The exact etiology of dementia is still unclear, but both genetic and lifestyle factors are thought to be key drivers of this complex disease. The recognition of familial patterns of dementia has led ...to the discovery of genetic factors that have a role in the pathogenesis of dementia, including the apolipoprotein E (APOE) genotype and a large and still-growing number of genetic variants
. Beyond genetic architecture, several modifiable risk factors have been implicated in the development of dementia
. Prevention trials of measures to halt or delay cognitive decline are increasingly recruiting older individuals who are genetically predisposed to dementia. However, it remains unclear whether targeted health and lifestyle interventions can attenuate or even offset increased genetic risk. Here, we leverage long-term data on both genetic and modifiable risk factors from 6,352 individuals aged 55 years and older in the population-based Rotterdam Study. In this study, we demonstrate that, in individuals at low and intermediate genetic risk, favorable modifiable-risk profiles are related to a lower risk of dementia compared to unfavorable profiles. In contrast, these protective associations were not found in those at high genetic risk.
Apart from blood pressure level itself, variation in blood pressure has been implicated in the development of stroke in subgroups at high cardiovascular risk. We determined the association between ...visit-to-visit blood pressure variability and stroke risk in the general population, taking into account the size and direction of variation and several time intervals prior to stroke diagnosis.
From 1990 to 2016, we included 9,958 stroke-free participants of the population-based Rotterdam Study in the Netherlands. This is a prospective cohort study including participants aged 45 years and older. Systolic blood pressure (SBP) variability was calculated as absolute SBP difference divided by mean SBP over 2 sequential visits (median 4.6 years apart). Directional SBP variability was defined as SBP difference over 2 visits divided by mean SBP. Using time-varying Cox proportional hazards models adjusted for age, sex, mean SBP, and cardiovascular risk factors, hazard ratios (HRs) for stroke up to January 2016 were estimated per SD increase and in tertiles of variability. We also conducted analyses with 3-, 6-, and 9-year intervals between variability measurement and stroke assessment. These analyses were repeated for diastolic blood pressure (DBP). The mean age of the study population was 67.4 ± 8.2 years and 5,776 (58.0%) were women. During a median follow-up of 10.1 years, 971 (9.8%) participants had a stroke, including 641 ischemic, 89 hemorrhagic, and 241 unspecified strokes. SBP variability was associated with an increased risk of hemorrhagic stroke (HR per SD 1.27, 95% CI 1.05-1.54, p = 0.02) and unspecified stroke (HR per SD 1.21, 95% CI 1.09-1.34, p < 0.001). The associations were stronger for all stroke subtypes with longer time intervals; the HR for any stroke was 1.29 (95% CI 1.21-1.36, p < 0.001) at 3 years, 1.47 (95% CI 1.35-1.59, p < 0.001) at 6 years, and 1.38 (95%CI 1.24-1.51, p < 0.001) at 9 years. For DBP variability, we found an association with unspecified stroke risk. Both the rise and fall of SBP and the fall of DBP were associated with an increased risk for unspecified stroke. Limitations of the study include that, due to an average interval of 4 years between visits, our findings may not be generalizable to blood pressure variability over shorter periods.
In this population-based study, we found that visit-to-visit blood pressure variation was associated with an increased risk of unspecified and hemorrhagic stroke, independent of direction of variation or mean blood pressure.
