Cardiovascular Risk Factors, Aging And Dementia Research Articles

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

BackgroundIt is of interest whether inflammatory biomarkers can improve dementia prediction models, such as the widely used Cardiovascular Risk Factors, Aging and Dementia (CAIDE) model.MethodsThe 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).ResultsThe 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.ConclusionsDespite 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.

Design and Rationale of a Two-Armed Randomized Controlled Trial on Yoga/Brisk Walking-Based Lifestyle Modification on Dementia Risk Reduction, and Influence of ApoE Genotypes on the Intervention.

Though considered a late-onset disease, the 2020 report of the Lancet Commission emphasizes the necessity of conducting primary prevention trials with an approach of never too early in the life course for dementia prevention. Driven by the same notion, we hereby aim to compare the dementia risk reduction potential of two potential interventions, 48 weeks (12 months) of yoga and brisk walking, in middle-aged high-risk subjects. A randomized controlled trial. Community in India. In total, 323 at-risk dementia subjects will be recruited from community settings through health awareness camps and door-to-door surveys across Delhi, India. Participants will be randomized into yoga or brisk-walking groups (1:1). The yoga intervention group will receive 60 contact yoga sessions per 60-min/day at the community parks, followed by continued tele-supervised home practice, further followed by at-home self-practice, and will be tested at 3-time points (baseline, 24-week and 48-week, post-randomization) to test the efficacy of the intervention. The control group will be asked to do brisk walking daily for 45 minutes at their convenience, followed by weekly telephone follow-ups. Applying the intention-to-treat principle, the primary endpoint will be the change from baseline at the 12th month in the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) Scores. Secondary outcomes will include the composite scores derived from a comprehensive neuropsychology battery, comprising the Trail Making Test, Digit Span Test, N Back, Color Trail, Animal Fluency Test, COWA (Controlled Oral Word Association Test), and Digit Symbol Substitution. The primary outcome will be analyzed using mixed-effect models for repeated measures, adjusted for covariates as fixed effects. The study has been prospectively registered (CTRI/2023/02/049746) on February 15, 2023. The protocol was conceptualized in 2021 and approved by the Institutional Ethics Committee of SVYASA. Recruitment began in February 2023 and is underway with patient enrollment. To our knowledge, this is the first controlled trial to investigate the longitudinal effects of a yoga-based intervention on dementia risk reduction using the CAIDE risk score. The findings of this trial will also provide insight into a better understanding of genotype-dependent responses to yoga intervention and open up avenues for understanding the implications of gene-intervention interactions for precision prevention using yoga.

Interaction between Oligomeric Amyloid‐β and Cardiovascular Risk Factors is Associated with Executive and Dorsal Attention Network Dysfunction in Pre‐dementia

AbstractBackgroundOligomeric amyloid‐β(OAβ) accumulation within brain tissue has been shown to be associated with major AD neuropathological features including tau pathology, synaptic loss, inflammation and oxidative damage; as well as cognitive impairment in dementia cohorts (Celine.E.N et.al.,2018). However, association of OAβ with functional connectivity (FC) and cardiovascular risk factors is not clearly known in the pre‐dementia stage. We aimed to examine association of FC with OAβ and other dementia risk factors in a pre‐dementia cohort to understand the underlying mechanisms related to OAβ.MethodsWe included 98 age and sex matched participants and classified them into OAβ+(28) and OAβ‐(70) subgroups using a OAβ cut‐off ratio of ≥ 0.9 (MDS‐ OAβ Test Kit, PeopleBio Inc, South Korea). Participants completed resting‐state functional MRI, clinical and lifestyle history questionnaires, blood, and neuropsychological assessments for global cognition on Montreal cognitive assessment and Visual Cognitive Assessment at Dementia Research Centre (Singapore). The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score was computed, and independent sample or chi‐squared analysis were performed to evaluate group‐level participant characteristics. Region‐of‐interest based FC analysis for 19 seeds from executive control (ECN), default‐mode, salience and dorsal‐attention networks (DAN) was performed to examine the network‐based FC differences in OAβ+ and OAβ‐ groups in association with CAIDE using ANCOVA model.ResultsMean age of OAβ+ and OAβ‐ were 62.04±8.84, and 62.05±8.07 (Table‐1). No significant FC differences were observed between OAβ+ vs OAβ‐ subjects. There were no significant FC differences related to CAIDE score in OAβ+ and OAβ‐ groups. Nonetheless, the OAβ*CAIDE interaction showed significant FC changes. The OAβ+*CAIDE interaction analyses showed reduced FC within ECN and DAN (Figure‐1a). Whereas OAβ‐*CAIDE interaction showed reduced FC only within ECN (Figure‐1b). Furthermore, OAβ interaction with apolipoprotein‐ε4 (OAβ*APOE4) was found to further influence FC trends in ECN and DAN (Figure‐1c,1d).ConclusionWhile no FC differences were observed between OAβ+ vs OAβ‐ subjects, the interaction between CAIDE and APOE4 moderated FC changes within the ECN and DAN. These observations in a pre‐dementia cohort suggest that the presence of cerebrovascular risk factors may result in differential FC dysfunction in ECN and DAN depending on APOE4 status.

