Association of serum 25-hydroxyvitamin D concentrations with risk of dementia among individuals with type 2 diabetes: A cohort study in the UK Biobank

Abstract

Background: Several epidemiological studies have suggested that vitamin D status is associated with risk of dementia in general populations. However, due to the synergistic effect between diabetic pathology and neuroinflammation, and the prothrombotic profile in patients with diabetes, whether vitamin D is associated with risk of dementia among patients with diabetes is unclear. This study aimed to investigate the associations of circulating vitamin D levels with risks of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VD) among adults with type 2 diabetes (T2D).

Methods and findings: This study included 13,486 individuals (≥60 years) with T2D and free of dementia at recruitment (2006-2010) from the UK Biobank study. Serum 25-hydroxyvitamin D (25[OH]D) concentrations were measured using the chemiluminescent immunoassay method at recruitment. Serum 25(OH)D ≥ 75 nmol/L was considered sufficient, according to the Endocrine Society Clinical Practice Guidelines. Incidence of all-cause dementia, AD, and VD cases was ascertained using electronic health records (EHRs). Each participant's person-years at risk were calculated from the date of recruitment to the date that dementia was reported, date of death, date of loss to follow-up, or 28 February 2018, whichever occurred first. Among the 13,486 individuals with T2D (mean age, 64.6 years; men, 64.3%), 38.3% had vitamin D ≥ 50 nmol/L and only 9.1% had vitamin D ≥ 75 nmol/L. During a mean follow-up of 8.5 years, we observed 283 cases of all-cause dementia, including 101 AD and 97 VD cases. Restricted cubic spline analysis demonstrated a nonlinear relationship between serum 25(OH)D and risk of all-cause dementia (Pnonlinearity < 0.001) and VD (Pnonlinearity = 0.007), and the nonlinear association reached borderline significance for AD (Pnonlinearity = 0.06), with a threshold at around a serum 25(OH)D value of 50 nmol/L for all the outcomes. Higher serum levels of 25(OH)D were significantly associated with a lower risk of all-cause dementia, AD, and VD. The multivariate hazard ratios and 95% confidence intervals for participants who had serum 25(OH)D ≥ 50 nmol/L, compared with those who were severely deficient (25[OH]D < 25 nmol/L), were 0.41 (0.29-0.60) for all-cause dementia (Ptrend < 0.001), 0.50 (0.27-0.92) for AD (Ptrend = 0.06), and 0.41 (0.22-0.77) for VD (Ptrend = 0.01). The main limitation of the current analysis was the potential underreporting of dementia cases, as the cases were identified via EHRs.

Conclusions: In this study, we observed that higher concentrations of serum 25(OH)D were significantly associated with a lower risk of all-cause dementia, AD, and VD among individuals with T2D. Our findings, if confirmed by replication, may have relevance for dementia prevention strategies that target improving or maintaining serum vitamin D concentrations among patients with T2D.

Fig 1. Multivariable adjusted hazard ratios (HRs) for risks of all-cause dementia, Alzheimer disease, and vascular dementia according to serum 25-hydroxyvitamin D (25[OH]D) level (nmol/L) among patients with type 2 diabetes (≥60 years old).

HRs were adjusted for age at recruitment (years, continuous); sex (male, female); education (college or university degree, A/AS levels or equivalent or O levels/General Certificate of Secondary Education or Certificate of Secondary Education or equivalent, National Vocational Qualification or Higher National Diploma or Higher National Certificate or equivalent or other professional qualifications, none of the above); Townsend deprivation index (continuous); ethnicity (White, Mixed, Asian, Black); blood collection season (Dec–Feb, Mar–May, Jun–Aug, Sep–Nov); sun-exposure time in summer (hours/day, continuous); APOE ε4 (carrier, non-carrier); BMI (kg/m², continuous); alcohol intake (never or special occasions, monthly to weekly, daily); smoking status (never, past, current); physical activity (MET-hours/week, continuous); healthy diet score (≤3, >3); sleep duration (≤6, 7–8, ≥9 hours/day); multivitamin supplements (yes, no); diabetes duration (years, continuous); concentration of HbA1c (mmol/mol, continuous); medication for diabetes (none, only oral medicine, insulin and others); history of hypertension, cardiovascular disease, cancer, and depression (yes, no); medication for hypertension and cholesterol (yes, no); circulating total cholesterol (mmol/L, continuous); triglycerides (mmol/L, continuous); low-density lipoprotein cholesterol (mmol/L, continuous); and C-reactive protein (mg/L, continuous). Values beyond the 1th and 99th percentile of serum 25(OH)D were winsorized to minimize the potential impact of extreme values. P_nonlinearity < 0.001 for all-cause mortality, P_nonlinearity = 0.06 for Alzheimer disease, and P_nonlinearity = 0.007 for vascular dementia. Black curves are HRs, and grey zones are 95% CIs.