Sleep disturbances may signal presence of prodromal parkinsonism, including Parkinson's disease. Whether general sleep quality or duration in otherwise healthy subjects is related to the risk of ...parkinsonism remains unclear. We hypothesized that both worse self-reported sleep quality and duration, as well as a longitudinal deterioration in these measures, are associated with the risk of parkinsonism, including Parkinson's disease. In the prospective population-based Rotterdam Study, we assessed sleep quality and duration with the Pittsburgh Sleep Quality Index in 7726 subjects (mean age 65 years, 57% female) between 2002 and 2008, and again in 5450 subjects between 2009 and 2014. Participants were followed until 2015 for a diagnosis of parkinsonism and Parkinson's disease. Outcomes were assessed using multiple modalities: interviews, physical examination, and continuous monitoring of pharmacy records and medical records of general practitioners. We used Cox regression to associate sleep, and changes in sleep over time, with incident parkinsonism and Parkinson's disease, adjusting for age, sex, education and smoking status. Over 64 855 person-years in 13 years of follow-up (mean: 8.4 years), 75 participants developed parkinsonism, of whom 47 developed Parkinson's disease. We showed that within the first 2 years of follow-up, worse sleep quality {hazard ratio (HR) 2.38 per standard deviation increase 95% confidence interval (CI 0.91-6.23)} and shorter sleep duration HR 0.61 per standard deviation increase (95% CI 0.31-1.21) related to a higher risk of parkinsonism. Associations of worse sleep quality HR 3.86 (95% CI 1.19-12.47) and shorter sleep duration HR 0.48 (95% CI 0.23-0.99) with Parkinson's disease were more pronounced, and statistically significant, compared to parkinsonism. This increased risk disappeared with longer follow-up duration. Worsening of sleep quality HR 1.76 per standard deviation increase (95% CI 1.12-2.78), as well as shortening of sleep duration HR 1.72 per standard deviation decrease (95% CI 1.08-2.72), were related to Parkinson's disease risk in the subsequent 6 years. Therefore, we argue that in the general population, deterioration of sleep quality and duration are markers of the prodromal phase of parkinsonism, including Parkinson's disease.
Alzheimer's disease is one of the most heritable diseases in elderly people and the most common type of dementia. In addition to the major genetic determinant of Alzheimer's disease, the APOE gene, ...23 genetic variants have been associated with the disease. We assessed the effects of these variants and APOE on cumulative risk and age at onset of Alzheimer's disease and all-cause dementia.
We studied incident dementia in cognitively healthy participants (aged >45 years) from the community-based Rotterdam Study, an ongoing prospective cohort study based in Rotterdam, the Netherlands, focusing on neurological, cardiovascular, endocrine, and ophthalmological disorders, and other diseases in elderly people. The Rotterdam Study comprises participants in three baseline cohorts (initiated in 1990, 2000, and 2006), who are re-invited to the research centre every 3–4 years, and continuously monitored by records from general practitioners and medical specialists. Cumulative incidence curves up to age 100 years were calculated for Alzheimer's disease and dementia, taking into account mortality as a competing event. These risk curves were stratified by APOE genotypes, tertiles of a weighted genetic risk score (GRS) of 23 Alzheimer's disease-associated genetic variants, and parental history of dementia.
12 255 of 14 926 participants (58·5% women) from the Rotterdam Study were included in this study. During a median follow-up of 11·0 years (IQR 4·9–15·9; 133 123 person years), 1609 participants developed dementia, of whom 1262 (78%) were classified as having Alzheimer's disease; 3310 people died of causes other than dementia. Both APOE and the GRS significantly modified the risks of Alzheimer's disease and dementia. There was evidence for a significant interaction between APOE genotypes and the GRS for the association with Alzheimer's disease (p=0·03) and dementia (p=0·04); the risk for carriers homozygous for APOE ε4 was modified most by the GRS. In carriers homozygous for APOE ε4, the difference between the high-risk tertile and the low-risk tertile by age 85 years was 27·0% for Alzheimer's disease (p=8·5 × 10−3) and 37·2% for dementia (p=2·2 × 10−4), which translates to a 7–10 year difference in age at onset. Comparing the risk extremes, which were carriers homozygous for APOE ε2 or heterozygous with one copy each of the ε2 and ε3 alleles in the low-risk tertile of the GRS versus carriers homozygous for APOE ε4 in the high-risk tertile of the GRS, the difference in risk by age 85 years was 58·6% (4·1% vs 62·7%; p=6·2 × 10−13) for Alzheimer's disease, and 70·3% (7·2% vs 77·5%; p=3·0 × 10−23) for dementia. These risk differences translate into an 18–29 years difference in age at onset for Alzheimer's disease and an 18–23 year difference in age at onset dementia. This difference becomes more pronounced when parental history of dementia is considered (difference in risk 83·8%; p=1·1 × 10−20).
Common variants with small individual effects jointly modify the risk and age at onset of Alzheimer's disease and dementia, particularly in APOE ε4 carriers. These findings highlight the potential of common variants in determining Alzheimer's disease risk.
None.
During the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic ...levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance.
On April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19-specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 95% confidence interval (CI) 1.08 to 1.21), female sex (1.58 1.38 to 1.82), low educational level (primary education versus higher vocational/university 1.21 1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 1.80 to 2.22), unemployment (versus employed 2.29 1.54 to 3.39), smoking (1.34 1.08 to 1.65), concern about contracting COVID-19 (per level increase 1.28 1.19 to 1.38) and symptoms of depression (per point increase 1.13 1.11 to 1.14) and anxiety (per point increase 1.16 1.14 to 1.18). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population.