Functional connectome‐based prediction of individual clinical and cognitive scores in midlife population with risk of dementia

AbstractBackgroundIt is well acknowledged that Alzheimer’s Disease (AD) neuropathology start decades before clinical manifestations, but the brain mechanism of sporadic AD in midlife remains unclear. Resting‐state functional connectivity (FC) is increasingly used to understand early brain changes in Alzheimer’s disease (AD) (Sperling, 2011; van den Heuvel & Sporns, 2019). We asked whether risk for late‐life dementia impacts functional connectivity in cognitively healthy middle‐aged individuals.MethodFunctional Magnetic Resonance Imaging and detailed neuropsychological assessments were obtained for 585 (207/378 female/male) cognitively healthy individuals, aged 40‐59 years (mean = 50.9), from the PREVENT‐Dementia study. Dementia risk was calculated with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score. A novel connectome‐based predictive method called NBS‐Predict was used to investigate the association between FC and CAIDE score and its role in cognition.ResultFC significantly predicted CAIDE scores across the whole cohort (r = 0.207, p < 0.001). FC within and between the cingulo‐opercular network (CON) and sensorimotor network (SMN), as well as between CON and fronto‐parietal network (FPN), and between SMN with default mode network (DMN), and FPN contributed the most (Figure 1). Furthermore, we found that, in the high dementia risk group (CAIDE > 6) only, FC, mainly in DMN‐SMN and DMN‐CON (Figure 2), significantly predicted multisensory processing cognitive score (r = 0.114, p<0.05).ConclusionOur results show that FC can be used to detect early brain changes associated with risk of future dementia in cognitively healthy individuals. This method has implications of the early detection of dementia in preclinical populations.

Lifestyle activities contribute to cognitive reserve in mid‐life, independently of education, in cognitively healthy middle‐aged individuals at risk for late‐life Alzheimer’s disease

AbstractBackgroundIt is now acknowledged that Alzheimer’s Disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid‐life. Intellectually, physically, and socially stimulating lifestyle activities are associated with maintenance of late‐life cognitive abilities (Chan et al., 2018), and lower cognitive impairment in AD (Livingston et al., 2020). We asked whether such activities contribute to cognitive reserve (CR) from mid‐life, in cognitively healthy individuals who are at risk for late‐life AD.MethodMiddle‐aged individuals (aged 40‐59 years, mean = 52 years) from the PREVENT Dementia study (www.preventdementia.co.uk) were assessed at baseline (N = 210, 62/148 male/female) and two‐year follow‐up (N = 188, 55/133 male/female), with cognitive ability (multidomain battery) and brain health (total grey matter volume, functional brain network segregation) measures. Mid‐life activities were measured using the Lifetime of Experiences Questionnaire, which comprises occupational as well as intellectually, physically, and socially stimulating leisure activities. Dementia risk was assessed with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score.ResultMultivariable linear regression showed that intellectual, physical, and social activities undertaken in mid‐life made a unique contribution to episodic and relational memory in mid‐life, independent of occupation and CAIDE at baseline (β (se) = 0.04 (0.02), p = 0.02, Figure 1a) and follow‐up (β (se) = 0.07 (0.02), p = 0.002, Figure 1b). Furthermore, these activities moderated the relationship between cognitive ability and brain health at follow‐up (β (se) = 3.47 (1.40), p = 0.01), with verbal and visuospatial functions, and short‐term (conjunctive) memory of people with higher activity levels less dependent on their brain functional integrity (Figure 2), consistent with the concept of CR (Brayne et al., 2010). Such a moderation by these mid‐life activities was more prominent in individuals with higher CAIDE scores (β (se) = 4.28 (1.83), p = 0.02, Figure 3).ConclusionThese findings suggest that modifiable lifestyle activities contribute uniquely to CR and may offset cognitive decrements due to AD risk in mid‐life. They support the targeting of modifiable lifestyle activities for the prevention of Alzheimer’s disease.

