Addition of inflammation-related biomarkers to the CAIDE model for risk prediction of all-cause dementia, Alzheimer's disease and vascular dementia in a prospective study.

BACKGROUND: It is of interest whether inflammatory biomarkers can improve dementia prediction models, such as the widely used Cardiovascular Risk Factors, Aging and Dementia (CAIDE) model. METHODS: The Olink Target 96 Inflammation panel was assessed in a nested case-cohort design within a large, population-based German cohort study (n = 9940; age-range: 50-75 years). All study participants who developed dementia over 20 years of follow-up and had complete CAIDE variable data (n = 562, including 173 Alzheimer's disease (AD) and 199 vascular dementia (VD) cases) as well as n = 1,356 controls were selected for measurements. 69 inflammation-related biomarkers were eligible for use. LASSO logistic regression and bootstrapping were utilized to select relevant biomarkers and determine areas under the curve (AUCs). RESULTS: The CAIDE model 2 (including Apolipoprotein E (APOE) ε4 carrier status) predicted all-cause dementia, AD, and VD better than CAIDE model 1 (without APOE ε4) with AUCs of 0.725, 0.752 and 0.707, respectively. Although 20, 7, and 4 inflammation-related biomarkers were selected by LASSO regression to improve CAIDE model 2, the AUCs did not increase markedly. CAIDE models 1 and 2 generally performed better in mid-life (50-64 years) than in late-life (65-75 years) sub-samples of our cohort, but again, inflammation-related biomarkers did not improve their predictive abilities. CONCLUSIONS: Despite a lack of improvement in dementia risk prediction, the selected inflammation-related biomarkers were significantly associated with dementia outcomes and may serve as a starting point to further elucidate the pathogenesis of dementia.

HSP70-HSP90 Chaperone Networking in Protein-Misfolding Disease.

Molecular chaperones and their associated co-chaperones are essential in health and disease as they are key facilitators of protein-folding, quality control and function. In particular, the heat-shock protein (HSP) 70 and HSP90 molecular chaperone networks have been associated with neurodegenerative diseases caused by aberrant protein-folding. The pathogenesis of these disorders usually includes the formation of deposits of misfolded, aggregated protein. HSP70 and HSP90, plus their co-chaperones, have been recognised as potent modulators of misfolded protein toxicity, inclusion formation and cell survival in cellular and animal models of neurodegenerative disease. Moreover, these chaperone machines function not only in folding but also in proteasome-mediated degradation of neurodegenerative disease proteins. This chapter gives an overview of the HSP70 and HSP90 chaperones, and their respective regulatory co-chaperones, and explores how the HSP70 and HSP90 chaperone systems form a larger functional network and its relevance to counteracting neurodegenerative disease associated with misfolded proteins and disruption of proteostasis.

High cholesterol levels change the association of biomarkers of neurodegenerative diseases with dementia risk: Findings from a population-based cohort.

INTRODUCTION: This study assessed whether in a population with comorbidity of neurodegenerative and cerebrovascular disease (mixed pathology) the association of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau181 (p-tau181) with dementia risk varied depending on levels of total cholesterol and apolipoprotein E (APOE) ε4 genotype. METHODS: Plasma biomarkers were measured using Simoa technology in 768 participants of a nested case-control study embedded within an ongoing population-based cohort. Logistic and spline regression models, and receiver operating characteristic curves were calculated. RESULTS: The strength of the association between GFAP and NfL with risk of a clinical diagnosis of dementia changed depending on cholesterol levels and on APOE ε4 genotype. No significant association was seen with p-tau181. DISCUSSION: In individuals with mixed pathology blood GFAP and NfL are better predictors of dementia risk than p-tau181, and their associations with dementia risk are amplified by hypercholesterolemia, also depending on APOE ε4 genotype. HIGHLIGHTS: Cholesterol levels changed the association of blood biomarkers with dementia risk. Blood biomarkers seem to perform differently in community- and clinic-based cohorts. Neurofilament light chain might be a biomarker candidate for dementia risk after stroke.

Association of plasma biomarkers, p-tau181, glial fibrillary acidic protein, and neurofilament light, with intermediate and long-term clinical Alzheimer's disease risk: Results from a prospective cohort followed over 17 years.

