Thomas J. Littlejohns

Vitamin D and the risk of dementia and Alzheimer disease

Objective: To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease. Methods: One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population–based Cardiovascular Health Study between 1992–1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992–1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimers Disease and Related Disorders Association criteria. Results: During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23–4.13) and 1.53 (95% CI: 1.06–2.21) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02–4.83) and 1.69 (95% CI: 1.06–2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L. Conclusion: Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.

'Vitamin D and cognition in older adults': updated international recommendations.

Hypovitaminosis D, a condition that is highly prevalent in older adults aged 65 years and above, is associated with brain changes and dementia. Given the rapidly accumulating and complex contribution of the literature in the field of vitamin D and cognition, clear guidance is needed for researchers and clinicians.

Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants With Those of the General Population.

Abstract The UK Biobank cohort is a population-based cohort of 500,000 participants recruited in the United Kingdom (UK) between 2006 and 2010. Approximately 9.2 million individuals aged 40–69 years who lived within 25 miles (40 km) of one of 22 assessment centers in England, Wales, and Scotland were invited to enter the cohort, and 5.5% participated in the baseline assessment. The representativeness of the UK Biobank cohort was investigated by comparing demographic characteristics between nonresponders and responders. Sociodemographic, physical, lifestyle, and health-related characteristics of the cohort were compared with nationally representative data sources. UK Biobank participants were more likely to be older, to be female, and to live in less socioeconomically deprived areas than nonparticipants. Compared with the general population, participants were less likely to be obese, to smoke, and to drink alcohol on a daily basis and had fewer self-reported health conditions. At age 70–74 years, rates of all-cause mortality and total cancer incidence were 46.2% and 11.8% lower, respectively, in men and 55.5% and 18.1% lower, respectively, in women than in the general population of the same age. UK Biobank is not representative of the sampling population; there is evidence of a “healthy volunteer” selection bias. Nonetheless, valid assessment of exposure-disease relationships may be widely generalizable and does not require participants to be representative of the population at large.

Vitamin D and Memory Decline: Two Population-Based Prospective Studies.

BACKGROUND Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown. OBJECTIVE To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline. METHODS We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Reys Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively. RESULTS In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34). CONCLUSIONS Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.

The acceptability of repeat Internet-based hybrid diet assessment of previous 24-h dietary intake: administration of the Oxford WebQ in UK Biobank.

Although dietary intake over a single 24-h period may be atypical of an individuals habitual pattern, multiple 24-h dietary assessments can be representative of habitual intake and help in assessing seasonal variation. Web-based questionnaires are convenient for the participant and result in automatic data capture for study investigators. This study reports on the acceptability of repeated web-based administration of the Oxford WebQ--a 24-h recall of frequency from a set food list suitable for self-completion from which energy and nutrient values can be automatically generated. As part of the UK Biobank study, four invitations to complete the Oxford WebQ were sent by email over a 16-month period. Overall, 176 012 (53% of those invited) participants completed the online version of the Oxford WebQ at least once and 66% completed it more than once, although only 16% completed it on all four occasions. The response rate for any one round of invitations varied between 34 and 26%. On most occasions, the Oxford WebQ was completed on the same day that they received the invitation, although this was less likely if sent on a weekend. Participants who completed the Oxford WebQ tended to be white, female, slightly older, less deprived and more educated, which is typical of health-conscious volunteer-based studies. These findings provide preliminary evidence to suggest that repeated 24-h dietary assessment via the Internet is acceptable to the public and a feasible strategy for large population-based studies.

Lifestyle factors and prostate-specific antigen (PSA) testing in UK Biobank: Implications for epidemiological research

Highlights • Prostate-specific antigen (PSA) testing is key in diagnosing prostate cancer.• Risk factors for prostate cancer were related to the likelihood of PSA testing.• There is potential for detection bias in epidemiological studies of prostate cancer.

Serum Leptin and Risk of Cognitive Decline in Elderly Italians

Background US studies suggest that leptin, a fat-derived hormone, may be protective against the development of dementia. Objective To investigate the complex relationship between leptin levels and cognitive decline in elderly Italians. Methods We studied circulating fasting leptin levels in 809 elderly adults free from dementia who participated in the prospective Italian population-based InCHIANTI study between 1998 and 2009 (mean follow-up of 8.0 years). Global cognitive decline was defined as a reduction of ≥5 points on the Mini-Mental State Examination (MMSE). Trail-Making Tests A and B were also incorporated, with cognitive decline defined as discontinued testing or the worst 10% of change from baseline. We also investigated whether any association could be explained by midlife weight and whether cognitive decline was associated with changing leptin levels. Results The multivariate adjusted relative risk ([RR]; 95% confidence interval [CI]) of cognitive decline on the MMSE was 0.84 (95% CI 0.73–0.97) in relation to baseline sex-standardized log-leptin levels. High leptin levels showed a non-significant trend toward a reduced risk of decline on the Trail-Making Tests A (RR = 0.85, 95% CI 0.71–1.02) and B (RR = 0.90, 0.79–1.02). Adjusting for midlife weight or change in weight did not alter the pattern of results, and cognitive decline was not associated with changing leptin levels. Conclusions High leptin levels were independently associated with a reduced risk of cognitive decline in elderly Italians.

UK Biobank: opportunities for cardiovascular research.