Effectiveness of a multicomponent lifestyle intervention against cognitive decline and dementia in an at‐risk‐population in Germany – Preliminary results of the cluster‐randomized AgeWell.de‐trial

AbstractBackgroundMounting evidence suggests that dementia can be prevented. Targeting several risk factors simultaneously constitutes a promising strategy for preserving cognitive function. The AgeWell.de‐study was a cluster‐randomized trial applying a multi‐domain intervention to preserve cognitive function in older adults at risk for dementia in Germany.MethodIndividuals with a Cardiovascular Risk Factors, Aging and Dementia (CAIDE) dementia risk score ≥ 9 points aged 60‐77 years were recruited. According to randomization of their general practitioner (GP) practice, patients received either a multi‐domain intervention (optimization of nutrition and medication, physical, social and cognitive activity, cardiovascular risk management, intervention in case of depressive symptoms and/or grief) or general health advice and GP treatment as usual over 24 months. Primary outcome was global cognitive performance, assessed using a composite score based on z‐scores of domain‐specific neuropsychological tests.ResultOf 1,030 participants at baseline (intervention/control: n = 487/543), n = 819 (intervention/control: n = 378/441) completed the follow‐up assessment. Intervention and control group did not differ regarding global cognitive performance (β = 0·010, 95% CI: ‐0·085; 0·105) at follow‐up. However, post‐hoc analyses revealed beneficial effects for social cognition (β = 0·132, 95% CI: 0·012; 0·252) and health‐related quality of life (β = 0·194, 95% CI: 0·065; 0·323). The intervention improved global cognitive performance (β = 0·221, 95% CI: 0·015; 0·428), social cognition (β = 0·259, 95% CI: 0·024; 0·494) and health‐related quality of life (β = 0·421; 95% CI: 0·114; 0·728) in participants with low education, and reduced depressive symptoms in highly educated participants (β = ‐0·431; 95% CI: ‐0·781; ‐0·082). Younger participants benefitted from the intervention regarding social cognition (β = 0·174, 95% CI: 0·010; 0·337) and health‐related quality of life (β = 0·405, 95% CI: 0·241; 0·570).ConclusionNo effect of the multi‐domain intervention on global cognitive performance was found for the overall sample. The intervention benefitted global cognitive functioning in individuals with low education and social cognition and health‐related quality of life across the sample. Further benefits regarding specific subgroups point towards the usefulness of tailored interventions.

Effects of Physical Activity, Vascular Burden and Clinical Diagnosis on White Matter Integrity

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia. Both degenerative and vascular pathology tend to contribute to dementia as AD coexists with single or multiple cardiovascular risk factors (vascular burden). Modifiable lifestyle factor such as physical activity has been associated with lower vascular burden (VB) and a lower risk of dementia. To test whether physical activity characterised as being inactive or active helped preserve white matter microstructure in a sample consisting of healthy controls and patients from the clinical AD continuum (mild cognitive impairment to dementia) with either low or high VB.Method213 participants were recruited from three memory clinics and were classified as being either physically active (n = 113) or inactive (n = 100) based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) questionnaire. Voxel‐wise tract‐based spatial statistics (TBSS) was carried out using a set of 5000 permutations and threshold‐free cluster enhancement (TFCE) to find significant clusters for fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity (MD) and radial diffusivity (RD).ResultParticipants who were physically active had higher FA and lower AxD, MD and RD values relative to the inactive participants. Changes in indices of WM integrity were widespread across the brain covering mainly association and projection tracts but a few commissural tracts. A three‐way interaction effect between Group × Physical Activity × VB was found for FA that was present in mainly projection tracts with a rightward asymmetry along with some association and commissural tracts. Post hocs revealed greater FA in physically active patients with high VB compared with inactive patients with high VB in projection and association/limbic tracts with a rightward asymmetry. Furthermore, the patients with high VB showed higher FA in bilateral projection fibers and cerebellar regions compared with inactive controls with high VB.ConclusionTBSS analysis revealed that high risk patients such as those with high VB achieved the maximum benefit by being physically active as it led to a much greater preservation of white microstructure relative to controls with high VB. This preservation of white matter microstructure was only observed in patients but not in controls.

