Sex-specific patterns and lifetime risk of multimorbidity in the general population: a 23-year prospective cohort study.

BACKGROUND: Multimorbidity poses a major challenge for care coordination. However, data on what non-communicable diseases lead to multimorbidity, and whether the lifetime risk differs between men and women are lacking. We determined sex-specific differences in multimorbidity patterns and estimated sex-specific lifetime risk of multimorbidity in the general population. METHODS: We followed 6,094 participants from the Rotterdam Study aged 45 years and older for the occurrence of ten diseases (cancer, coronary heart disease, stroke, chronic obstructive pulmonary disease, depression, diabetes, dementia, asthma, heart failure, parkinsonism). We visualised participants' trajectories from a single disease to multimorbidity and the most frequent combinations of diseases. We calculated sex-specific lifetime risk of multimorbidity, considering multimorbidity involving only somatic diseases (1) affecting the same organ system, (2) affecting different organ systems, and (3) multimorbidity involving depression. RESULTS: Over the follow-up period (1993-2016, median years of follow-up 9.2), we observed 6334 disease events. Of the study population, 10.3% had three or more diseases, and 27.9% had two or more diseases. The most frequent pair of co-occurring diseases among men was COPD and cancer (12.5% of participants with multimorbidity), the most frequent pair of diseases among women was depression and dementia (14.9%). The lifetime risk of multimorbidity was similar among men (66.0%, 95% CI: 63.2-68.8%) and women (65.1%, 95% CI: 62.5-67.7%), yet the risk of multimorbidity with depression was higher for women (30.9%, 95% CI: 28.4-33.5%, vs. 17.5%, 95% CI: 15.2-20.1%). The risk of multimorbidity with two diseases affecting the same organ is relatively low for both sexes (4.2% (95% CI: 3.2-5.5%) for men and 4.5% (95% CI: 3.5-5.7%) for women). CONCLUSIONS: Two thirds of people over 45 will develop multimorbidity in their remaining lifetime, with women at nearly double the risk of multimorbidity involving depression than men. These findings call for programmes of integrated care to consider sex-specific differences to ensure men and women are served equally.

Prevalence and determinants of healthcare avoidance during the COVID-19 pandemic: A population-based cross-sectional study.

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

Intracranial arteriosclerosis is related to cerebral small vessel disease: a prospective cohort study.

Intracranial arteriosclerosis has been increasingly recognized as a risk factor for cognitive impairment and even dementia. A possible mechanism linking intracranial arteriosclerosis to cognitive impairment and dementia involves structural brain changes including cerebral small vessel disease (CSVD). To assess whether intracranial carotid artery calcification (ICAC) and vertebrobasilar artery calcification (VBAC), as proxies for intracranial arteriosclerosis, are related to CSVD. Within the population-based Rotterdam Study, between 2003 and 2006 a computed tomography (CT)-based measurement of ICAC and VBAC and at least one magnetic resonance imaging (MRI) measurement of structural brain changes were performed from 2005 onwards in 1,489 participants. To estimate the burden of calcification independent of age, we computed age-adjusted percentile curves for ICAC and VBAC separately, based on the calcification volumes. Using the longitudinal MRI data, we assessed whether a larger calcification burden accelerates structural brain changes using appropriate statistical models for repeated outcome measures. A larger burden of ICAC and VBAC was associated with an increase of CSVD markers accelerating over time. A larger burden of ICAC and VBAC was not significantly (p > 0.05) associated with accelerated brain atrophy. Arteriosclerosis is related to accelerating structural brain changes over time.

Lung Function Impairment and the Risk of Incident Dementia: The Rotterdam Study.

