Healthy Lifestyle and all-cause and cause-specific dementia in Individuals with or without Type 2 diabetes: the roles of diabetes duration and insulin use

doi:10.21203/rs.3.rs-2308153/v1

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Research Article

Healthy Lifestyle and all-cause and cause-specific dementia in Individuals with or without Type 2 diabetes: the roles of diabetes duration and insulin use

https://doi.org/10.21203/rs.3.rs-2308153/v1

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Background

Diabetes and dementia share common lifestyle risk factors, while few studies have examined the effect of seven healthy lifestyle factors as recommended by the diabetes management guidelines on all-cause and cause-specific dementia in individuals with type 2 diabetes (T2DM). Also, the roles of diabetes duration and insulin therapy in their association remain unclear.

Methods

This study analyzed data of 459 840 participants from the UK Biobank. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of an overall healthy lifestyle score (derived from smoking, social connection, alcohol consumption, physical activity, sedentary, sleep duration and diet) with all-cause and cause-specific dementia of Alzheimer's disease (AD), Vascular dementia (VD) and Non-Alzheimer non-vascular dementia (NAVD), using people without T2DM as the reference group. We also analyzed the role of diabetes duration and insulin use on the association between lifestyle score and dementia.

Results

During a mean follow-up of 12.1 years, 5 268 incident dementia events were recorded. Using diabetes-free participants who had a lifestyle score of 5–7 as reference group, in diabetes-free participants, we observed a clear trend that higher healthy lifestyle score was related to lower risk of all-cause and cause-specific dementia. However, in people with T2DM, we did not observe such a trend with all-cause dementia. People with lifestyle score of 2–3, 4 and 5–7 all had around two-time risk of all-cause dementia (HR: 2.20–2.36), while those with a score of 0–1 had over three-time risk (HR: 3.14, 95% CI 2.34–4.21). After separating the analyses with dementia subtypes, a dose-response trend was only observed with VD (each two-point increase: 0.75, 0.61–0.93), and no significant association with AD (0.95, 0.77–1.16). The reduced risk of all-cause dementia, AD, VD, and NACD with higher lifestyle score was only observed in patients with diabetes duration less than 10 years, or in patients with no insulin use.

Conclusions

In people with T2DM, higher healthy lifestyle score was associated with lower risk of all-cause dementia, while the relationship with cause-specific dementia was inconsistent. A dose-response trend was only observed with VD, not with AD. The beneficial effect of healthy lifestyle was only observed in people with diabetes duration less than 10 years, or in those with no insulin use.

Type 2 diabetes

Healthy lifestyle

Dementia

Diabetes duration

Insulin use

Both diabetes and dementia are great public health issues globally [1, 2]. Currently, more than 536 million people worldwide have diabetes and this number is expected to rise to 783 million by 2045 [2]. Also, there were over 55 million people living with dementia and the number will reach 78 million by 2030 [3]. Evidence suggests that people with type 2 diabetes (T2DM) are more likely to experience dementia [3, 4]. It is significant to identify cost-effective strategies to prevent or delay the development of dementia in patients with T2DM.

The American Diabetes Association (ADA) highlights the important roles of seven healthy lifestyles in achieving diabetes treatment goals [5]. Similarly, these healthy lifestyles reduce the risk of dementia [6–9]. Diabetes and dementia share common lifestyle risk factors such as physical inactivity, heavy alcohol consumption [10]. However, the impact of healthy lifestyles on risk of subsequent dementia is less well studied in patients with T2DM. Research has suggested that in people with diabetes, engagement in social leisure activities [11], regular physical activity [12–14] and cohabitation status [15] could reduce the risk of dementia, and sleep disturbance [16], may increase the risk, while smoking and alcohol consumption had no clear relationship with dementia [17–19]. Previous studies usually analyzed the role of a single lifestyle factor on risk of dementia in people with T2DM. Few studies have examined the overall lifestyle exposure (e.g., a comprehensive lifestyle score) on all-cause and cause-specific dementia risk in people with T2DM.

In addition, the average duration of T2DM ranged from 5–10 years [20, 21] and around 30% patients with T2DM need insulin treatment with the disease progression [22]. Diabetes duration and insulin use status may affect the association of healthy lifestyle with risk of dementia in people with T2DM.

Thus, the aim of this study is to examine the effect of seven healthy lifestyle factors (an overall score) as defined by the diabetes management guidelines on all-cause and cause-specific dementia in individuals with T2DM. We also investigated how diabetes duration and insulin use status modify their association.