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

AbstractBackgroundSubjective cognitive decline (SCD) and polygenic risk scores (PRS) have both been shown to be associated with the risk of developing dementia. However, it is of interest whether they can improve the established and well‐validated cardiovascular risk factors aging and dementia (CAIDE) model and how their predictive abilities compare.MethodsSCD and PRS were assessed and determined in a large, population‐based cohort study. In this study, the CAIDE model was applied to a sub‐sample of 5,360 study participants 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 SCD and PRS was further examined using the net reclassification improvement (NRI) method and integrated discrimination improvement (IDI). Besides evaluations in the total sample, predictive abilities were evaluated in the mid‐life and late‐life sub‐cohort.ResultsDuring 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 to the CAIDE model led to a significant increase in NRI for all‐cause dementia (4.4%, p = 0.0401) and VD (7.7%, p = 0.0095). In contrast, prediction models for AD further improved when PRS was added to the model (NRI, 8.4%, p = 0.0257). The latter became more substantial when applied to the mid‐life sub‐group (50‐64 years), achieving an NRI of 19.6% (p = 0.0075). When APOE ε4 carrier status was included in CAIDE model 2, the discriminative ability of the basic CAIDE model increased, and SCD and PRS did not further improve the prediction.ConclusionWhile PRS significantly improved the prediction of the CAIDE model for AD, information on SCD increased its discriminative ability for all‐cause dementia and VD. In contrast to PRS, information on SCD can be assessed more efficiently, and thus models including SCD can be more easily transferred to the clinical setting. Nevertheless, the two variables seem negligible if APOE ε4 carrier status is available.

A multidomain intervention against cognitive decline in an at-risk-population in Germany: Results from the cluster-randomized AgeWell.de trial.

We investigated the effectiveness of a multidomain intervention to preserve cognitive function in older adults at risk for dementia in Germany in a cluster-randomized trial. Individuals with a Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) risk score ≥ 9 aged 60 to 77 years were recruited. After randomization of their general practitioner (GP), patients received a multidomain intervention (including optimization of nutrition and medication, and physical, social, and cognitive activity) or general health advice and GP treatment as usual over 24 months. Primary outcome was global cognitive performance (composite z score, based on domain-specific neuropsychological tests). Of 1030 participants at baseline, n=819 completed the 24-month follow-up assessment. No differences regarding global cognitive performance (average marginal effect=0.010, 95% confidence interval: -0.113, 0.133) were found between groups at follow-up. Perceived restrictions in intervention conduct by the COVID-19 pandemic did not impact intervention effectiveness. The intervention did not improve global cognitive performance. Overall, no intervention effects on global cognitive performance were detected. The multidomain intervention improved health-related quality of life in the total sample. In women, the multidomain intervention reduced depressive symptoms. The intervention was completed during the COVID-19 pandemic.

CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk.

While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited. To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI). This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023. Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk. Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar. CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.

The effect of physical activity on white matter integrity in aging and prodromal to mild Alzheimer's disease with vascular comorbidity.

Physical activity is a modifiable lifestyle factor that has been previously associated with reduced vascular burden and reduced risk of dementia. This study tested whether physical activity (i.e., being inactive vs. active) contributed to preservation of white matter microstructure in healthy aging controls and patients in prodromal to mild Alzheimer's disease with low/high vascular burden. A total of 213 participants were recruited from memory clinics. They were classified as being either physically active (n = 113) or inactive (n = 100) based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) questionnaire. Diffusion-weighted images were acquired for all participants and pre-processed based on a standard protocol. A factorial design using voxel-wise tract-based spatial statistics (TBSS) was adopted, with 5,000 permutations and threshold-free cluster enhancement (TFCE), to identify significant clusters for fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity (MD), and radial diffusivity (RD). Clusters of higher FA and lower AxD, MD, and RD values were found for physically active compared with inactive participants that were widespread covering mainly association and projection tracts but also some commissural tracts. A three-way Group × Physical Activity × Vascular Burden interaction effect was found for FA mostly in a variety of projection tracts with a right predominance, and some commissural and association tracts. Post hoc analyses revealed higher FA in patients with high vascular burden who were physically active compared with those patients with high vascular burden who were inactive mainly in projection and association/limbic tracts with a right predominance. Additionally, higher FA was observed in physically active patients with high vascular burden as compared with physically inactive controls with high vascular burden, mainly in bilateral projection fibers and cerebellar regions. Voxel-wise TBSS analysis revealed better preservation of white matter microstructure that was prominent in the high-risk group such as the patients with high vascular burden, specifically those who were physically active. The beneficial effects of physical activity on white matter microstructure were not observed in the controls.