INTRODUCTION: Blood biomarkers for Alzheimer's disease (AD) are the future of AD risk assessment. The aim of this study was to determine the association between plasma-measured phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) levels and risk of clinical AD incidence with consideration to the impact of cardiovascular health. METHODS: Within a community-based cohort, biomarker levels were measured at baseline using single molecule array technology in 768 participants (aged 50-75) followed over 17 years. Associations among biomarkers and AD, vascular dementia, and mixed dementia incidence were assessed. RESULTS: GFAP was associated with clinical AD incidence even more than a decade before diagnosis (9-17 years), while p-tau181 and NfL were associated with more intermediate AD risk (within 9 years). Significant interaction was detected between cardiovascular health and p-tau181/NfL. DISCUSSION: GFAP may be an early AD biomarker increasing before p-tau181 and NfL and the effect modifying role of cardiovascular health should be considered in biomarker risk stratification.

Axon-Myelin Unit Blistering as Early Event in MS Normal Appearing White Matter.

OBJECTIVE: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease of unknown etiology. Although the prevalent view regards a CD4+ -lymphocyte autoimmune reaction against myelin at the root of the disease, recent studies propose autoimmunity as a secondary reaction to idiopathic brain damage. To gain knowledge about this possibility we investigated the presence of axonal and myelinic morphological alterations, which could implicate imbalance of axon-myelin units as primary event in MS pathogenesis. METHODS: Using high resolution imaging histological brain specimens from patients with MS and non-neurological/non-MS controls, we explored molecular changes underpinning imbalanced interaction between axon and myelin in normal appearing white matter (NAWM), a region characterized by normal myelination and absent inflammatory activity. RESULTS: In MS brains, we detected blister-like swellings formed by myelin detachment from axons, which were substantially less frequently retrieved in non-neurological/non-MS controls. Swellings in MS NAWM presented altered glutamate receptor expression, myelin associated glycoprotein (MAG) distribution, and lipid biochemical composition of myelin sheaths. Changes in tethering protein expression, widening of nodes of Ranvier and altered distribution of sodium channels in nodal regions of otherwise normally myelinated axons were also present in MS NAWM. Finally, we demonstrate a significant increase, compared with controls, in citrullinated proteins in myelin of MS cases, pointing toward biochemical modifications that may amplify the immunogenicity of MS myelin. INTERPRETATION: Collectively, the impaired interaction of myelin and axons potentially leads to myelin disintegration. Conceptually, the ensuing release of (post-translationally modified) myelin antigens may elicit a subsequent immune attack in MS. ANN NEUROL 2021;89:711-725.

Risk of Late-Onset Depression and Cognitive Decline: Results From Inflammatory Proteome Analyses in a Prospective Population-Based Cohort Study.

OBJECTIVE: Research suggests that inflammation is linked to both late-onset depression (LOD) and cognitive decline, and that LOD might have biological underpinnings differentiating it from recurrent depression. Evidence from inflammatory proteome analyses in large prospective cohorts is scarce. The aim of this study was to assess whether and which inflammation-related biomarkers are associated with LOD, recurrent depression, and cognitive decline due to vascular pathology (vascular dementia). DESIGN: Ongoing population-based cohort study of older adults followed for up to 17 years with regard to clinical diagnosis of various age-related diseases (ESTHER study, n = 9,940). SETTING: Longitudinal cohort started in 2000-2002 in a community setting in Saarland, a southwestern German state. PARTICIPANTS: Subgroup of randomly selected participants of the ESTHER study (n = 1,665). MEASUREMENTS: Inflammatory biomarkers were measured with the Olink Target 96 in baseline samples. RESULTS: Out of 78 biomarkers interleukin 10 (IL-10) and C-C chemokine ligand 4 (CCL4) were associated with significantly increased risk of LOD after multiple testing correction. Hazard ratios (95-confidence interval) per 1 standard deviation increase were 1.37 (1.15-1.63) for IL-10 and 1.34 (1.13-1.59) for CCL4. None of the inflammatory markers was associated with recurrent depression. The dose-response analysis showed a similar monotonic risk increase for LOD and vascular dementia with increasing IL-10 levels. CONCLUSION: These results suggest that inflammatory markers are involved in the etiology of LOD, but not of recurrent depression and that LOD and vascular dementia might share common inflammatory etiology with respect to IL-10.

