Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer's Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project.

The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer's disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.

Multimodal Precision Prevention - A New Direction in Alzheimer's Disease.

At least 40% of all dementia has been linked to modifiable risk factors suggesting a clear potential for preventative approaches targeting these factors. Despite the recent promising findings from anti-amyloid monoclonal antibodies, a limited proportion of patients are expected to be eligible for these novel AD treatments. Given the heterogeneous nature of AD and the complex multi-level pathological processes leading to dementia (involving, e.g., shared risk factors, interaction of different pathology mechanisms, and their putative synergistic effects on cognition), targeting a single pathology may not be sufficient to halt or significantly impact disease progression. With exponentially increasing numbers of patients world-wide, in parallel to the unprecedented population ageing, new multimodal therapy approaches targeting several modifiable risk factors and disease mechanisms simultaneously are urgently required. Developing the next generation of combination therapies with lifestyle intervention and pharmacological treatments, implementing the right interventions for the right people at the right time, and defining accessible and sustainable strategies worldwide are crucial. Here, we summarize the state-of-the-art multimodal lifestyle-based approaches, especially findings and lessons learned from the FINGER trial, for prevention and risk reduction of cognitive impairment and dementia. We also discuss some emerging underlying biological mechanisms and the current development of precision prevention approaches. We present an example of a novel trial design combining healthy lifestyle changes with a repurposed putative disease-modifying drug and place this study in the context of the World-Wide FINGERS, the first interdisciplinary network of multimodal trials dedicated to the prevention and risk reduction of cognitive impairment and dementia.

Combined Evidence for a Long-Term, Clinical Slowing Effect of Multinutrient Intervention in Prodromal Alzheimer's Disease: Post-Hoc Analysis of 3-Year Data from the LipiDiDiet Trial.

The LipiDiDiet randomized clinical trial is evaluating the long term effects of a multinutrient intervention (Fortasyn Connect) compared with control in participants with prodromal AD. In this post-hoc analysis we used the Alzheimer's Disease Composite Score (ADCOMS) as a measure of cognition and global function, together with a global statistical test (GST) and Bayesian hierarchical modelling (BHM) to evaluate the totality of evidence for an effect of the intervention over 36 months. The analysis includes 67 participants (39 active, 28 control) with change from baseline data after 36 months intervention. All outcome measures showed a statistically significant effect for the intervention: ADCOMS (P =0.045), GST (P <0.001), and BHM (P =0.008 based on 3 outcomes and P <0.001 including all primary and secondary quantitative clinical outcomes). Fortasyn Connect was associated with significantly less clinical decline over 36 months, suggesting the long-lasting beneficial effects of the multinutrient in prodromal AD.

Blood Derived Amyloid Biomarkers for Alzheimer's Disease Prevention.