Estimating Dementia Risk Using Multifactorial Prediction Models

The clinical value of current multifactorial algorithms for individualized assessment of dementia risk remains unclear. To evaluate the clinical value associated with 4 widely used dementia risk scores in estimating 10-year dementia risk. This prospective population-based UK Biobank cohort study assessed 4 dementia risk scores at baseline (2006-2010) and ascertained incident dementia during the following 10 years. Replication with a 20-year follow-up was based on the British Whitehall II study. For both analyses, participants who had no dementia at baseline, had complete data on at least 1 dementia risk score, and were linked to electronic health records from hospitalizations or mortality were included. Data analysis was conducted from July 5, 2022, to April 20, 2023. Four existing dementia risk scores: the Cardiovascular Risk Factors, Aging and Dementia (CAIDE)-Clinical score, the CAIDE-APOE-supplemented score, the Brief Dementia Screening Indicator (BDSI), and the Australian National University Alzheimer Disease Risk Index (ANU-ADRI). Dementia was ascertained from linked electronic health records. To evaluate how well each score predicted the 10-year risk of dementia, concordance (C) statistics, detection rate, false-positive rate, and the ratio of true to false positives were calculated for each risk score and for a model including age alone. Of 465 929 UK Biobank participants without dementia at baseline (mean [SD] age, 56.5 [8.1] years; range, 38-73 years; 252 778 [54.3%] female participants), 3421 were diagnosed with dementia at follow-up (7.5 per 10 000 person-years). If the threshold for a positive test result was calibrated to achieve a 5% false-positive rate, all 4 risk scores detected 9% to 16% of incident dementia and therefore missed 84% to 91% (failure rate). The corresponding failure rate was 84% for a model that included age only. For a positive test result calibrated to detect at least half of future incident dementia, the ratio of true to false positives ranged between 1 to 66 (for CAIDE-APOE-supplemented) and 1 to 116 (for ANU-ADRI). For age alone, the ratio was 1 to 43. The C statistic was 0.66 (95% CI, 0.65-0.67) for the CAIDE clinical version, 0.73 (95% CI, 0.72-0.73) for the CAIDE-APOE-supplemented, 0.68 (95% CI, 0.67-0.69) for BDSI, 0.59 (95% CI, 0.58-0.60) for ANU-ADRI, and 0.79 (95% CI, 0.79-0.80) for age alone. Similar C statistics were seen for 20-year dementia risk in the Whitehall II study cohort, which included 4865 participants (mean [SD] age, 54.9 [5.9] years; 1342 [27.6%] female participants). In a subgroup analysis of same-aged participants aged 65 (±1) years, discriminatory capacity of risk scores was low (C statistics between 0.52 and 0.60). In these cohort studies, individualized assessments of dementia risk using existing risk prediction scores had high error rates. These findings suggest that the scores were of limited value in targeting people for dementia prevention. Further research is needed to develop more accurate algorithms for estimation of dementia risk.

Mediation effect of WMH on the associations of dementia risk with cognition and AD‐related brain changes

AbstractBackgroundThe Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score, a validated tool estimating dementia risk, has been suggested to be associated with accelerated brain atrophy but the imaging biomarkers and AD pathologies remains to be elucidated. We aimed to explore the relationships of CAIDE score with cognition and AD‐related brain changes, including beta‐amyloid (Aβ) deposition and glucose metabolism and the mediation effect of the WMH on these associations.MethodA sample of 1,285 participants underwent CAIDE dementia risk assessment, of these, 958 individuals had a CAIDE score of less than or equal to 8. Memory and executive function were used to measure cognitive performance. We analyzed data using linear mixed‐effects and mediation.ResultCAIDE score was significantly associated with WMH volume, and also had significant association with Aβ deposition, AD‐metabolism, and memory and executive function. WMH volume mediated 6.04%, 12.87%, 6.93% and 7.92% of the total association of CAIDE score with memory, executive function, FDG‐PET and AV45‐PET, respectively.ConclusionMemory, executive function, AD‐metabolism and Aβ deposition are strongly associated with dementia risk. Besides, the associations could be mediated by WMH volume and whether this represents a causal relationship remains to be determined.