Subjective short-term memory difficulties at ages 50-75 predict dementia risk in a community-based cohort followed over 17 years.

INTRODUCTION: Subjective cognitive decline (SCD) is an established precursor of dementia. However, the relationship between SCD and dementia has been mostly studied among people aged 65+. We aimed to assess the association between subjective memory difficulties at ages 50-75 with all-cause dementia and dementia-subtypes in a community-based cohort with long-term follow-up. METHODS: 6,190 individuals (51% female) aged 50-75 years (median age, 62) attending a general health examination (by a total of 684 general practitioners) in Saarland, Germany, in 2000-2002 were recruited for a community-based cohort study. Subjective difficulties regarding short-term and long-term memory were assessed at baseline with two simple yes/no questions. Associations with dementia (-subtypes) diagnoses during 17 years of follow-up were estimated by Cox proportional hazards models. RESULTS: 492 participants were diagnosed with dementia during 17 years of follow-up. Participants with short-term memory difficulties were at higher risk to receive incident all-cause dementia and vascular dementia diagnoses both within 0-9 years (age and sex adjusted hazard ratios (aHR), 1.80 and 2.00, respectively) and within 0-17 years (aHR 1.55 and 1.78, respectively) from recruitment (P < 0.05 in all cases). For clinical Alzheimer's disease, a significant association was only seen within the initial 6 years. There were no associations of long-term memory difficulties with any type of dementia. CONCLUSIONS: Subjective difficulties in short-term memory predict both intermediate and long-term risk of vascular and all-cause dementia even among late middle-age adults. These results underline the importance of cardiovascular disease prevention efforts well before old age for maintaining cognitive health.

Type 2 diabetes mellitus and cognitive decline in older adults in Germany - results from a population-based cohort.

BACKGROUND: A large body of evidence supports a link between type 2 diabetes mellitus (T2DM) and cognitive function, including dementia. However, longitudinal studies on the association between T2DM and decline of cognitive function are scarce and reported mixed results, and we hence set out to investigate the cross-sectional and longitudinal association between T2DM and global as well as domain-specific cognitive performance. METHODS: We used multivariable regression models to assess associations of T2DM with cognitive performance and cognitive decline in a subsample of a population-based prospective cohort study (ESTHER). This subsample (n = 732) was aged 70 years and older and had participated in telephone-based cognitive function assessment (COGTEL) measuring global and domain-specific cognitive performance during the 5- and 8-year follow-up. RESULTS: Total COGTEL scores of patients with prevalent T2DM were 27.4 ± 8.3 and 29.4 ± 8.7 at the 5- and 8-year measurements, respectively, and were roughly two points lower than those of T2DM-free participants after adjustment for age and sex. In cross-sectional models, after adjustment for several potential confounders, performance in verbal short-term and long-term memory tasks was statistically significantly lower in participants with T2DM, but the association was attenuated after further adjustment for vascular risk factors. The difference in total COGTEL scores reflecting global cognitive function by T2DM status after full adjustment for confounders and vascular risk factors was equivalent to a decrement in global cognitive function associated with a four-year age difference. In longitudinal models, a statistically significantly stronger cognitive decline in patients with T2DM was observed for working memory. CONCLUSIONS: In this sample of older individuals, T2DM was associated with worse performance and stronger decline in a cognitive function test. Memory-related domains were found to be particularly sensitive to T2DM. Further large-scale prospective studies are needed to clarify potential T2DM-related predictors of cognitive decline and possible consequences on the abilities to perform patient self-management tasks in diabetes care.

New use of psychotropic medication after hospitalization among people with dementia.