BACKGROUND: Reliable, widely accessible and affordable biomarkers for predicting Alzheimer's disease (AD) brain pathology status are a necessity to aid development of prevention strategies in cognitively healthy at-risk older adults, at the right timepoint. Measurements of the key neuropathological hallmark beta-amyloid (Aß) by PET neuroimaging or cerebrospinal fluid measures reflect its accumulation in the brain, yet recent methodological advancements now enable blood-based measures reflecting cerebral amyloid burden. OBJECTIVES: The current study validated the capacity of plasma Aß42/Aß40 measured using six different assays to predict amyloid positivity in a subgroup of cognitively unimpaired (CU) participants in the ADNI study and assessed its ability to discriminate CU from AD cases. We also explored economic viability of using two different plasma amyloid assays for pre-screening in AD prevention trials and as routine clinical diagnostic tool, versus amyloid PET alone. DESIGN: A cross-sectional analysis of plasma and brain amyloid data, including comparative cost analysis of the plasma biomarkers in relation to brain amyloid PET. SETTING: Alzheimer's Disease Neuroimaging Initiative (ADNI). PARTICIPANTS: ADNI participants consisting of 115 CU, mild cognitive impairment and AD cases who had plasma Aß42/Aß40 measured with six platforms. MEASUREMENTS: Plasma Aß42/Aß40 was measured via six different platforms: three immunoassays (Roche, Quanterix and ADx Neurosciences) and three mass spectrometry (MS) based assays (WashU, Shimadzu and Gothenburg). Aß-PET imaging was conducted within three months of plasma sampling using [18F]florbetapir. RESULTS: There was a weak to moderate correlation of plasma Aß42/Aß40 ratio between platforms. The MS-based WashU test had the highest capacity to discriminate between CU and AD (area under the curve, AUC = 0.734, 95% CI: 0.613-0.854; P = 0.008). Within the CU group, the WashU plasma amyloid test had the best discriminative capacity to distinguish Aß+ from Aß- (AUC = 0.753, 95% CI: 0.601-0.905; P = 0.003) closely followed by the immunoassay from Roche (AUC = 0.737, 95% CI: 0.597-0.877; P = 0.006). The exploratory economic analyses showed that the use of Roche or WashU plasma amyloid assay as a pre-screening tool prior to Aß-PET scans for clinical trial recruitment significantly reduced total screening cost (saving up to $5882 per recruited patient) expected in an AD prevention trial. CONCLUSIONS: With few available treatment strategies, dementia prevention is a global priority. CU individuals at risk for AD are the target population for dementia prevention but have been poorly studied. Our findings confirming diagnostic value of ultrasensitive immunoassays and high-performance immunoprecipitation coupled with MS for measurement of plasma Aß42/Aß40 to detect PET amyloid positivity in CU participants allude to potential clinical utility of this biomarker. Plasma Aß42/Aß40 could be optimal for pre-selecting at-risk candidates for more invasive and expensive investigations across AD prevention clinical trials and clinical care for a rapidly ageing population.

Multimodal Preventive Trial for Alzheimer's Disease: MIND-ADmini Pilot Trial Study Design and Progress.

BACKGROUND: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer's disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear. OBJECTIVES: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. METHODS: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes. RESULTS: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned. CONCLUSIONS: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions).

Mechanisms Underlying Non-Pharmacological Dementia Prevention Strategies: A Translational Perspective.

Since developing an effective treatment for Alzheimer's disease (AD) has been encountered as a challenging task, attempts to prevent cognitive decline by lifestyle modifications have become increasingly appealing. Physical exercise, healthy diet, and cognitive training are all modifiable, non-pharmacological lifestyle factors considered to influence cognitive health. Implementing lifestyle modifications on animal models of AD and cognitive impairment may reveal underlying mechanisms of action by which healthy lifestyle contribute to brain health. In mice, different types of lifestyle interventions have been shown to improve cognitive abilities, alleviate AD-related pathology and neuroinflammation, restore mitochondrial function, and have a positive impact on neurogenesis and cell survival. Different proteins and pathways have been identified to mediate some of the responses, amongst them BDNF, Akt-GSK3ß, JNK, and ROCK pathway. Although some important pathways have been identified as mediating improvements in brain health, more research is needed to confirm these mechanisms of action and to improve the understanding of their interplay. Moreover, multidomain lifestyle interventions targeting multiple risk factors simultaneously may be a promising avenue in future dementia prevention strategies. Therefore, future work is needed to better understand the synergistic impact of combinatory lifestyle strategies on cellular mechanisms and brain health.

Body mass index and Mini Nutritional Assessment-Short Form as predictors of in-geriatric hospital mortality in older adults with COVID-19.

BACKGROUND & AIMS: Overweight and obesity have been consistently reported to carry an increased risk for poorer outcomes in coronavirus disease 2019 (COVID-19) in adults. Existing reports mainly focus on in-hospital and intensive care unit mortality in patient cohorts usually not representative of the population with the highest mortality, i.e. the very old and frail patients. Accordingly, little is known about the risk patterns related to body mass and nutrition in very old patients. Our aim was to assess the relationship between body mass index (BMI), nutritional status and in-geriatric hospital mortality among geriatric patients treated for COVID-19. As a reference, the analyses were performed also in patients treated for other diagnoses than COVID-19. METHODS: We analyzed up to 10,031 geriatric patients with a median age of 83 years of which 1409 (14%) were hospitalized for COVID-19 and 8622 (86%) for other diagnoses in seven geriatric hospitals in the Stockholm region, Sweden during March 2020-January 2021. Data were available in electronic hospital records. The associations between 1) BMI and 2) nutritional status, assessed using the Mini-Nutritional Assessment - Short Form (MNA-SF) scale, and short-term in-geriatric hospital mortality were analyzed using logistic regression. RESULTS: After adjusting for age, sex, comorbidity, polypharmacy, frailty and the wave of the pandemic (first vs. second), underweight defined as BMI<18.5 increased the risk of in-hospital mortality in COVID-19 patients (odds ratio [OR] = 2.30; confidence interval [CI] = 1.17-4.31). Overweight and obesity were not associated with in-hospital mortality. Malnutrition; i.e. MNA-SF 0-7 points, increased the risk of in-hospital mortality in patients treated for COVID-19 (OR = 2.03; CI = 1.16-3.68) and other causes (OR = 6.01; CI = 2.73-15.91). CONCLUSIONS: Our results indicate that obesity is not a risk factor for very old patients with COVID-19, but emphasize the role of underweight and malnutrition for in-hospital mortality in geriatric patients with COVID-19.