A comparative study of cardiovascular risk factors and its impact on cognitive function in rural and urban Indian cohorts

AbstractBackgroundThe Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) risk score is used to assess the future risk of developing dementia based on cardiovascular risk factors. In this study, we compared the cognitive functions of participants with higher and lower risk of dementia assessed using CAIDE score, in the rural and urban Indian populations. Data was obtained from participants enrolled in the TATA Longitudinal Study of Aging (TLSA) and Srinivaspura Aging, Neuro Senescence, and COGnition (SANSCOG) study, which are two large, harmonized studies from urban and rural India, respectively.MethodsThe clinical and blood biochemistry data from rural (n = 2005) and urban (n = 291) participants were used to estimate the CAIDE score and classify participants as high risk (score ≥ 9) and low risk of dementia (score < 9). The neuropsychological evaluation was performed using COGNITO battery, a computerized neuropsychometric platform that tests five cognitive domains. The cognitive scores of the high‐risk and the low‐risk groups were compared.ResultsThe rural cohort, compared to the urban cohort, had a lower proportion of people with formal education ≥10 years (17.0% vs. 99.3%), age above 54 years (63.5% vs. 90.8%), systolic BP > 140 mm Hg (10.1% vs. 33.7%) and BMI >30 kg/m2 (6.6% vs. 20.9%). The proportion of people with higher total cholesterol, gender distribution, and physical activity was comparable in both cohorts.On risk stratification, the high‐risk category comprised 26.34% of the rural and 9.46% of the urban cohort. The participants belonging to the high‐risk category from the rural cohort performed poorly in all cognitive domains, compared to the low‐risk category. In the urban cohort, there was no significant difference between both groups.ConclusionThe rural population had a higher proportion of people at high risk of dementia in the future, despite the younger age and lower proportion of participants with higher systolic BP and BMI. It seems that the lack of formal education may be primarily responsible for higher CAIDE scores in the rural population. Their baseline neuropsychological profile probably forecasts the possibility of cognitive dysfunction in the future. Interventions may help modify the cardiovascular risk factors and decrease the future burden of dementia.

Prediction Abilities of SCORE2 Risk Algorithms for Incident Dementia and All-Cause Mortality: Results From the UK Biobank Cohort Study.

Whether the updated Systematic COronary Risk Evaluation (SCORE2) risk algorithm is suitable for the prediction of incident dementia and all-cause mortality and whether its discrimination abilities for these outcomes are higher than those of the SCORE and Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) risk algorithms are unclear. The present study included 429 033 participants (mean age: 57.1 ± 8.1 years; male: 46.2%; White: 94.1%) free of dementia from the UK Biobank at baseline, with a median follow-up of 12.8 years. Cox regression models were adopted to investigate the longitudinal relationships of SCORE2 risk categories with outcomes, and receiver operating characteristic curve analyses were used to compare the discrimination abilities of the 3 algorithms. During 5 376 778 person-years of follow-up, 6 477 all-cause dementia, 2 726 Alzheimer's disease (AD), 1 439 vascular disease (VD), and 31 981 all-cause deaths were identified. We found that higher SCORE2 risk was associated with higher risks of all-cause dementia, AD, VD, and all-cause mortality. The C-indices of SCORE2 risk for discriminating incident all-cause dementia, AD, VD, and all-cause death were 0.750 (95% confidence interval [CI]: 0.745 to 0.755), 0.750 (95% CI: 0.743 to 0.757), 0.800 (95% CI: 0.791 to 0.809), and 0.721 (95% CI: 0.718 to 0.724), respectively, which were significantly improved in comparison to those of the SCORE and CAIDE risk algorithms. The SCORE2 risk algorithm is applicable in predicting incident all-cause dementia, AD, VD, and all-cause mortality in European populations, and its discrimination abilities for dementia and death are significantly higher than those of the SCORE and CAIDE risk algorithms. Further validations in other populations are warranted.