OBJECTIVES: Psychotropic medication is commonly used among people with dementia (PWD), but it shows modest efficacy and it has been associated with severe adverse events. Hospitalizations are an opportunity for medication management as well as treatment recommendations for outpatient physicians. The aim of this study was to asses factors associated with new use of psychotropic medication after hospitalization among PWD. METHODS: We conducted a retrospective dynamic cohort study from 2004 to 2015 using claims data from a German health insurance company. PWD were identified by an algorithm that included ICD-10 diagnosis and diagnostic measures. The medication classes included were antidepressants, antipsychotics, anxiolytics or hypnotics/sedatives, and Alzheimer's medication. The assessment period was up to 30 days after discharge from the hospital across four hospitalizations. RESULTS: The main predictors for new use of psychotropic medication were similar across medication classes. Neuropsychiatric symptoms (NPS) and the need of care were associated with higher odds of new use of antidepressants, antipsychotics, and anxiolytics or hypnotics/sedatives. A hospital stay due to dementia was an independent predictor for new use across medication classes as well. Delirium increased the odds for new use of antipsychotics and anxiolytics or hypnotics/sedatives. CONCLUSIONS: Factors associated with new use of psychotropic medication included delirium, NPS, and the need of care in PWD. The findings highlight the need for preventive interventions and non-medical treatment options in regards to delirium and NPS as well as for a more intensive use of screening tools for inappropriate medication use among PWD. Key points The percentage of new users was 1.8%, 7.1%, 2.1%, and 2.5% across hospitalizations for antidepressants, antipsychotics, anxiolytics or hypnotics/sedatives, and Alzheimer's medication, respectively. 83.0%, 61.9%, 56.9%, and 88.1% of new users received antidepressants, antipsychotics, anxiolytics or hypnotics/sedatives, and Alzheimer's medication for more than 6 weeks. Delirium and neuropsychiatric symptoms were associated with significantly increased odds of new psychotropic medication use. Hospital stays due to dementia and the need of care were predictors for new use of psychotropic medication.

Associations of urinary 8-iso-prostaglandin F2α levels with all-cause dementia, Alzheimer's disease, and vascular dementia incidence: results from a prospective cohort study.

INTRODUCTION: Prospective studies on a potential association of 8-iso-prostaglandin F2α (8-iso-PGF2α ) levels, a biomarker of lipid peroxidation, with dementia are limited. METHODS: Multivariate Cox regression models were used to assess potential associations of urinary 8-iso-PGF2α levels with all-cause, Alzheimer's disease (AD), and vascular dementia (VD) incidence in 5853 older adults from a German, population-based cohort. RESULTS: Over 14 years of follow-up, 365 all-cause dementia cases including 127 VD and 109 AD cases were diagnosed. Participants in the top compared to the bottom 8-iso-PGF2α tertile had a 45% increased risk of all-cause dementia incidence (hazard ratio [95% confidence interval]: 1.45 [1.12 to 1.88]). Interaction with the apolipoprotein E (APOE) ԑ4/ԑ4 genotype was detected (P = .02). Furthermore, continuously modeled, logarithmized 8-iso-PGF2α levels were statistically significantly associated with all-cause dementia and AD incidence. DISCUSSION: Oxidative stress may be involved in the pathogenesis of dementia. Individuals with increased 8-iso-PGF2α levels and the APOE ԑ4/ԑ4 genotype showed a considerably increased dementia risk.

Prediction of Alzheimer's disease diagnosis within 14 years through Aß misfolding in blood plasma compared to APOE4 status, and other risk factors.

INTRODUCTION: Alzheimer's disease (AD) has a long prodromal stage and identifying high-risk individuals is critical. We aimed to investigate the ability of Aß misfolding in blood plasma, APOE4 status, and dementia risk factors to predict diagnosis of AD. METHODS: Within a community-based cohort, Aß misfolding in plasma measured by immuno-infrared sensor and APOE genotype were determined at baseline in 770 participants followed over 14 years. Associations between Aß misfolding, APOE4, and other predictors with clinical AD, vascular dementia, and mixed dementia diagnoses were assessed. RESULTS: Aß misfolding was associated with a 23-fold increased odds of clinical AD diagnosis within 14 years. No association was observed with vascular dementia/mixed dementia diagnoses. APOE4-positive participants had a 2.4-fold increased odds of clinical AD diagnosis within 14 years. DISCUSSION: Aß misfolding in blood plasma was a strong, specific risk prediction marker for clinical AD even many years before diagnosis in a community-based setting.