Digital Screening for Cognitive Impairment - A Proof of Concept Study.

BACKGROUND: Due to an ageing demographic and rapid increase of cognitive impairment and dementia, combined with potential disease-modifying drugs and other interventions in the pipeline, there is a need for the development of accurate, accessible and efficient cognitive screening instruments, focused on early-stage detection of neurodegenerative disorders. OBJECTIVE: In this proof of concept report, we examine the validity of a newly developed digital cognitive test, the Geras Solutions Cognitive Test (GCST) and compare its accuracy against the Montreal Cognitive Assessment (MoCA). METHODS: 106 patients, referred to the memory clinic, Karolinska University Hospital, due to memory complaints were included. All patients were assessed for presence of neurodegenerative disorder in accordance with standard investigative procedures. 66% were diagnosed with subjective cognitive impairment (SCI), 25% with mild cognitive impairment (MCI) and 9% fulfilled criteria for dementia. All patients were administered both MoCA and GSCT. Descriptive statistics and specificity, sensitivity and ROC curves were established for both test. RESULTS: Mean score differed significantly between all diagnostic subgroups for both GSCT and MoCA (p<0.05). GSCT total test time differed significantly between all diagnostic subgroups (p<0.05). Overall, MoCA showed a sensitivity of 0.88 and specificity of 0.54 at a cut-off of <=26 while GSCT displayed 0.91 and 0.55 in sensitivity and specificity respectively at a cut-off of <=45. CONCLUSION: This report suggests that GSCT is a viable cognitive screening instrument for both MCI and dementia.

How can dementia and disability be prevented in older adults: where are we today and where are we going?

Ageing of the population, together with population growth, has brought along an ample increase in the number of older individuals living with dementia and disabilities. Dementia is the main cause of disability in old age, and promoting healthy brain ageing is considered as a key element in diminishing the burden of age-related disabilities. The World Health Organization recently launched the first risk reduction guidelines for cognitive impairment and dementia. According to recent estimates, approximately 40% of dementia cases worldwide could be attributable to 12 modifiable risk factors: low education; midlife hypertension and obesity; diabetes, smoking, excessive alcohol use, physical inactivity, depression, low social contact, hearing loss, traumatic brain injury and air pollution indicating clear prevention potential. Dementia and physical disability are closely linked with shared risk factors and possible shared underlying mechanisms supporting the possibility of integrated preventive interventions. FINGER trial was the first large randomized controlled trial indicating that multidomain lifestyle-based intervention can prevent cognitive and functional decline amongst at-risk older adults from the general population. Within the World-Wide FINGERS network, the multidomain FINGER concept is now tested and adapted worldwide proving evidence and tools for effective and easily implementable preventive strategies. Close collaboration between researchers, policymakers and healthcare practitioners, involvement of older adults and utilization of new technologies to support self-management is needed to facilitate the implementation of the research findings. In this scoping review, we present the current scientific evidence in the field of dementia and disability prevention and discuss future directions in the field.

The European Prevention of Alzheimer's Dementia (EPAD) Longitudinal Cohort Study: Baseline Data Release V500.0.