Study design and participants

We used data from the UK Biobank which is a large population-based prospective cohort study that recruited over 502 000 participants aged 40–70 years from 2006 to 2010 [23]. Written informed consent was obtained for collection of questionnaire and biological data. UK Biobank received ethical approval from the UK National Health Service’s National Research Ethics Service (ref 11/NW/0382). This research was conducted under UK Biobank application number 68369. A prospective design was adopted based on participants with no dementia at baseline, and if a participant had dementia during follow-up and also experienced T2DM, his/her diagnosis of T2DM had to be in advance of dementia. Finally, 459 840 people were included in this prospective analysis (Figure S1). This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Assessment Of Type 2 Diabetes And Lifestyle Factors

Physician-diagnosed T2DM was ascertained from linkage data to primary care, hospital admission and death register records. The International Classification of Diseases 10th Edition (ICD-10) code E11 and ICD-9 code 250 were used to identify participants with T2DM. Insulin use status was self-reported. Specific field IDs or ICD codes for T2DM were listed in Table S1.

All lifestyle information was self-reported at baseline. In our study, we considered 7 low-risk behaviors recommended in diabetes management guidelines [5] and ever used in previous studies [10–12, 15, 16], including smoking, physical activity, social connection, alcohol consumption, sedentary behavior, sleep duration and diet, to generate an overall lifestyle score. Definitions and field IDs of each lifestyle factor were listed Table S2. Never smoker, regular physical activity, not socially isolated, moderate drinking on a relatively regular frequency [24], watching TV for less than four hours every day [25], 6–9 h/day of sleep duration [26], an adequate intake of at least 6 of 10 food types [27] were viewed as low risk behavior. For each behavioral factor, a low risk level was assigned 1 point and otherwise 0 point. An overall lifestyle score was constructed as the sum of all seven factors, ranging from 0 to 7, with a higher score indicating better adherence to an overall healthy lifestyle. For avoidance of extreme groups with limited cases, the lifestyle score was subsequently categorized into four groups (0–1, 2–3, 4 and 5–7).

Assessment Of Outcomes

The outcome variable was incident all-cause dementia including dementia subtypes of Alzheimer's disease (AD), Vascular dementia (VD) and Non-Alzheimer non-vascular dementia (NAVD). The ICD-10 codes F00, F01, F02, F03, G30, G31·0, G31·1, G31·8 and ICD-9 code 290·1 were used to identify participants with all-cause dementia if one or more of these codes were recorded as a primary or secondary diagnosis in the health records. Incident AD was defined by ICD-10 codes F00, G30 and ICD-9 code 290·1. Incident VD was defined by ICD-10 code F01. Incident NAVD was defined by ICD-10 codes F02, F03, G31·0, G31·1 and G31·8. Outcome adjudication for incident dementia was conducted by the UK Biobank Outcome Adjudication team. Specific field IDs or ICD codes dementia types were listed in Table S1.

Assessment Of Covariates

We included the following factors in the analyses as covariates according to evidence from previous studies: age of follow up, race/ethnicity, years of education, income level, BMI, hypertension status, APOE4 allele status, Hemoglobin A1c (HbA1c) level, cardiovascular diseases (CVD) status and depressive status. Race/ethnicity was categorized as white and non-white. Years of education was categorized as ≤ 10, 11–12, and > 12 years. Income level was divided into four categories of level 1 (Less than£18,000), level 2 (£18,000 to £30,999), level 3 (£31,000 to £51,999) and level 4 (greater than 52,000). BMI was calculated as weight in kilograms divided by the square of height in meters and categorized according to the World Health Organization criteria as < 18.5 kg/m2, 18.5 to 24.9 kg/m2, 25 to 29.9 kg/m2, and ≥ 30 kg/m2. Hypertension status was dichotomized as present or absent based on self-report at baseline. APOE allele status was based on two single nucleotide polymorphisms (SNPs): rs7412 and rs429358. Participants with APOE e4 allele (e3/e4, e4/e4 and occasionally e2/e4 genotypes) were compared with those with the e2/e2, e2/e3 or e3/e3 genotype. HbA1c level was divided into two categories based on the target of less than 7% or not. CVD or depressive status was dichotomized as present or absent based on hospital medical records at baseline.

Statistical Analyses

Baseline characteristics were presented as means and standard deviation (SD) for continuous variables and as percentages (%) for categorical variables. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of the effect of lifestyle score on all-cause and case-specific dementia of AD, VD and NAVD. People without T2DM were used as the reference group, to compare the effect of lifestyle score in people with T2DM. The proportional hazards (PH) assumption was tested graphically using a plot of the log cumulative hazard, where the logarithm of time is plotted against the estimated log cumulative hazard. The curves for different lifestyle score categories were approximately parallel, thus the PH assumption was deemed reasonable. Hospital inpatient data and death data were censored on the 30 January 2021 or when death, fatal or non-fatal dementia was recorded. For participants who experienced a dementia, follow-up time was calculated as their age when dementia was diagnosed minus baseline age; for participants without experiencing dementia, follow-up time was defined as their age at last follow-up (censored date) minus baseline age. First, we analyzed the effect of lifestyle score on all-cause and case-specific dementia, using people without T2DM as the reference group. Second, given that dementia generally occurs at older ages, we restricted analysis to individuals aged at least 60 years at baseline. Third, considering the varying degrees of associations between each single factor and dementia risk in people with T2DM, we constructed a weighted lifestyle score that gave equal weight to each lifestyle factor. Fourth, in people with T2DM, to examine how diabetes duration moderate the association between healthy lifestyle score and dementia, we stratified the analyses by diabetes duration of < 10 years, 10–15 years, and ≥ 15 years. Last, in people with T2DM, we examined the role of insulin use on the association between healthy lifestyle score and dementia. All HRs (95% CI) were adjusted for age at last follow up, sex, race/ethnicity, years of education, income level, BMI, hypertension status, HbA1c level, APOE4 allele status, CVD status and depression status.