Length of hospital stay and dementia: A systematic review of observational studies.

OBJECTIVE: Hospitalizations of people with dementia (PWD) are often accompanied by complications or functional loss and can lead to adverse outcomes. Unsystematic findings suggest an influence of comorbidities on the extent of differences in the length of hospital stay (LOS). This systematic review aimed to identify and evaluate all studies reporting LOS in PWD as compared to PwoD in general hospitals. METHODS: A systematic review of observational studies using PubMed and ISI Web of Knowledge. Inclusion criteria comprised original studies written in English or German, assessment of diagnosis of dementia, measurement of LOS, and comparison of people with and without dementia. RESULTS: Fifty-two of 60 studies reported a longer hospitalization time for PWD compared to PwoD. The extent of the difference in LOS varied between and within countries as well as by type of primary morbidity (eg, injuries, cardiovascular diseases). The range of the LOS difference for studies without restriction to a primary morbidity was -2 to +22 days after matching or adjustment for a variable number and selection of potentially relevant covariates. For studies with injuries/fractures/medical procedures and infectious/vascular disease as the primary morbidity, the range was -2.9 to +12.4 and -11.2 to +21.8 days, respectively. CONCLUSIONS: The majority of studies reported a longer hospitalization of PWD compared to PwoD. Length of hospital stay seems to be influenced by a variety of medical, social, organizational factors, including reasons for hospital admission, whose role should be explored in detail in further research.

Incident depression and mortality among people with different types of dementia: results from a longitudinal cohort study.

PURPOSE: The aim of this study was to investigate the independent and combined association of incident depression and dementia with mortality and to explore whether the magnitude of the association varies according to different types of dementia, including Alzheimer's disease and vascular dementia. METHODS AND DESIGN: The study was based on a population-based longitudinal cohort consisting of 9940 participants at baseline and followed for over 14 years. The sample used for the analyses included 6114 participants with available information on diagnosis of incident dementia and depression. For survival analyses, Cox regression models with incident dementia (n = 293; 5%) and incident depression (n = 746; 12%) as time-dependent variables were used. RESULTS: Cox models adjusted for relevant confounders indicated that comorbidity of incident vascular dementia and incident depression was associated with a much higher mortality risk (HR 6.99; 95% CI 3.84-12.75) than vascular dementia in the absence of depression (HR 2.80; 95% CI 1.92-4.08). In contrast, estimates for comorbidity of Alzheimer's disease and depression were slightly lower than those for Alzheimer in absence of depression (HR 3.56; 95% CI 1.83-6.92 and HR 4.19; 95% CI 2.97-5.90, respectively). Incident depression in the absence of incident dementia was only weakly associated with mortality. CONCLUSIONS: These findings indicate that depression and vascular dementia might have synergistic effects on mortality. The results have relevant public health implications for prevention, routine screening for and early treatment of depression among older people, especially those at risk of vascular dementia.

Apolipoprotein E e4 and Cognitive Function: A Modifiable Association Results from Two Independent Cohort Studies.

BACKGROUND: The apolipoprotein E (APOE) e4 genetic polymorphism is a major risk factor for Alzheimer' s disease, hence the possible prevention of its detrimental effects on cognition is of high relevance. METHODS: We used linear regression models to assess associations of APOE e4 with cognitive performance in a population-based cohort study (n = 1,434) and in a cohort of patients with coronary heart disease (n = 366), and restricted cubic splines to explore dose-response relationships between serum cholesterol levels and cognition depending on APOE polymorphism. RESULTS: The association of APOE e4 with cognitive function was strongly amplified in the presence of hypercholesterolemia and cardiovascular disease in both independent cohorts; hypercholesterolemia was associated with cognitive function only among APOE e4 carriers in the presence of cardiovascular disease. The interaction effect between APOE genotype and hypercholesterolemia was statistically significant in both cohorts. CONCLUSIONS: The detrimental effects of APOE e4 polymorphism on cognition may strongly depend on modifiable risk factors.

The Relation of Obesity to Performance in Verbal Abilities, Processing Speed, and Cognitive Flexibility in Old Age: The Role of Cognitive Reserve.