BACKGROUND: The European Prevention of Alzheimer's Dementia (EPAD) Programme is a pan-European project whose objective is to deliver a platform, adaptive, Phase 2 proof of concept (PoC) trial for the secondary prevention of Alzheimer's dementia. A component of this platform is the Longitudinal Cohort Study (LCS) which acts as a readiness cohort for the PoC Trial as well as generating data for disease modelling work in the preclinical and prodromal phases of Alzheimer's dementia. OBJECTIVES: The first data wave has been collected, quality checked, released and now available for analysis to answer numerous research questions. Here we describe the results from key variables in the EPAD LCS with the objective of using these results to compliment analyses of these data in the future. DESIGN: EPAD LCS is a cohort study whose primary objective is as a readiness cohort for the EPAD PoC Trial. As such recruitment is not capped at any particular number but will continue to facilitate delivery of the EPAD PoC Trial. Research Participants are seen annually (with an additional 6 month visit in the first year). SETTING: The EPAD Trial Delivery Network comprises currently 21 centres across Europe. PARTICIPANTS: Research participants are included if they are over 50 years old and do not have a diagnosis of dementia. MEASUREMENTS: All research participants undergo multiple assessments to fully characterise the biology of Alzheimer's disease and relate this to risk factors (both fixed and modifiable) and biomarker expression of disease through brain imaging, fluid samples (CSF, blood, urine and saliva), cognitive performance, functional abilities and neuropsychiatric symptomatology. RESULTS: V500.0 represents the first 500 research participants baselined into EPAD LCS. The mean age was 66.4 (SD=6.7) and 47.8% were male. The data was split for presentation into 4 groups: [1] CDR=0 and Amyloid + (preclinical AD), [2] CDR=0 and Amyloid -, [3] CDR=0.5 and Amyloid + (prodromal AD) and [4] CDR=0.5 and Amyloid -. CONCLUSIONS: The EPAD LCS is achieving its primary objective of trial readiness and the structured approach to data release as manifest by this first data release of V500.0 will assist researchers to describe and compare their findings as well as in systematic reviews and meta-analyses. It is anticipated given current recruitment rates that V1500.0 data release will take place in Autumn 2019. V500.1 (when the 1 year follow up is completed on the V500.0 (sub)cohort will be in Autumn 2019 also.

Multidomain Interventions to Prevent Cognitive Impairment, Alzheimer's Disease, and Dementia: From FINGER to World-Wide FINGERS.

Alzheimer's disease (AD) and dementia are a global public health priority, and prevention has been highlighted as a pivotal component in managing the dementia epidemic. Modifiable risk factors of dementia and AD include lifestyle-related factors, vascular and metabolic disorders, and psychosocial factors. Randomized controlled clinical trials (RCTs) are needed to clarify whether modifying such factors can prevent or postpone cognitive impairment and dementia in older adults. Given the complex, multifactorial, and heterogeneous nature of late-onset AD and dementia, interventions targeting several risk factors and mechanisms simultaneously may be required for optimal preventive effects. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is the first large, long-term RCT to demonstrate that a multidomain lifestyle-based intervention ameliorating vascular and lifestyle-related risk factors can preserve cognitive functioning and reduce the risk of cognitive decline among older adults at increased risk of dementia. To investigate the multidomain intervention in other populations and diverse cultural and geographical settings, the World-Wide FINGERS (WW-FINGERS) network was recently launched (https://alz.org/wwfingers). Within this network, new FINGER-type trials with shared core methodology, but local culture and context-specific adaptations, will be conducted in several countries. The WW-FINGERS initiative facilitates international collaborations, provides a platform for testing multidomain strategies to prevent cognitive impairment and dementia, and aims at generating high-quality scientific evidence to support public health and clinical decision-making. Furthermore, the WW-FINGERS network can support the implementation of preventive strategies and translation of research findings into practice.

Midlife improvements in financial situation are associated with a reduced dementia risk later in life: the CAIDE 30-year study.