All analyses were performed using SAS version 9.4 and a 2-sided P < 0.05 was set as the threshold for statistical significance.

Characteristics of participants (Table 1)

Of the 459 840 people included in this study, the mean (SD) age was 56.4 (8.1) years. A majority of participants (94.9%) were white and 54.7% were female. The median (SD) follow-up of 12.1 (1.7) years. There were 21 801 (4.7%) people with T2DM and 5 268 incident dementia which occurred after T2DM were recorded. The crude incidence rate of all-cause dementia was 0.87 for those without T2DM and 2.59 for people with T2DM, per 1 000 person-years respectively. In people with T2DM, the proportion of people with 0–1 score was higher than that in people with no T2DM (4.2% vs 1.6%), while the proportion of people with 5–7 score was lower than that in diabetes-free people (29.2 vs 43.0). Besides, people with T2DM were mainly male, less educated and with hypertension.

Table 1

Baseline characteristics of participants by type 2 diabetes experienced or not, n (%)
Characteristics	N	Participants without T2DM (n = 438, 039)	Participants with T2DM (n = 21, 801)
Age (mean ± SD)		56.3 ± 8.1	60.5 ± 6.7
Lifestyle score
0–1	7999	7078 (1.6)	921 (4.2)
2–3	116427	108371 (24.7)	8056 (37.0)
4	140521	134069 (30.6)	6452 (29.6)
5–7	194893	188521 (43.0)	6372 (29.2)
Sex
Female	251500	243661 (55.6)	7839 (36.0)
Male	208340	194378 (44.4)	13962 (64.0)
Race/ethnicity
White	436150	417045 (95.2)	19105 (87.6)
Non-White	23690	20994 (4.8)	2696 (12.4)
Education level (years)
≤10	227892	215054 (49.1)	12838 (58.9)
10–12	54766	52484 (12.0)	2282 (10.5)
>12	177182	170501 (38.9)	6681 (30.7)
Income level (£)
Less than 18,000	103213	96181 (22.0)	7032 (32.3)
18,000 to 30,999	112130	106397 (24.3)	5733 (26.3)
31,000 to 51,999	119298	114565 (26.2)	4733 (21.7)
Greater than 52,000	125199	120896 (27.6)	4303 (19.7)
Body mass index (kg/m²)
Underweight < 18.5	2443	2423 (0.6)	20 (0.1)
Normal [18.5,25.0)	154424	152353 (34.8)	2071 (9.5)
Overweight [25.0,30.0)	197232	189640 (43.3)	7592 (34.8)
Obese ≥ 30	105741	93623 (21.4)	12118 (55.6)
Hypertension status
No	335998	328551 (75.0)	7447 (34.2)
Yes	123842	109488 (25.0)	14354 (65.8)
Depressive status
No	435950	415934 (95.0)	20016 (91.8)
Yes	23890	22105 (5.1)	1785 (8.2)
CVD status
No	435121	417270 (95.3)	17851 (81.9)
Yes	24719	20769 (4.7)	3950 (18.1)
Apolipoprotein E (APOE)
No APOE4	111198	105447 (24.1)	5751 (26.4)
One APOE4	339323	323649 (73.9)	15674 (71.9)
Two APOE4	9319	8943 (2.0)	376 (1.7)
Dementia
All-cause dementia	5268	4615 (1.1)	653 (3.0)
Alzheimer's disease (AD)	2283	2040 (0.5)	243 (1.1)
Vascular Dementia (VD)	859	688 (0.2)	171 (0.8)
Non-Alzheimer non-vascular dementia (NAVD)	2126	1887 (0.4)	239 (1.1)

The effect of healthy lifestyle score on dementia risk (Figure 1, Figure S2 and Table S3-S4)

Using people without T2DM and having a lifestyle score of 5–7 as the reference group, in people without T2DM, there was a clear trend that higher healthy lifestyle score was related to lower risk of all-cause and cause-specific dementia, while in people with T2DM, we only observed such a trend in the association with VD, no clear trend was observed with AD and NAVD (Fig. 1). After analyzing in people aged at least 60 years at baseline (Figure S2), similar results were observed. In people with T2DM, the HR (95% CI) for each two-point increase with all-cause dementia, AD, VD, and NAVD were 0.85 (0.76, 0.97), 0.95 (0.77, 1.16), 0.75 (0.61, 0.93), and 0.78 (0.67, 0.91) respectively (Table S3). After using weighted healthy lifestyle score as a sensitivity analysis (Table S4), we observed similar findings.