BACKGROUND: The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia. OBJECTIVE: To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia. METHODS: In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1/FVC≥0.7, FEV1 < 80% predicted) and in participants with COPD (FEV1/FVC < 0.7) compared to those with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80% predicted). Hazard ratios (HRs) with 95% confidence intervals (CI) for dementia were adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE) genotype. RESULTS: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95% CI, 1.53-4.75; adjusted HRCOPD 1.03; 95% CI, 0.61-1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC% predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95% CI, 1.31-3.98), as well as Alzheimer's disease (AD; adjusted HR 2.13; 95% CI, 1.13-4.02). CONCLUSION: Participants with PRISm or a low FVC% predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC% predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis.

Plasma Brain-Derived Neurotropic Factor Levels Are Associated with Aging and Smoking But Not with Future Dementia in the Rotterdam Study.

BACKGROUND: Brain-derived neurotropic factor (BDNF) plays a vital role in neuronal survival and plasticity and facilitates long-term potentiation, essential for memory. Alterations in BDNF signaling have been associated with cognitive impairment, dementia, and Alzheimer's disease. Although peripheral BDNF levels are reduced in dementia patients, it is unclear whether changes in BDNF levels precede or follow dementia onset. OBJECTIVE: In the present study, we examined the association between BDNF plasma levels and dementia risk over a follow-up period of up to 16 years. METHODS: Plasma BDNF levels were assessed in 758 participants of the Rotterdam Study. Dementia was assessed from baseline (1997-1999) to follow-up until January 2016. Associations of plasma BDNF and incident dementia were assessed with Cox proportional hazards models, adjusted for age and sex. Associations between plasma BDNF and lifestyle and metabolic factors are investigated using linear regression. RESULTS: During a follow up of 3,286 person-years, 131 participants developed dementia, of whom 104 had Alzheimer's disease. We did not find an association between plasma BDNF and risk of dementia (adjusted hazard ratio 0.99; 95%CI 0.84-1.16). BDNF levels were positively associated with age (B = 0.003, SD = 0.001, p = 0.002), smoking (B = 0.08, SE = 0.01, p = < 0.001), and female sex (B = 0.03, SE = 0.01, p = 0.03), but not with physical activity level (B = -0.01, SE = 0.01, p = 0.06). CONCLUSION: The findings suggest that peripheral BDNF levels are not associated with an increased risk of dementia.

Assessment of Advanced Glycation End Products and Receptors and the Risk of Dementia.

Importance: Advanced glycation end products (AGEs) and their receptor (RAGE) are implicated in the pathophysiological processes of dementia and potentially underlie the association of diabetes with neurodegeneration. However, longitudinal studies examining this association are lacking. Objective: To determine whether markers of the AGE-RAGE system are associated with prevalent and incident dementia and with cognition. Design, Setting, and Participants: In this population-based cohort study including participants from the prospective Rotterdam Study, extracellular newly identified RAGE binding protein (EN-RAGE) and soluble RAGE (S-RAGE) were measured in plasma collected between 1997 and 1999 in a random selection of participants, and additionally in participants with prevalent dementia. Participants without dementia were followed up for dementia until 2016. Skin AGEs, measured as skin autofluorescence, and cognition were measured between 2013 and 2016 in participants without dementia. Data analysis was performed from June 2019 to December 2019. Exposures: EN-RAGE, S-RAGE, and skin autofluorescence. Main Outcomes and Measures: Prevalent and incident dementia and cognition, adjusted for potential confounders, including age, sex, diabetes, educational level, APOE ε4 carrier status, smoking, and estimated glomerular filtration rate. Results: Of 3889 included participants (mean [SD] age, 72.5 [8.9] years; 2187 [56.2%] women), 1021 participants had data on plasma markers (mean [SD] age 73.6 [7.8] years; 564 [55.2%] women), 73 participants had dementia at baseline, and during 10 711 person-years of follow-up, 161 participants developed incident dementia. Compared with low levels, high EN-RAGE level was associated with a higher prevalence of dementia (odds ratio [OR], 3.68 [95% CI, 1.50-8.03]; P = .003), while high S-RAGE level was associated with a lower prevalence of dementia (OR, 0.37 [95% CI, 0.17-0.78]; P = .01). These associations attenuated in a longitudinal setting, with hazard ratios of 0.65 (95% CI, 0.42-1.01) for high EN-RAGE (P = .05) and 1.22 (95% CI, 0.82-1.81) for high S-RAGE (P = .33). Among 2890 participants without dementia (mean [SD] age, 72.5 [9.4] years; 1640 [57%] women), higher skin autofluorescence was associated with lower global cognitive function (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.07 [95% CI, -0.11 to -0.04]), especially among carriers of the APOE ε4 allele (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.15 [95% CI, -0.22 to -0.07]). Conclusions and Relevance: These findings suggest that the AGE-RAGE system is associated with cognitive decline and dementia cross-sectionally but not longitudinally. This indicates either a short-term association or reverse causality. Findings of cross-sectional associations between higher skin autofluorescence and lower cognitive function and an association with APOE status also warrant replication and prospective studies.