Improved risk prediction of all‐cause dementia, Alzheimer’s disease, and vascular dementia by inflammation‐related biomarkers

AbstractBackgroundDementia risk prediction models, such as the widely used Cardiovascular Risk Factors, Aging and Dementia (CAIDE) model, combining factors from the fields of demographic, cognition, physical and health, have proven themselves. However, it is of interest whether inflammatory biomarkers additionally improve such dementia risk prediction models.MethodsThe Olink Target 96 Inflammation panel was assessed in serum samples of a large German, population‐based cohort study. In a nested case‐cohort design (n=1688), the CAIDE model was used for dementia risk prediction and aimed to improve by adding 72 inflammation‐related biomarkers of the Olink panel. Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression and bootstrapping were utilized to select relevant biomarkers and determine areas under the curve (AUCs) for all‐cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD) in the total cohort, as well as in mid‐life and late‐life sub‐samples.ResultsOver 17 years of follow‐up, 440 participants developed dementia. Of those, 147 were diagnosed with AD and 195 with VD. The prediction model including APOE ε4 carrier status (CAIDE model 2) had a better discriminative ability for all‐cause dementia, AD, and VD than the model without APOE ε4 (CAIDE model 1) with AUCs of 0.751, 0.767, and 0.725, respectively. Adding 16 inflammation‐related biomarkers selected by LASSO regression to the CAIDE model significantly increased the AUC for all‐cause dementia risk prediction by 0.025 (95%CI: 0.001–0.045). The AUC increases for AD (0.024) and VD (0.019) were of similar magnitude but not statistically significant due to lower case numbers. Moreover, the CAIDE model generally performed better in mid‐life (50‐64 years) than in late‐life (65‐75 years) sub‐samples, and all increases in the AUC caused by inflammation‐related biomarkers were larger in the mid‐life sub‐sample.ConclusionInflammation‐related biomarkers significantly improved the CAIDE model for all‐cause dementia prediction. Especially the predictive abilities of these blood‐based biomarkers in mid‐life are of clinical relevance to guide early preventive measures.

C‐reactive protein, APOE status, and cognitive impairment in older adults

AbstractBackgroundThe aim of this study was to investigate the impact of Apolipoprotein ε4 (APOEε4) on the possible relationship between high sensitive serum CRP (hsCRP) and risk of incident dementia, Alzheimer’s disease (AD), and cognitive impairment over seven years in a longitudinal, population based study of community dwelling older adults.MethodSerum hsCRP was measured at baseline in 304 dementia‐free individuals aged 65‐79 years derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study. Participants were re‐examined seven years later, and global cognition, episodic memory, executive functioning, verbal expression, and psychomotor speed were assessed both at baseline and at follow‐up. Incident dementia was diagnosed using DSM‐IV criteria. Multiple linear regression and logistic‐regression models were used to investigate the association of serum hsCRP and its interaction with APOEε4 status on cognitive performance and incident dementia at follow‐up, after adjusting for several potential confounders, including common vascular risk factors.ResultAfter adjustment for age, sex, education, duration of follow‐up, systolic blood pressure, diastolic blood pressure, body mass index, prevalent stroke, and smoking status, odds ratio (95% confidence intervals (CI)) was 3.02 (1.18 – 7.73) for those who had at least one alle of APOEε4 compared to those who did not. The odds ratio (95%CI) for incident dementia was 1.00 (0.96 – 1.04) oer unit increase in hsCRP. No associations between hsCRP and cognitive impairment seven years later was detected. However, raised hsCRP values were related to worse performance in episodic memory seven years later in participants who had at least one allele of APOEε4 (β (standard error): ‐0.005 (0.002); p = 0.025).ConclusionRaised values of hsCRP is associated with higher risk of cognitive impairment seven years later among individuals who carry at least one allele of APOEε4. Randomized controlled trials are needed to determine this issue.