The roles of diabetes duration in patients with T2DM (Table 2)

In patients with diabetes duration less than 10 years, we observed a clear trend that higher healthy lifestyle score was associated with lower risk of all-cause dementia, AD, VD, and NACD, with HR (95%CI) of (0.81, 0.78–0.85), (0.92, 0.85–0.98), (0.81, 0.73–0.90) and (0.77, 0.72–0.81) respectively for every two-point lifestyle score increase. In patients with diabetes duration 10–15 years, higher healthy lifestyle score was associated with lower risk of VD and NAVD, while no relationship with AD was observed, with HR (95%CI) of (0.56, 0.38–0.82), (0.71, 0.54–0.95) and (1.17, 0.83–1.65) respectively for every two-point lifestyle score increase. No significant association was found between healthy lifestyle score and dementia in patients with diabetes duration more than 15 years.

Table 2

The association of lifestyle score with all-cause and cause-specific dementia among T2DM patients with different diabetes durations *
Diabetes duration (years)	Lifestyle score	Adjusted HR (95% CI) *
Diabetes duration (years)	Lifestyle score	All-cause dementia	Alzheimer's disease	Vascular Dementia	Non-Alzheimer non-vascular dementia
< 10	0–1	1	1	1	1
	2–3	0.84 (0.71, 0.99)	0.94 (0.72, 1.24)	0.79 (0.57, 1.10)	0.76 (0.62, 0.92)
	4	0.72 (0.61, 0.85)	0.86 (0.65, 1.13)	0.71 (0.51, 0.99)	0.64 (0.53, 0.78)
	5–7	0.65 (0.55, 0.77)	0.84 (0.64, 1.10)	0.60 (0.43, 0.84)	0.55 (0.45, 0.67)
	Every 2 points	0.81 (0.78, 0.85)	0.92 (0.85, 0.98)	0.81 (0.73, 0.90)	0.77 (0.72, 0.81)
10–15	0–1	1	1	1	1
	2–3	0.68 (0.40, 1.15)	0.80 (0.27, 2.30)	0.66 (0.30, 1.43)	0.61 (0.32, 1.19)
	4	0.76 (0.44, 1.32)	1.24 (0.43, 3.60)	0.36 (0.15, 0.90)	0.64 (0.32, 1.28)
	5–7	0.58 (0.33, 1.04)	1.10 (0.37, 3.28)	0.37 (0.14, 0.96)	0.47 (0.23, 0.99)
	Every 2 points	0.81 (0.65, 1.00)	1.17 (0.83, 1.65)	0.56 (0.38, 0.82)	0.71 (0.54, 0.95)
≥ 15	0–1	1	1	1	1
	2–3	0.77 (0.50, 1.19)	1.05 (0.48, 2.32)	0.87 (0.41, 1.85)	0.62 (0.36, 1.04)
	4	0.77 (0.49, 1.22)	1.01 (0.45, 2.29)	0.80 (0.36, 1.77)	0.62 (0.36, 1.08)
	5–7	0.74 (0.46, 1.18)	0.91 (0.39, 2.13)	0.65 (0.27, 1.52)	0.61 (0.34, 1.08)
	Every 2 points	0.94 (0.79, 1.12)	0.94 (0.71, 1.24)	0.90 (0.66, 1.23)	0.91 (0.73, 1.13)
* All HRs were adjusted for age at last follow up, sex, race/ethnicity, educational years, income level, body mass index (BMI), HbA1c level, hypertension status, depressive status, CVD status and APOE4 allele status.

The roles of insulin use status in patients with T2DM (Table 3)

In T2DM patients without using insulin therapy, higher healthy lifestyle score was associated with reduced risk of all-cause dementia, VD and NAVD, but no relationship with AD, with HR (95%CI) of (0.87, 0.76-1.00), (0.72, 0.57–0.91), (0.81, 0.69–0.96) and (0.98, 0.79–1.22) respectively for every two-point lifestyle score increase. In patients who used insulin therapy, higher healthy lifestyle score was only associated with lower risk of NAVD.