Balance between innate versus adaptive immune system and the risk of dementia: a population-based cohort study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Alzheimer's disease as a multistage process: an analysis from a population-based cohort study.

In cancer research, multistage models are used to assess the multistep process that leads to the onset of cancer. In view of biological and clinical similarities between cancer and dementia, we used these models to study Alzheimer's disease (AD). From the population-based Rotterdam Study, we included 9,362 non-demented participants, of whom 1,124 developed AD during up to 26 years of follow-up. Under a multistage model, we regressed the logarithm of AD incidence rate against the logarithm of five-year age categories. The slope in this model reflects the number of steps (n-1) required for disease onset before the final step leading to disease manifestation. A linear relationship between log incidence rate and log age was observed, with a slope of 12.82 (95% confidence interval: 9.01-16.62), equivalent to 14 steps. We observed fewer steps for those at high genetically determined risk: 12 steps for APOE-ε4 carriers, and 10 steps for those at highest genetic risk based on APOE and a genetic risk score. The pathogenesis of AD complies with a multistage disease-model, requiring 14 steps before disease manifestation. Genetically predisposed individuals require fewer steps indicating that they already inherited multiple of these steps. Unravelling these steps in AD pathogenesis could benefit the development of intervention strategies.

Lifetime risk and multimorbidity of non-communicable diseases and disease-free life expectancy in the general population: A population-based cohort study.

BACKGROUND: Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk factors on this risk. METHODS AND FINDINGS: Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam Study aged 45 years and older who were free from NCDs at baseline for incident stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease. We quantified occurrence/co-occurrence and remaining lifetime risk of any NCD in a competing risk framework. We additionally studied the lifetime risk of any NCD, age at onset, and overall life expectancy for strata of 3 shared risk factors at baseline: smoking, hypertension, and overweight. During 75,354 person-years of follow-up from a total of 9,061 participants (mean age 63.9 years, 60.1% women), 814 participants were diagnosed with stroke, 1,571 with heart disease, 625 with diabetes, 1,004 with chronic respiratory disease, 1,538 with cancer, and 1,065 with neurodegenerative disease. NCDs tended to co-occur substantially, with 1,563 participants (33.7% of those who developed any NCD) diagnosed with multiple diseases during follow-up. The lifetime risk of any NCD from the age of 45 years onwards was 94.0% (95% CI 92.9%-95.1%) for men and 92.8% (95% CI 91.8%-93.8%) for women. These risks remained high (>90.0%) even for those without the 3 risk factors of smoking, hypertension, and overweight. Absence of smoking, hypertension, and overweight was associated with a 9.0-year delay (95% CI 6.3-11.6) in the age at onset of any NCD. Furthermore, the overall life expectancy for participants without these risk factors was 6.0 years (95% CI 5.2-6.8) longer than for those with all 3 risk factors. Participants aged 45 years and older without the 3 risk factors of smoking, hypertension, and overweight at baseline spent 21.6% of their remaining lifetime with 1 or more NCDs, compared to 31.8% of their remaining life for participants with all of these risk factors at baseline. This difference corresponds to a 2-year compression of morbidity of NCDs. Limitations of this study include potential residual confounding, unmeasured changes in risk factor profiles during follow-up, and potentially limited generalisability to different healthcare settings and populations not of European descent. CONCLUSIONS: Our study suggests that in this western European community, 9 out of 10 individuals aged 45 years and older develop an NCD during their remaining lifetime. Among those individuals who develop an NCD, at least a third are subsequently diagnosed with multiple NCDs. Absence of 3 common shared risk factors is associated with compression of morbidity of NCDs. These findings underscore the importance of avoidance of these common shared risk factors to reduce the premature morbidity and mortality attributable to NCDs.