AIMS: The present study set out to investigate the relation of obesity to performance in verbal abilities, processing speed, and cognitive flexibility and its interplay with key correlates of cognitive reserve in a large sample of older adults. METHODS: A total of 2,812 older adults served as a sample for the present study. Psychometric tests on verbal abilities, processing speed, and cognitive flexibility were administered. In addition, individuals were interviewed on their weight and height (to calculate body mass index; BMI), educational attainment, occupation, and engaging in different activities throughout adulthood. RESULTS: Obesity (BMI ≥30) was significantly associated with a lower performance in verbal abilities, processing speed, and cognitive flexibility. Moderation analyses showed that obesity was related to lower processing speed and cognitive flexibility only in individuals with low engagement in activities and low education. Hierarchical regression analyses showed that obesity was not related to any of the three investigated cognitive performance measures when cognitive reserve in early and midlife was taken into account. CONCLUSION: Present data suggest that cognitive reserve accumulated during the life course may reduce the detrimental influences of obesity on cognitive functioning in old age.

Pre-diagnostic vitamin D concentrations and cancer risks in older individuals: an analysis of cohorts participating in the CHANCES consortium.

The associations of circulating 25-hydroxyvitamin D [25(OH)D] concentrations with total and site-specific cancer incidence have been examined in several epidemiological studies with overall inconclusive findings. Very little is known about the association of vitamin D with cancer incidence in older populations. We assessed the association of pre-diagnostic serum 25(OH)D levels with incidence of all cancers combined and incidence of lung, colorectal, breast, prostate and lymphoid malignancies among older adults. Pre-diagnostic 25(OH)D concentrations and cancer incidence were available in total for 15,486 older adults (mean age 63, range 50-84 years) participating in two cohort studies: ESTHER (Germany) and TROMSØ (Norway); and a subset of previously published nested-case control data from a another cohort study: EPIC-Elderly (Greece, Denmark, Netherlands, Spain and Sweden) from the CHANCES consortium on health and aging. Cox proportional hazards or logistic regression were used to derive multivariable adjusted hazard and odds ratios, respectively, and their 95% confidence intervals across 25(OH)D categories. Meta-analyses with random effects models were used to pool study-specific risk estimates. Overall, lower 25(OH)D concentrations were not significantly associated with increased incidence of most of the cancers assessed. However, there was some evidence of increased breast cancer and decreased lymphoma risk with higher 25(OH)D concentrations. Our meta-analyses with individual participant data from three large European population-based cohort studies provide at best limited support for the hypothesis that vitamin D may have a major role in cancer development and prevention among European older adults.

Cognitive impairment, all-cause and cause-specific mortality among non-demented older adults.

BACKGROUND: cognitive impairment is widespread among older adults even in the absence of dementia, but very little is known about the association between cognitive impairment not due or not yet converted to dementia and mortality. The association between cognitive impairment and mortality contributes to assessing cognitive impairment-related risk constellation in old age in the absence of manifest dementia. OBJECTIVE: to assess the impact of cognitive impairment on all-cause and cause-specific mortality among non-demented older adults and to explore the nature of the association between cognitive impairment and mortality. DESIGN: an observational cohort study (ESTHER study; 2000-present). SETTING: German state of Saarland. SUBJECTS: a subsample of 1,622 participants aged ≥70 with measurement of cognitive function through the Cognitive Telephone Screening Instrument (COGTEL) and exclusion of a possible dementia diagnosis at both COGTEL baseline (2005-08) and over the mortality follow-up (2005-13). RESULTS: during an average follow-up of 6.1 years, 231 participants (14.2%) died. Participants with low COGTEL total scores had ∼60% increased mortality compared with participants with higher COGTEL total scores in Cox regression models adjusting for a wide range of possible confounders (hazard ratio = 1.62; confidence interval 1.13-2.33). Dose-response analyses with restricted cubic splines indicate a monotonic inverse relationship between cognitive function and mortality. CONCLUSION: cognitive impairment in the absence of manifest dementia is an important independent predictor of mortality, especially among men. The administration of cognitive tests among older adults may provide relevant information for patient care and treatment decisions. SOURCES OF FUNDING: financial sponsors played no role in the design, execution, analysis and interpretation of data.