OBJECTIVES: Perceived financial strain is associated with various health conditions, but it is unknown whether it is associated with an increased risk for dementia. The goal is to examine the associations between midlife perceptions of financial situation and dementia risk later in life. METHODS: Participants were derived from the Cardiovascular Risk Factors, Aging, and Dementia population-based cohort study (n = 2000) (between 1972 and 1987, baseline mean age 50 years) in Finland. Participants returned for two re-examinations in late life (in 1998 and 2005-2008, mean age 71 and 78 years). In this study, 1442 subjects that participated in at least one re-examination (mean total follow-up 25 years) were included in analyses. Financial strain was measured using two questions in midlife on perceptions of financial situation and perceptions of changes in financial situation. For each question, participants were categorized into three groups reporting improvement, worsening, or stability, with the latter set as the reference group. Analyses were adjusted for potential confounding factors. RESULTS: The group reporting better financial situation had a reduced risk for dementia (fully adjusted model: odds ratio (OR): 0.53, 95% confidence interval (CI): 0.33-0.86). In contrast, the group reporting worse financial situation did not have an increased risk for dementia (OR: 1.04, 95% CI: 0.53-2.02). Analyses on perceptions of current financial situation showed that the groups reporting satisfaction or dissatisfaction with financial situation did not differ in risk for dementia. CONCLUSION: This study is the first to show that midlife improvements in financial situation are associated with a reduced dementia risk later in life. Potential pathways related to stress reduction, improved lifestyle, and potential biological mechanisms are discussed.

Alzheimer's Disease Composite Score: A Post-Hoc Analysis Using Data from the LipiDiDiet Trial in Prodromal Alzheimer's Disease.

As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference -0.048 (95% confidence intervals -0.090, -0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure.

Bisphosphonates and mortality: confounding in observational studies?

Numerous observational studies suggest that bisphosphonates reduce mortality. This study showed that bisphosphonate use is associated with lower mortality within days of treatment, although the association was not significant until the second week. Such an early association is consistent with confounding, although an early treatment effect cannot be ruled out. INTRODUCTION: The purpose of this study was to examine whether confounding explains why numerous observational studies show that bisphosphonate use is associated with lower mortality. To this end, we examined how soon after treatment initiation a lower mortality rate can be observed. We hypothesized that, due to confounding, the association would be observed immediately. METHODS: This was a retrospective cohort study of hip fracture patients discharged from Swedish hospitals between 1 July 2006 and 31 December 2015. The data covered 260,574 hip fracture patients and were obtained from the Swedish Hip Fracture Register and national registers. Of the 260,574 patients, 49,765 met all eligibility criteria and 10,178 were pair matched (bisphosphonate users to controls) using time-dependent propensity scores. The matching variables were age, sex, diagnoses, prescription medications, type of hip fracture, type of surgical procedure, known or suspected dementia, and physical functioning status. RESULTS: Over a median follow-up of 2.8 years, 2922 of the 10,178 matched patients died. The mortality rate was 7.9 deaths per 100 person-years in bisphosphonate users and 9.4 deaths in controls, which corresponded to a 15% lower mortality rate in bisphosphonate users (hazard ratio 0.85, 95% confidence interval 0.79-0.91). The risk of death was lower in bisphosphonate users from day 6 of treatment, although the association was not significant until the second week. CONCLUSION: Bisphosphonate use was associated with lower mortality within days of treatment initiation. This finding is consistent with confounding, although an early treatment effect cannot be ruled out.

Brain ß-Amyloid and Atrophy in Individuals at Increased Risk of Cognitive Decline.

BACKGROUND AND PURPOSE: The relationship between brain ß-amyloid and regional atrophy is still incompletely understood in elderly individuals at risk of dementia. Here, we studied the associations between brain ß-amyloid load and regional GM and WM volumes in older adults who were clinically evaluated as being at increased risk of cognitive decline based on cardiovascular risk factors. MATERIALS AND METHODS: Forty subjects (63-81 years of age) were recruited as part of a larger study, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability. Neuroimaging consisted of PET using 11C Pittsburgh compound-B and T1-weighted 3D MR imaging for the measurement of brain ß-amyloid and GM and WM volumes, respectively. All subjects underwent clinical, genetic, and neuropsychological evaluations for the assessment of cognitive function and the identification of cardiovascular risk factors. RESULTS: Sixteen subjects were visually evaluated as showing cortical ß-amyloid (positive for ß-amyloid). In the voxel-by-voxel analyses, no significant differences were found in GM and WM volumes between the samples positive and negative for ß-amyloid. However, in the sample positive for ß-amyloid, increases in 11C Pittsburgh compound-B uptake were associated with reductions in GM volume in the left prefrontal (P = .02) and right temporal lobes (P = .04). CONCLUSIONS: Our results show a significant association between increases in brain ß-amyloid and reductions in regional GM volume in individuals at increased risk of cognitive decline. This evidence is consistent with a model in which increases in ß-amyloid incite neurodegeneration in memory systems before cognitive impairment manifests.

