.33, 1.85) 1.61 (1.20, 2.15) 1.77 (1.24, 2.52) 2.02 (1.54, 2.64)
  Participants with diabetes p for trend
  Model 1 NA NA Reference (1.00) 1.06 (0.78, 1.45) 1.23 (0.85, 1.78) 1.42 (1.06, 1.89) .015
  Model 2 NA NA Reference (1.00) 1.05 (0.77, 1.43) 1.13 (0.78, 1.64) 1.26 (1.01, 1.69) .043
   Model 2 + diabetes duration NA NA Reference (1.00) 1.02 (0.75, 1.39) 1.05 (0.72, 1.52) 1.18 (0.88, 1.59) .230
Alzheimer’s disease
  No. of events 588 137 62 11 10 25
 Person-years 3 285 497 518 693 126 639 33 171 20 241 39 248
  All participants
  Model 1 Reference (1.00) 0.98 (0.81, 1.18) 1.64 (1.26, 2.14) 1.16 (0.64, 2.10) 1.87 (1.00, 3.50) 2.88 (1.93, 4.29)
  Model 2 Reference (1.00) 0.94 (0.79, 1.14) 1.48 (1.11, 1.96) 1.03 (0.56, 1.89) 1.56 (0.83, 2.95) 2.47 (1.63, 3.75)
  Participants with diabetes p for trend
  Model 1 NA NA Reference (1.00) 0.71 (0.37, 1.34) 1.14 (0.58, 2.22) 1.75 (1.10, 2.79) .029
  Model 2 NA NA Reference (1.00) 0.71 (0.37, 1.36) 1.05 (0.54, 2.06) 1.63 (1.01, 2.60) .046
   Model 2 + diabetes duration NA NA Reference (1.00) 0.70 (0.37, 1.34) 1.00 (0.51, 1.96) 1.56 (0.96, 2.52) .080
Vascular dementia
  No. of events 266 88 53 28 13 25
 Person-years 3 309 400 521 874 127 271 33 314 20 383 39 480
  All participants
  Model 1 Reference (1.00) 1.40 (1.10, 1.78) 2.87 (2.13, 3.86) 6.01 (4.06, 8.89) 4.97 (2.84, 8.66) 5.94 (3.94, 8.96)
  Model 2 Reference (1.00) 1.13 (0.88, 1.45) 1.88 (1.37, 2.59) 3.81 (2.52, 5.77) 2.93 (1.65, 5.22) 3.52 (2.27, 5.45)
  Participants with diabetes p for trend
  Model 1 NA NA Reference (1.00) 2.08 (1.32, 3.29) 1.71 (0.93, 3.14) 1.98 (1.23, 3.19) .002
  Model 2 NA NA Reference (1.00) 2.03 (1.28, 3.22) 1.60 (0.87, 2.95) 1.88 (1.15, 3.05) .004
   Model 2 + diabetes duration NA NA Reference (1.00) 1.97 (1.24, 3.12) 1.44 (0.78, 2.67) 1.68 (1.03, 2.74) .015

Notes: Model 1: adjusted for age and sex. Model 2: further adjusted for ethnicity, Townsend score, education level, body mass index, smoking, macrovascular disease, microvascular disease, antihypertensive medication
use, cholesterol-lowering medication use, and APOE status. The conversion of HbA1c levels of <7%, ≥7.0 to <7.5%, ≥7.5 to <8.0%, and ≥8.0% are <53.0 mmol/mol, ≥53.0 to <58.5 mmol/mol, ≥58.5 to <64.0 mmol/mol,
and 64.0 mmol/mol, respectively. Table 3 indicated that poorer glycemic control was associated with higher risk of all the outcomes among all participants and participants with diabetes. APOE = apolipoprotein E; CI = con-
fidential interval; HbA1c = glycated hemoglobin.
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Journals of Gerontology: MEDICAL SCIENCES, 2021, Vol. 76, No. 11
Figure 2. Adjusted hazard ratios (95% CIs) for incident dementia among
participants with diabetes based on the combination of baseline glycemic
control levels and diabetes duration. Model 1: adjusted for age and sex.
Model 2: further adjusted for ethnicity, Townsend score, education level,
body mass index, smoking, macrovascular disease, microvascular disease,
antihypertensive medication use, cholesterol-lowering medication use,
and APOE status. APOE  =  apolipoprotein E; CI  =  confidential interval.
Full color version is available within the online issue.
because a lag time exists between onset and diagnosis. Fifth, as the
UK Biobank uses register ICD codes to detect dementia diagnosis
and thus the information on outpatient encounters and mediations
for treating dementia were not available, some of the cases of de-
mentia among the study participants might have involved cerebral
small vessel disease or even microinfarcts. Sixth, our ability to distin-
guish the contribution of diabetes to Alzheimer’s disease beyond its
vascular component was hindered by the lack of specific Alzheimer’s
disease markers (eg, beta-amyloid). Seventh, the potential ascertain-
ment bias is also worth noting, participants with long-term diabetes
may be more likely to receive a hospital diagnosis of dementia as
they are hospitalized more often. Finally, as 2-hour glucose levels
may better identify incident diabetes among older adults, some in-
dividuals who were included in the normal category may have had
undiagnosed diabetes, resulting in misclassification bias.
Conclusions
In conclusion, diabetes duration appeared to be associated with the risk
of incident dementia due to factors beyond glycemic control. Clinicians
should consider not only glycemic control but also diabetes duration in
dementia risk assessments for participants with diabetes.
Supplementary Material
Supplementary data are available at The Journals of Gerontology,
Series A: Biological Sciences and Medical Sciences online.
Funding
This research was supported by Open Project of Guangdong Provincial Key
Laboratory of Tropical Disease Research and Guangdong Basic and Applied
Basic Research Foundation.
Conflict of Interest
None declared.
2069
Acknowledgments
We are grateful to UK Biobank participants. This research has been conducted
using the UK Biobank Resource under Application Number 55794.
Author Contributions
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F.-R.L. contributed to the literature research, study design, and manuscript
writing. H.-L.Y. and R.Z. contributed to the data acquisition. F.-R.L. con-
tributed to data analyses. H.-L.Y., and J.-Z.Z.  contributed to literature
research. G.-C.C., J.-Y.W., Q.F., J.-Z.Z., H.M.L., X.-X.W., M.-C.Z., and
X.-B.W. reviewed the manuscript. X.-B.W. is the guarantor of this research
and, as such, had full access to all of the data in the study and takes respon-
sibility for the integrity of the data and the accuracy of the data analysis.
Data Availability
Data from the UK Biobank are publicly available and can be accessed at
https://www.ukbiobank.ac.uk/.
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