Table 3

HRs (95% CI) between lifestyle score and all-cause and cause-specific dementia by insulin use or not *
	Adjusted HR (95% CI) *
	All-cause dementia	Alzheimer's disease	Vascular Dementia	Non-Alzheimer non-vascular dementia
T2DM patients without insulin use
0–1	1	1	1	1
2–3	0.67 (0.48, 0.93)	0.81 (0.44, 1.49)	0.59 (0.36, 0.97)	0.60 (0.40, 0.90)
4	0.69 (0.49, 0.98)	0.92 (0.49, 1.72)	0.43 (0.25, 0.75)	0.61 (0.40, 0.93)
5–7	0.66 (0.46, 0.94)	0.88 (0.46, 1.67)	0.49 (0.28, 0.86)	0.57 (0.37, 0.88)
Every 2 points	0.87 (0.76, 1.00)	0.98 (0.79, 1.22)	0.72 (0.57, 0.91)	0.81 (0.69, 0.96)
T2DM patients with insulin use
0–1	1.14 (0.48, 2.69)	1.57 (0.35, 7.05)	-	1.74 (0.72, 4.21)
2–3	1.14 (0.75, 1.75)	1.84 (0.89, 3.83)	1.12 (0.60, 2.11)	0.89 (0.52, 1.55)
4	0.88 (0.52, 1.50)	1.13 (0.44, 2.89)	1.18 (0.57, 2.44)	0.52 (0.24, 1.14)
5–7	0.53 (0.27, 1.04)	0.85 (0.30, 2.43)	-	0.42 (0.17, 1.01)
Every 2 points	0.72 (0.51, 1.02)	0.74 (0.43, 1.26)	0.88 (0.52, 1.48)	0.57 (0.35, 0.92)
* All HRs were adjusted for age at last follow up, sex, race/ethnicity, educational years, income level, body mass index (BMI), HbA1c level, hypertension status, depressive status, CVD status and APOE4 allele status. “-” indicated no enough number of dementia events for analysis.

Summary of finding

Healthy lifestyle can increase brain reserves to slow cognitive decline, and prevent the occurrence of cardiometabolic disease related dementia [28]. Our findings showed that in people without T2DM, higher healthy lifestyle score was associated with lower risk of all-cause and each cause-specific dementia, while in people with T2DM, a dose-response trend was observed with VD, and no significant association with AD, and the association with NAVD was different only between the lowest score (0–1 score) and other score. The effect of healthy lifestyle on dementia was interacted by diabetes duration and no longer significant after having diabetes over 15 years. Insulin use status also play a role, and higher healthy lifestyle score was linked to lower risk of all-cause dementia in those without using insulin.

Healthy Lifestyle And Dementia In General Population

A few reviews and observational studies have examined the association between lifestyle factors and dementia among general populations. Ilianna Lourida et al. reported that favorable healthy lifestyle (no current smoking, regular physical activity, healthy diet and moderate alcohol consumption) reduces all-cause dementia risk independently of genetic factors [6]. Similarly, Klodian Dhana et al. found that people who adhered to 4–5 healthy lifestyle factors (not current smoking, regular physical activity, light to moderate alcohol intake, high-quality diet and engagement in cognitive activities) had 60% lower risk of AD than those with 0–1 healthy lifestyle factors [7]. However, most of these studies focused on all-cause dementia and AD, without analyzing the association with VD and NAVD. In addition, when calculated healthy lifestyle score, previous studies did not take into account factors such as sleep, sedentary behavior and social connection. Consistent with previous studies, in people without diabetes, those scored 0–1 had 1.54 times risk of all-cause dementia than people scored 5–7, and similar results were observed in the analysis with VD and NAVD.

Healthy Lifestyle And Dementia In People With T2dm

In people with T2DM, previous research on lifestyle and dementia have mainly focused on the role of individual lifestyle factors. For instance, a systematic review reported that smoking or heavy drinking did not significantly increase the risk of dementia in people with diabetes [17]. However, this review included only two relevant studies, and neither of which analyzed the relationship with dementia subtypes. Another systematic review suggested that sedentary behavior may contribute to cognitive decline by affecting glycemic control in patients with T2DM [29], while its effect on subsequent dementia was unclear. A meta-analysis found no association between physical inactivity and cardiometabolic disease (including T2DM) related dementia, while this study did not separate the effect of physical inactivity on dementia among diabetes patients [12]. Also, a review found that a higher frequency of social isolation in elderly with diabetes was associated with cognitive impairment [30]. Few studies have examined an overall healthy lifestyle score on all-cause and cause-specific dementia risk in patients with T2DM. In people aged over 60 years, Bin Wang et al reported each one-point lifestyle score increase at baseline was associated with a 14% lower risk of all-cause dementia in people with T2DM [31], while this study did not consider midlife lifestyle and the roles of diabetes’ duration and insulin use. Besides observing that higher healthy lifestyle score was linked to lower risk of all-cause dementia, we also found that the relationship between healthy lifestyle score and cause-specific dementia was inconsistent. There was a dose-response trend with VD, but no significant association with AD, and the association with NAVD was different only between the lowest score (0–1 score) and other score.