In this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences.
Plasma amyloid-β (Aβ) levels are increasingly studied as a potential accessible marker of cognitive impairment and dementia. However, it remains underexplored whether plasma Aβ levels including the ...novel Aβ peptide 1-38 (Aβ
) relate to preclinical markers of neurodegeneration and risk of dementia. We investigated the association of plasma Aβ
, Aβ
, and Aβ
levels with imaging markers of neurodegeneration and risk of dementia in a prospective population-based study.
We analyzed plasma Aβ levels in 458 individuals from the Rotterdam Study. Brain volumes, including gray matter, white matter, and hippocampus, were computed on the basis of 1.5-T magnetic resonance imaging (MRI). Dementia and its subtypes were defined on the basis of internationally accepted criteria.
A total of 458 individuals (mean age, 67.8 ± 7.7 yr; 232 50.7% women) with baseline MRI scans and incident dementia were included. The mean ± SD values of Aβ
, Aβ
, and Aβ
(in pg/ml) were 19.4 ± 4.3, 186.1 ± 35.9, and 56.3 ± 6.2, respectively, at baseline. Lower plasma Aβ
levels were associated with smaller hippocampal volume (mean difference in hippocampal volume per SD decrease in Aβ
levels, - 0.13; 95% CI, - 0.23 to - 0.04; p = 0.007). After a mean follow-up of 14.8 years (SD, 4.9; range, 4.1-23.5 yr), 79 persons developed dementia, 64 of whom were diagnosed with Alzheimer's disease (AD). Lower levels of Aβ
and Aβ
were associated with increased risk of dementia, specifically AD (HR for AD per SD decrease in Aβ
levels, 1.39; 95% CI, 1.00-2.16; HR for AD per SD decrease in Aβ
levels, 1.35; 95% CI, 1.05-1.75) after adjustment for age, sex, education, cardiovascular risk factors, apolipoprotein E ε4 allele carrier status, and other Aβ isoforms.
Our results show that lower plasma Aβ levels were associated with risk of dementia and incident AD. Moreover, lower plasma Aβ
levels were related to smaller hippocampal volume. These results suggest that plasma Aβ
and Aβ
maybe useful biomarkers for identification of individuals at risk of dementia.
Exercise may be a promising target for depression interventions. However, evidence for a beneficial effect of exercise interventions on the prevention of depression differs substantially across ...different studies.
A systematic search was performed up to July 2018 using PubMed, Embase, PsycINFO, and Cochrane. Articles were included if a meta-analysis of randomized controlled trials was performed that examined the effect of exercise interventions on the onset of depression or depressive symptoms in the general population. Meta-analyses focusing on treatment of diagnosed depression were excluded. Two authors independently screened the articles and graded the quality of included meta-analyses using AMSTAR 2.
Eight meta-analyses were included that showed little overlap in 134 included studies. All meta-analyses reported on depressive symptoms rather than onset of depression. Five of these were rated as moderate quality and three of low quality. Six meta-analyses found significant effects, and two found non-significant effects of exercise interventions in reducing depressive symptoms in children, adolescents, adults and the elderly (effect sizes ranging from - 0.10 to - 0.81). Scarce evidence did not allow to draw conclusions about the role of sex and characteristics of exercise on depression. However, some findings suggest that low intensity exercise was as effective as high intensity exercise. Heterogeneity among primary studies was high, likely caused by differences in study quality and exercise characteristics.
The evidence from this study suggests that exercise interventions have a beneficial effect on depressive symptoms in the general population across a wide age-range.
Total hippocampal volume has been consistently linked to cognitive function and dementia. Yet, given its complex and parcellated internal structure, the role of subregions of the hippocampus in ...cognition and risk of dementia remains relatively underexplored. We studied subregions of the hippocampus in a large population-based cohort to further understand their role in cognitive impairment and dementia risk.
We studied 5035 dementia- and stroke-free persons from the Rotterdam Study, aged over 45 years. All participants underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Automatic segmentation of the hippocampus and 12 of its subregions was performed using the FreeSurfer software (version 6.0). A cognitive test battery was performed, and participants were followed up for the development of dementia until 2015. Associations of hippocampal subregion volumes with cognition and incident dementia were examined using linear and Cox regression models, respectively. All analyses were adjusted for age, sex, education, and total hippocampal volume.