Cardiovascular diseases are a major cause of morbidity and mortality, accounting for 45% of all deaths in European countries in 20161 and almost a third of deaths worldwide in 2013.2 A similar pattern is observed in the UK where cardiovascular diseases were responsible for 27% of deaths in 2014, with coronary heart disease resulting in the largest number of deaths attributable to a single cause (n = ∼69 000) whilst stroke is the third biggest cause (n = ∼39 000).3 Although age-standardized cardiovascular disease mortality rates are decreasing worldwide, the total deaths and burden as measured through disability-adjusted life years of cardiovascular diseases are increasing.4,5 Furthermore, in the UK, cardiovascular risk factors such as high blood pressure and high cholesterol are among the leading causes of disease burden.6 Epidemiological studies have historically played an essential role in identifying the causes and consequences of cardiovascular disease and have resulted in improvements in prevention and treatment. The seminal US-based Framingham Heart Study which recruited 5200 participants between 1948 and 1952, was integral in identifying a range of important risk factors for cardiovascular disease, such as high blood pressure, a high cholesterol level, cigarette smoking, obesity and physical inactivity, and consequently shifted the focus from management to preventative strategies for cardiovascular disease.7 This, together with findings from other epidemiological studies, such as the Seven Countries Study and the MONICA project,8 have been influential in leading to treatments for the primary and secondary prevention of cardiovascular events, most notably statins (that act to lower cholesterol levels), and anithypertensives.9,10 Epidemiological studies such as the Framingham Heart Study with moderate sample sizes are useful in detecting risk factors with large effects on common outcomes; however, they lack statistical power to reliably identify risk factors which have small to moderate effects or to assess associations with disease across subgroups of the population. The need for large sample sizes has led to collaborative efforts, such as the Prospective Studies Collaboration (an individual participant meta-analysis of data from 61 studies and more than a million participants11) that has demonstrated conclusively that a continuous increase in blood pressure corresponds with an increased risk of vascular death across all age groups (see Figure ​Figure11 that illustrates the importance of a large sample size (about 500 000 participants) for detecting this association).12 Sample size is also of particular importance in the current era of genome-wide association studies, where many investigations are aiming to detect either small effects from common variants or large effects from rare variants.13 Open in a separate window Figure 1 Absolute risk of ischaemic heart disease mortality by usual systolic blood pressure and age at risk in 5000, 50 000, and 500 000 participants. Unpublished figure containing data from the Prospective Studies Collaboration, obtained through personal communication. CI, confidence interval; IHD, ischaemic heart disease.

OP41 The representativeness of the UK Biobank cohort on a range of sociodemographic, physical, lifestyle and health-related characteristics

Background UK Biobank (UKB) is a population-based cohort study of half a million participants aged 40–69 recruited between 2006 and 2010 in England, Wales and Scotland. In order to investigate the representativeness of UKB, the distribution of a range of sociodemographic, physical, lifestyle and health-related characteristics was compared between UKB participants and (a) UKB invitees (i.e. all those invited to join UKB including those who did not participate) and (b) findings from nationally representative surveys. Methods The response rate for age, sex and socioeconomic status was compared between 503,310 UKB participants and 8,761,869 UKB invitees. Other characteristics of the cohort were compared with nationally representative data sources, including the UK Census (for data on ethnicity), the Health Survey for England (for data on body mass index, smoking, alcohol consumption and prevalence of self-reported health outcomes) and the Office for National Statistics (for data on national cancer incidence and mortality rates). For all data sources, summary data was selected that matched, as closely as possible, the UKB cohort with regard to population characteristics (age, sex), geographical coverage and period of data collection (2006–2010). Methods The overall response rate to UKB was 5.5%, and was higher in women, older age groups and those from less socioeconomically deprived areas. Compared with the general population, UKB participants were less likely to be obese, to smoke, to drink on a daily basis and have fewer self-reported diseases. The ethnic background of UKB was similar to that of the national population from the 2001 UK Census (both with 95% from a white ethnic background) but less similar compared with the 2011 UK census (91% white ethnic background). Total cancer incidence rates were 31% lower in men and 42% lower in women at ages 65–69 compared with the national population. All-cause mortality in UKB at ages 65–69 was 56.0% lower in men and 67.6% lower in women compared to national death rates. Conclusion UKB is not representative of the general population on a variety of sociodemographic, physical, lifestyle and health-related characteristics, with evidence of a ‘healthy volunteer’ selection bias. As a result, UKB is not suitable for deriving generalizable disease prevalence and incidence rates, although its large size and heterogeneity of exposure measures do provide valid scientific inferences of associations between exposures and health outcomes that are generalizable to many other populations.

Coronary Artery Bypass Graft Surgery and Dementia Risk in the Cardiovascular Health Study

Introduction: The association between history of coronary artery bypass graft surgery (CABG) and dementia risk remains unclear. Methods: We conducted a prospective cohort analysis using data on 3155 elderly adults free from prevalent dementia from the US population-based Cardiovascular Health Study (CHS) with adjudicated incident all-cause dementia, Alzheimer disease (AD), vascular dementia (VaD), and mixed dementia. Results: In the CHS, the hazard ratio (HR) for all-cause dementia was 1.93 [95% confidence interval (CI), 1.36-2.74] for those with CABG history compared with those with no CABG history after adjustment for potential confounders. Similar HRs were observed for AD (HR=1.71; 95% CI, 0.98-2.98), VaD (HR=1.42; 95% CI, 0.56-3.65), and mixed dementia (HR=2.73; 95% CI, 1.55-4.80). The same pattern of results was observed when these CHS findings were pooled with a prior prospective study, the pooled HRs were 1.96 (95% CI, 1.42-2.69) for all-cause dementia, 1.71 (95% CI, 1.04-2.79) for AD and 2.20 (95% CI, 0.78-6.19) for VaD. Discussion: Our results suggest CABG history is associated with long-term dementia risk. Further investigation is warranted to examine the causal mechanisms which may explain this relationship or whether the association reflects differences in coronary artery disease severity.