Role Of Diabetes Duration

Previous studies have shown that diabetes duration was associated with dementia risk, while whether individuals with diabetes duration could benefit from healthy lifestyle was unclear. Andreea M. Rawlings et al reported that patients with diabetes duration more than 5 years had 1.91 times higher risk of developing dementia than those less than 5 years [32]. Another study observed that the longer diabetes duration, the higher the risk of all- cause dementia, AD and VD [33]. Also, a study involved people over 65 found a U-shaped association between diabetes duration and the risk of dementia [34]. In our findings, every two-point lifestyle score increase was associated with reduced risk of all-cause and cause-specific dementia of AD, VD and NAVD among patients with T2DM whose diabetes duration was less than 10 years, whereas this association was no longer significant with a course more than 15 years. This suggests that for people with T2DM, adopting a healthy lifestyle in the first decade of diabetes may reduce their future risk of experiencing dementia.

Role Of Insulin Use

A systematic review and meta-analysis showed that patients with T2DM who used insulin was related to 36% higher risk of all-cause dementia compared to those who did not use insulin [35]. Similarly, Weinstein et al reported that patients with T2DM who used insulin had 1.6 times higher risk of all-cause dementia than those without insulin therapy, while no significant association with AD was observed [36]. This may explain the findings of our study, every two-point lifestyle score increase was associated with a 13% lower risk for all-cause dementia in patients without insulin use, whereas no significant association was found among insulin users.

Insulin use can increase dementia risk through the following pathways. First, insulin use may induce the onset of hypoglycemia, which increases the risk of dementia [37]. Second, insulin use leads to increased S100β secretion via PI3 K signaling, and the increase of S100β in cerebrospinal fluid is related to AD [38]. Further, peripheral insulin administration is a treatment for patients with diabetes, which can impair insulin transport across the blood-brain barrier (BBB), resulting in ineffective treatment [39].

One strength of this study was the large sample size which enabled us to examine the graded healthy lifestyle score with all-cause and cause-specific dementia. Second, we used people with no diabetes as the reference group, to see the effect of healthy lifestyle on dementia both in general population and in people with diabetes. Third, T2DM and dementia were ascertained from primary care, hospital admissions and mortality data, avoiding bias from self-reported data. Dementia outcomes have been validated in previous studies, demonstrating positive predictive value for all-cause dementia was 80–87% [40]. Further, we also analyzed how diabetes duration and insulin use may moderate the association between healthy lifestyle score and risk of dementia, which usually not reported in previous studies.

Our study also has several limitations. First, a lifestyle score that gives equal weight to each lifestyle factor may ignore the varying degrees of associations between single factors and dementia risk in people with T2DM. Nevertheless, we calculated a weighted lifestyle score to do a sensitivity analysis and observed similar results. Second, there might be some other potential confounders that may affect the relationship between healthy lifestyle and risk of dementia in patients with T2DM. Further, the participants were predominantly white, which may limit the extrapolation of the findings.

Our study demonstrated that higher healthy lifestyle score was associated with lower risk of all-cause dementia in people with T2DM, while the relationships with cause-specific dementia was inconsistent. A dose-response relationship was only observed with VD, but no significant association was observed with AD. Diabetes duration and insulin use moderated the association between healthy lifestyle score and risk of dementia. The beneficial effect healthy lifestyle on all-cause and cause-specific dementia of AD, VD and NAVD were mainly observed in people with diabetes duration less than 10 years, or in those with no insulin use. How the combination patterns of different single lifestyle factors influence the risk of dementia in people with diabetes needs to be further explored.

T2DM: Type 2 diabetes; AD: Alzheimer's disease; VD: Vascular dementia; NAVD: Non-Alzheimer non-vascular dementia; HR: hazard ratio; CI: Confidence interval; SNPs: Single nucleotide polymorphisms; HbA1c: Hemoglobin A1c; CVD: Cardiovascular diseases; BBB: Blood-brain barrier.

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. As part of the UK Biobank recruitment process, informed consent was obtained from all individual participants included in the study.

Consent for publication

Non-applicable.

Availability of data and materials

UK Biobank data are available via www.ukbiobank.ac.uk. Syntax for the generation of derived variables and for the analysis used for this study will be submitted to UK Biobank for record.

Competing interests

No potential conflicts of interest relevant to this article were reported.

Funding

This work was supported by the National Natural Science Foundation of China (82273702), Science Fund Program for Excellent Young Scholars of Shandong Provence (Overseas)(2022HWYQ-030), Taishan Scholars Project Special Fund, and the Start-up Foundation for Scientific Research in Shandong University (202099000066).

Authors’ contributors

D.Z. conceived the study and contributed to interpretation of the results. C.Z. did statistical analyses and draft the first manuscript. C.D., Q.W., C.F, Z.X., W.H., and H.S. searched databases and prepared data. D.Z. contributed to critical revision of the manuscript.