Kidney Function and the Risk of Stroke and Dementia: The Rotterdam Study.

Longitudinal population-based data on effects of kidney dysfunction in the development of stroke and dementia remains inconclusive. We investigated associations of kidney function with risk of stroke and dementia in 5,993 community-dwelling individuals (mean age: 69.0 years, 57.2% women). We calculated estimated glomerular filtration rates based on creatinine, cystatin-C, and a combination of these two. During a mean follow-up of 11.6 years (69,790 person-years), 1,360 individuals suffered a stroke (n = 601) or developed dementia (n = 759). We found that an impaired kidney function was related to a higher risk of stroke, but not to dementia.

Cognitive Impairment, Sexual Activity and Physical Tenderness in Community-Dwelling Older Adults: A Cross-Sectional Exploration.

BACKGROUND: The ability to engage in sexual activity and better cognitive functioning are both associated with better health. However, the association between cognitive functioning and sexual activity is understudied. OBJECTIVE: To examine the association between cognitive functioning with sexual activity and physical tenderness among community-dwelling older adults. METHODS: From the Rotterdam Study, cognitive impairment and sexual activity were assessed in 4,201 community-dwelling, 60+ year olds between 2008 and 2014 in the Netherlands. Mild cognitive impairment (MCI) was based upon subjective complaints related to age and education-adjusted test scores. Mini-Mental State Examination (MMSE) impairment was defined by a score of < 26. Sexual activity and physical tenderness (e.g., fondling or kissing) in the last 6 months were assessed at an interview. Analyses were stratified by gender and partner status, with prevalence rates for the "no impairment" categories weighted based on age from the cognitive impairment categories. Inter-rater reliability was examined utilising 74 cohabiting couples of opposite gender. RESULTS: It was found that 14% were categorised as having cognitive impairment, and < 1% as dementia (excluded from subsequent analyses). There was strong evidence that the odds of engaging in physical tenderness (observed through MMSE < 26, OR 2.14, 95% CI 1.32-3.48, p = 0.002) and sexual activity (MCI, OR 2.36, 95% CI 1.35-4.12, p = 0.003) among partnered females with no impairment was twice that observed among cognitively impaired partnered females. There was weak evidence that the odds of engaging in physical tenderness (MMSE < 26, OR 1.59, 95% CI 1.04-2.42, p = 0.03) and sexual activity (MMSE < 26, OR 1.51, 95% CI 1.02-2.24, p = 0.04) among partnered males with no impairment was 50% greater than observed among cognitively impaired partnered males. The associations between cognitive functioning and physical tenderness continued to remain after adjustment for physical function, diabetes, cardiovascular disease and cancer. There was no clear evidence of a difference between amnestic and non-amnestic MCI for sexual behaviour. There was moderate to substantial agreement among the coupled adults who had 1 partner categorised with MCI. CONCLUSION: Having no cognitive impairment was associated with more engagement in sexual activity and physical tenderness among community-dwelling older adults. Sexuality is an important aspect of active aging and our findings illustrate a potential barrier to maintaining or instigating intimate relationships as we age. Longitudinal analyses are required to explore the direction of effect.