Serum 25-hydroxyvitamin D and cognitive decline: a longitudinal study among non-demented older adults.

BACKGROUND/AIMS: Very few studies have investigated the longitudinal association between serum levels of 25-hydroxyvitamin D [25(OH)D] and cognitive impairment not due to dementia. This longitudinal study analysed 25(OH)D and the risk of cognitive decline among non-demented older adults. METHODS: A subsample of the ESTHER cohort study, aged ≥70 years, was assessed with the Cognitive Telephone Screening Instrument (COGTEL) and underwent 25(OH)D measurements standardized with a reference method (n = 1,302). After an average follow-up of 4.6 years, 527 participants had repeated COGTEL testing and were eligible for analysis. Linear regression models were used to assess longitudinal associations between 25(OH)D levels and cognitive function. Possible practice effects of repeated cognitive testing were addressed with the reliable change index. RESULTS: A trend of a more pronounced cognitive decline with lower vitamin D levels was observed among both women and men, with a statistically significant difference in COGTEL scores in the lowest vitamin D quintile of the total sample. CONCLUSIONS: This study indicates that low levels of vitamin D might be associated with cognitive decline among non-demented elderly individuals and highlights the need for further large-scale prospective studies to clarify the potential role of vitamin D in cognitive function at an old age.

Is vitamin D deficiency a cause of increased morbidity and mortality at older age or simply an indicator of poor health?

To assess whether vitamin D deficiency is a cause of increased morbidity and mortality or simply an indicator of poor health, we assessed (1) the cross-sectional and longitudinal association of vitamin D deficiency with self-rated health (SRH) and frailty and (2) the association of vitamin D deficiency with mortality, with and without control for SRH and frailty. Analyses were performed in 9,579 participants of the German, population-based ESTHER cohort (age-range at baseline: 50-74 years), with follow-ups after 2, 5 and 8 years (mortality: 12 years). During follow-up, 129 subjects newly reported poor SRH, 510 developed frailty and 1,450 died. In cross-sectional analyses, subjects with vitamin D deficiency had higher odds of a poor SRH and frailty but no association with SRH or frailty was observed in longitudinal analyses. The association of vitamin D deficiency with all-cause and several cause-specific mortalities was strong and unaltered by time-dependent adjustment for classic mortality risk factors, SRH and frailty. In conclusion, vitamin D deficiency may not cause frailty or poor general health but may nevertheless be a prognostic marker for mortality, independent of the individual's morbidity.

Comparison of subjective cognitive decline and polygenic risk score in the prediction of all-cause dementia, Alzheimer's disease and vascular dementia.

BACKGROUND: Polygenic risk scores (PRS) and subjective cognitive decline (SCD) are associated with the risk of developing dementia. It remains to examine whether they can improve the established cardiovascular risk factors aging and dementia (CAIDE) model and how their predictive abilities compare. METHODS: The CAIDE model was applied to a sub-sample of a large, population-based cohort study (n = 5,360; aged 50-75) and evaluated for the outcomes of all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VD) by calculating Akaike's information criterion (AIC) and the area under the curve (AUC). The improvement of the CAIDE model by PRS and SCD was further examined using the net reclassification improvement (NRI) method and integrated discrimination improvement (IDI). RESULTS: During 17 years of follow-up, 410 participants were diagnosed with dementia, including 139 AD and 152 VD diagnoses. Overall, the CAIDE model showed high discriminative ability for all outcomes, reaching AUCs of 0.785, 0.793, and 0.789 for all-cause dementia, AD, and VD, respectively. Adding information on SCD significantly increased NRI for all-cause dementia (4.4%, p = 0.04) and VD (7.7%, p = 0.01). In contrast, prediction models for AD further improved when PRS was added to the model (NRI, 8.4%, p = 0.03). When APOE ε4 carrier status was included (CAIDE Model 2), AUCs increased, but PRS and SCD did not further improve the prediction. CONCLUSIONS: Unlike PRS, information on SCD can be assessed more efficiently, and thus, the model including SCD can be more easily transferred to the clinical setting. Nevertheless, the two variables seem negligible if APOE ε4 carrier status is available.