Acknowledgments

This research has been conducted using the UK Biobank resource. We are grateful to UK Biobank participants.

Frankish H, Horton R. Prevention and management of dementia: a priority for public health. Lancet. 2017;390(10113):2614-5.
Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.
Gauthier S R-NP, Morais JA, & Webster C. World Alzheimer Report 2021: Journey through the diagnosis of dementia. London, England: Alzheimer’s Disease International. 2021.
Srikanth V, Sinclair AJ, Hill-Briggs F, Moran C, Biessels GJ. Type 2 diabetes and cognitive dysfunction-towards effective management of both comorbidities. Lancet Diabetes Endocrinol. 2020;8(6):535-45.
Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, Freeman R, et al. 5. Facilitating Behavior Change and Well-being to Improve Health Outcomes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S60-S82.
Lourida I, Hannon E, Littlejohns TJ, Langa KM, Hyppönen E, Kuzma E, et al. Association of Lifestyle and Genetic Risk With Incidence of Dementia. JAMA. 2019;322(5):430-7.
Dhana K, Evans DA, Rajan KB, Bennett DA, Morris MC. Healthy lifestyle and the risk of Alzheimer dementia: Findings from 2 longitudinal studies. Neurology. 2020;95(4):e374-e83.
Petersson SD, Philippou E. Mediterranean Diet, Cognitive Function, and Dementia: A Systematic Review of the Evidence. Adv Nutr. 2016;7(5):889-904.
Bakrania K, Edwardson CL, Khunti K, Bandelow S, Davies MJ, Yates T. Associations Between Sedentary Behaviors and Cognitive Function: Cross-Sectional and Prospective Findings From the UK Biobank. Am J Epidemiol. 2018;187(3):441-54.
Dolan C, Glynn R, Lawlor B. A Systematic Review and Delphi Study to Ascertain Common Risk Factors for Type 2 Diabetes Mellitus and Dementia and Brain-Related Complications of Diabetes in Adults. Can J Diabetes. 2020;44(7):628-35.
Marseglia A, Wang H-X, Rizzuto D, Fratiglioni L, Xu W. Participating in Mental, Social, and Physical Leisure Activities and Having a Rich Social Network Reduce the Incidence of Diabetes-Related Dementia in a Cohort of Swedish Older Adults. Diabetes Care. 2019;42(2):232-9.
Kivimäki M, Singh-Manoux A, Pentti J, Sabia S, Nyberg ST, Alfredsson L, et al. Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis. BMJ. 2019;365:l1495.
De Sousa RAL, Improta-Caria AC, Cassilhas RC. Effects of physical exercise on memory in type 2 diabetes: a brief review. Metab Brain Dis. 2021;36(7):1559-63.
Yoo JE, Han K, Kim B, Park S-H, Kim SM, Park HS, et al. Changes in Physical Activity and the Risk of Dementia in Patients With New-Onset Type 2 Diabetes: A Nationwide Cohort Study. Diabetes Care. 2022;45(5):1091-8.
Fink A, Buchmann N, Tegeler C, Steinhagen-Thiessen E, Demuth I, Doblhammer G. Physical activity and cohabitation status moderate the link between diabetes mellitus and cognitive performance in a community-dwelling elderly population in Germany. PLoS One. 2017;12(10):e0187119.
Brzecka A, Madetko N, Nikolenko VN, Ashraf GM, Ejma M, Leszek J, et al. Sleep Disturbances and Cognitive Impairment in the Course of Type 2 Diabetes-A Possible Link. Curr Neuropharmacol. 2021;19(1):78-91.
Pal K, Mukadam N, Petersen I, Cooper C. Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-analysis. Soc Psychiatry Psychiatr Epidemiol. 2018;53(11):1149-60.
Bruce DG, Davis WA, Starkstein SE, Davis TM. Mid-life predictors of cognitive impairment and dementia in type 2 diabetes mellitus: the Fremantle Diabetes Study. J Alzheimers Dis. 2014;42 Suppl 3:S63-S70.
Wu K, Liu H, Zheng J, Zou L, Gu S, Zhou R, et al. Diabetes Treatment Is Associated With Better Cognitive Function: The Age Disparity. Front Aging Neurosci. 2021;13:753129.
de Jong M, Woodward M, Peters SAE. Duration of diabetes and the risk of major cardiovascular events in women and men: A prospective cohort study of UK Biobank participants. Diabetes Res Clin Pract. 2022;188:109899.
Reis JP, Allen NB, Bancks MP, Carr JJ, Lewis CE, Lima JA, et al. Duration of Diabetes and Prediabetes During Adulthood and Subclinical Atherosclerosis and Cardiac Dysfunction in Middle Age: The CARDIA Study. Diabetes Care. 2018;41(4):731-8.
Lipska KJ, Yao X, Herrin J, McCoy RG, Ross JS, Steinman MA, et al. Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006-2013. Diabetes Care. 2017;40(4):468-75.
Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779.
National Health Service. The risks of drinking too much. 2019 [Available from: www. nhs.uk/live-well/alcohol-support/the-risks-of-drinking-too-much/.
Han H, Cao Y, Feng C, Zheng Y, Dhana K, Zhu S, et al. Association of a Healthy Lifestyle With All-Cause and Cause-Specific Mortality Among Individuals With Type 2 Diabetes: A Prospective Study in UK Biobank. Diabetes Care. 2022;45(2):319-29.
Wang C, Bangdiwala SI, Rangarajan S, Lear SA, AlHabib KF, Mohan V, et al. Association of estimated sleep duration and naps with mortality and cardiovascular events: a study of 116 632 people from 21 countries. Eur Heart J. 2019;40(20):1620-9.
Said MA, Verweij N, van der Harst P. Associations of Combined Genetic and Lifestyle Risks With Incident Cardiovascular Disease and Diabetes in the UK Biobank Study. JAMA Cardiol. 2018;3(8):693-702.
Marseglia A, Darin-Mattsson A, Kalpouzos G, Grande G, Fratiglioni L, Dekhtyar S, et al. Can active life mitigate the impact of diabetes on dementia and brain aging? Alzheimers Dement. 2020;16(11):1534-43.
Michael J. Wheeler PCD, Megan S. Grace, Kathryn A. Ellis, Paul A. Gardiner, Daniel J. Green, David W. Dunstan. Sedentary behavior as a risk factor for cognitive decline? A focus on the influence of glycemic control in brain health. Alzheimers Dement. 2017;3(3):291-300.
Ida S, Murata K. Social Isolation of Older Adults With Diabetes. Gerontol Geriatr Med. 2022;8.
Wang B, Sun Y, Tan X, Zhang J, Wang N, Lu Y. Association of Combined Healthy Lifestyle Factors With Incident Dementia in Patients With Type 2 Diabetes. Neurology. 2022.
Rawlings AM, Sharrett AR, Albert MS, Coresh J, Windham BG, Power MC, et al. The Association of Late-Life Diabetes Status and Hyperglycemia With Incident Mild Cognitive Impairment and Dementia: The ARIC Study. Diabetes Care. 2019;42(7):1248-54.
Li F-R, Yang H-L, Zhou R, Zheng J-Z, Chen G-C, Wu X-X, et al. Influence of Diabetes Duration and Glycemic Control on Dementia: A Cohort Study. J Gerontol A Biol Sci Med Sci. 2021;76(11):2062-70.
Reinke C, Buchmann N, Fink A, Tegeler C, Demuth I, Doblhammer G. Diabetes duration and the risk of dementia: a cohort study based on German health claims data. Age Ageing. 2022;51(1).
Xue M, Xu W, Ou Y-N, Cao X-P, Tan M-S, Tan L, et al. Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies. Ageing Res Rev. 2019;55:100944.
Weinstein G, Davis-Plourde KL, Conner S, Himali JJ, Beiser AS, Lee A, et al. Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer's disease: Pooled analysis from 5 cohorts. PLoS One. 2019;14(2).
Zhou JB, Tang XY, Han M, Yang JK, Simo R. Impact of antidiabetic agents on dementia risk: A Bayesian network meta-analysis. Metabolism-Clinical and Experimental. 2020;109.
D'Cunha NM, McKune AJ, Panagiotakos DB, Georgousopoulou EN, Thomas J, Mellor DD, et al. Evaluation of dietary and lifestyle changes as modifiers of S100beta levels in Alzheimer's disease. Nutr Neurosci. 2019;22(1):1-18.
Sedzikowska A, Szablewski L. Insulin and Insulin Resistance in Alzheimer's Disease. Int J Mol Sci. 2021;22(18).
Wilkinson T, Schnier C, Bush K, Rannikmäe K, Henshall DE, Lerpiniere C, et al. Identifying dementia outcomes in UK Biobank: a validation study of primary care, hospital admissions and mortality data. Eur J Epidemiol. 2019;34(6):557-65.

No competing interests reported.

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Healthy Lifestyle and all-cause and cause-specific dementia in Individuals with or without Type 2 diabetes: the roles of diabetes duration and insulin use

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Abstract

Background

Methods

Results

Conclusions

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Background

Methods

Study design and participants

Assessment Of Type 2 Diabetes And Lifestyle Factors

Assessment Of Outcomes

Assessment Of Covariates

Statistical Analyses

Results

Discussion

Summary of finding

Healthy Lifestyle And Dementia In General Population

Healthy Lifestyle And Dementia In People With T2dm

Role Of Diabetes Duration

Role Of Insulin Use

Strengths And Limitations

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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