Mean age was 64.3 years (SD 10.6) with 56% women. Smaller volumes of the hippocampal fimbria, presubiculum and subiculum showed the strongest associations with poor performance on several cognitive domains, including executive function but not memory. During a mean follow-up of 5.5 years, 76 persons developed dementia. Smaller subiculum volume was associated with risk of dementia adjusted for total volume (hazard ratio per SD decrease in volume: 1.75, 95% confidence interval 1.35; 2.26).
In a community-dwelling non-demented population, we describe patterns of association between hippocampal subregions with cognition and risk of dementia. Specifically, the subiculum was associated with both poorer cognition and higher risk of dementia.
•Hippocampal subregions were related to many cognitive domains.•The subiculum and pre-subiculum displayed strong relations to executive dysfunction.•Smaller subiculum volume was associated to risk of incident dementia.•The subiculum relation to dementia risk remained stable over the follow-up period.
Immunity has been suggested to be important in the pathogenesis of dementia. However, the contribution of innate versus adaptive immunity in the development of dementia is not clear. In this study, ...we aimed to investigate (1) the association between components of innate immunity (granulocytes and platelets) and adaptive immunity (lymphocytes) with risk of dementia and (2) the association between their derived ratios (granulocyte-to-lymphocyte ratio GLR, platelet-to-lymphocyte ratio PLR, and systemic immune-inflammation index SII), reflecting the balance between innate and adaptive immunity, with risk of dementia.
Blood cell counts were measured repeatedly between 2002 and 2015 in dementia-free participants of the prospective population-based Rotterdam Study. Participants were followed-up for dementia until 1 January 2016. Joint models were used to determine the association between granulocyte, platelets, and lymphocyte counts, and their derived ratios with risk of dementia.
Of the 8313 participants (mean standard deviation age 61.1 7.4 years, 56.9% women), 664 (8.0%) developed dementia during a median follow-up of 8.6 years. Doubling of granulocyte and platelet counts tended to be associated with an increased risk of dementia (HR 95%CI 1.22 0.89-1.67 and 1.45 1.07-1.95, respectively). Doubling of the derived ratios GLR, PLR, and SII were all associated with an increased dementia risk (HR 95%CI 1.26 1.03-1.53, 1.27 1.05-1.53, and 1.15 0.98-1.34, respectively).
GLR, PLR, and SII are associated with an increased risk of dementia in the general population. This supports the role of an imbalance in the immune system towards innate immunity in the pathogenesis of dementia.
Herpes simplex virus 1 (HSV1) is a neuroinvasive virus capable of entering the brain which makes it a candidate pathogen for increasing risk of dementia. Previous studies are inconsistent in their ...findings regarding the link between HSV1 and dementia, therefore, we investigated how HSV1 relates to cognitive decline and dementia risk using data from a population-based study. We measured HSV1 immunoglobulin (IgG) antibodies in serum collected between 2002 and 2005 from participants of the Rotterdam Study. We used linear regression to determine HSV1 in relation to change in cognitive performance during 2 consecutive examination rounds on average 6.5 years apart. Next, we determined the association of HSV1 with risk of dementia (until 2016) using a Cox regression model. We repeated analyses for Alzheimer's disease. All models were adjusted for age, sex, cardiovascular risk factors, and apolipoprotein E genotype. Of 1915 non-demented participants (mean age 71.3 years, 56.7% women), with an average follow-up time of 9.1 years, 244 participants developed dementia (of whom 203 Alzheimer's disease). HSV1 seropositivity was associated with decline in global cognition (mean difference of HSV1 seropositive vs seronegative per standard deviation decrease in global cognition - 0.16; 95% confidence interval (95%CI), - 0.26; - 0.07), as well as separate cognitive domains, namely memory, information processing, and executive function, but not motor function. Finally, HSV1 seropositivity was not associated with risk of dementia (adjusted hazard ratio 1.18, 95% CI 0.83; 1.68), similar for Alzheimer's disease. HSV1 is associated with cognitive decline but not with incident dementia in the general population. These data suggest HSV1 to be associated only with subtle cognitive disturbances but not with greater cognitive disorders that result in dementia.
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