Social functioning and cognitive impairment among the oldest old

AbstractBackgroundFindings from observational studies support the benefits of social activities on cognition. The ability to carry out social activities is described by social functioning. However, only little data exists on the associations between social functioning and cognition among the oldest old. The aim of this study is to explore if social functioning is associated with cognitive impairment among the oldest old.MethodThe study uses cross‐sectional data from a Finnish population‐based Cardiovascular Risk Factors, Aging and Dementia (CAIDE) 85+ study. Altogether 187 individuals aged 85+ provided data on health‐related quality of life, RAND‐36, from which the following question on social functioning was used: “During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities (like visiting with friends, relatives, etc.)?“ Social functioning was divided into three categories: 1) Low (all the time or most of the time), 2) Moderate (some time), and 3) High (a little time or not at all). Cognitive impairment was defined as Mini‐Mental State Examination score < 25. Logistic regression model was used in the analyses which were adjusted for sex.ResultAccording to these preliminary results, individuals with low social functioning were 7 times more likely to have cognitive impairment as compared to individuals with high social functioning (Odds ratio [OR] 7.46, 95% Confidence Interval [CI] 2.16–25.75). No differences in cognitive impairment were found between individuals with moderate social functioning as compared to high social functioning (OR 0.68, 95% CI 0.26–1.84).ConclusionLower social functioning appears to be associated with cognitive impairment among the oldest old. These results need further exploration. Causality behind the found association should be examined and if supporting social activities particularly among cognitively impaired would carry health benefits.

A Modified CAIDE Risk Score as a Screening Tool for Cognitive Impairment in Older Adults.

Although an efficacious dementia-risk score system, Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) was derived using midlife risk factors in a population with low educational attainment that does not reflect today's US population, and requires laboratory biomarkers, which are not always available. Develop and validate a modified CAIDE (mCAIDE) system and test its ability to predict presence, severity, and etiology of cognitive impairment in older adults. Population consisted of 449 participants in dementia research (N = 230; community sample; 67.9±10.0 years old, 29.6%male, 13.7±4.1 years education) or receiving dementia clinical services (N = 219; clinical sample; 74.3±9.8 years old, 50.2%male, 15.5±2.6 years education). The mCAIDE, which includes self-reported and performance-based rather than blood-derived measures, was developed in the community sample and tested in the independent clinical sample. Validity against Framingham, Hachinski, and CAIDE risk scores was assessed. Higher mCAIDE quartiles were associated with lower performance on global and domain-specific cognitive tests. Each one-point increase in mCAIDE increased the odds of mild cognitive impairment (MCI) by up to 65%, those of AD by 69%, and those for non-AD dementia by > 85%, with highest scores in cases with vascular etiologies. Being in the highest mCAIDE risk group improved ability to discriminate dementia from MCI and controls and MCI from controls, with a cut-off of ≥7 points offering the highest sensitivity, specificity, and positive and negative predictive values. mCAIDE is a robust indicator of cognitive impairment in community-dwelling seniors, which can discriminate well between dementia severity including MCI versus controls. The mCAIDE may be a valuable tool for case ascertainment in research studies, helping flag primary care patients for cognitive testing, and identify those in need of lifestyle interventions for symptomatic control.

Change in CAIDE Dementia Risk Score and Neuroimaging Biomarkers During a 2-Year Multidomain Lifestyle Randomized Controlled Trial: Results of a Post-Hoc Subgroup Analysis.

The CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Risk Score is a validated tool estimating dementia risk. It was previously associated with imaging biomarkers. However, associations between dementia risk scores (including CAIDE) and dementia-related biomarkers have not been studied in the context of an intervention. This study investigated associations between change in CAIDE score and change in neuroimaging biomarkers (brain magnetic resonance imaging [MRI] and Pittsburgh Compound B-positron emission tomography [PiB-PET] measures) during the 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (post-hoc analyses). FINGER targeted at-risk older adults, aged 60–77 years, from the general population. Participants were randomized to either multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice). Neuroimaging (MRI and PiB-PET) data from baseline and 2-year visits were used. A toal of 112 participants had repeated brain MRI measures (hippocampal, total gray matter, and white matter lesion volumes, and Alzheimer’s disease signature cortical thickness). Repeated PiB-PET scans were available for 39 participants. Reduction in CAIDE score (indicating lower dementia risk) during the intervention was associated with less decline in hippocampus volume in the intervention group, but not the control group (Randomization group × CAIDE change interaction β coefficient = −0.40, p = .02). Associations for other neuroimaging measures were not significant. The intervention may have benefits on hippocampal volume in individuals who succeed in improving their overall risk level as indicated by a reduction in CAIDE score. This exploratory finding requires further testing and validation in larger studies.