CAIDE Dementia Risk Score, Alzheimer and cerebrovascular pathology: a population-based autopsy study.

BACKGROUND: CAIDE Dementia Risk Score is a tool for estimating dementia risk in the general population. Its longitudinal associations with Alzheimer or vascular neuropathology in the oldest old are not known. AIM: To explore the relationship between CAIDE Dementia Risk Score at baseline and neuritic plaques, neurofibrillary tangles, cerebral infarcts and cerebral amyloid angiopathy (CAA) after up to 10-year follow-up in the Vantaa 85 +  population. METHODS: Study population included 149 participants aged ≥85 years, without dementia at baseline, and with available clinical and autopsy data. Methenamine silver staining was used for ß-amyloid and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, CAA and α-synuclein pathologies. The CAIDE Dementia Risk Score was calculated based on scores for age, sex, BMI, total cholesterol, systolic blood pressure, physical activity and APOEε4 carrier status (range 0-18 points). RESULTS: A CAIDE Dementia Risk Score above 11 points was associated with more cerebral infarctions up to 10 years later: OR (95% CI) was 2.10 (1.06-4.16). No associations were found with other neuropathologies. CONCLUSION: In a population of elderly aged ≥85 years, higher CAIDE Dementia Risk Score was associated with increased risk of cerebral infarcts.

Self-rated physical fitness and estimated maximal oxygen uptake in relation to all-cause and cause-specific mortality.

This study investigated the longitudinal associations of self-rated physical fitness and estimated maximal oxygen uptake (VO2max) with all-cause and cause-specific mortality. A total of 59 741 participants in the Finnish National FINRISK Study Cohort had data on self-rated physical fitness and covariates. A subsample of 4823 participants had estimated VO2max data. Follow-up ranged from 3 to 38 years. Associations of self-rated physical fitness and VO2max with mortality were analyzed using multivariate Cox proportional hazard models. The study showed that poor self-rated physical fitness was related to all-cause mortality (hazard ratio [HR] 1.9; 95% confidence interval [CI] 1.8-2.0) and mortality due to cardiovascular (HR 2.0, 95% CI 1.9-2.2), cerebrovascular (HR 1.9, 95% CI 1.6-2.2) and respiratory diseases (HR 2.1, 95% CI 1.9-2.4), trauma (HR 1.7, 95% CI 1.3-2.0), infections (HR 1.8, 95% CI 1.3-2.7), dementia (HR 1.9, 95% CI 1.6-2.3), and cancer (HR 1.7, 95% CI 1.5-1.9). Coexisting higher age, physical inactivity, male gender, and severe chronic conditions further increased the risk. In men, higher VO2max was associated with a lower risk of lung cancer mortality (HR 0.8, 95% CI 0.7-0.96). Based on the results, self-rated physical fitness reflects a combination of unfavorable biological and lifestyle-related factors, which increase mortality risk. A simple question about perceived physical fitness may reveal at-risk individuals who would benefit from more intensive treatment of chronic conditions and other interventions aiming to promote better fitness and well-being.

Association of Long-Term Dietary Fat Intake, Exercise, and Weight with Later Cognitive Function in the Finnish Diabetes Prevention Study.

OBJECTIVES: To investigate associations of long-term nutrient intake, physical activity and obesity with later cognitive function among the participants in the Finnish Diabetes Prevention Study, in which a lifestyle intervention was successful in diabetes prevention. DESIGN: An active lifestyle intervention phase during middle age (mean duration 4 years) and extended follow-up (additional 9 years) with annual lifestyle measurements, followed by an ancillary cognition assessment. SETTING: 5 research centers in Finland. PARTICIPANTS: Of the 522 middle-aged, overweight participants with impaired glucose tolerance recruited to the study, 364 (70%) participated in the cognition assessment (mean age 68 years). MEASUREMENTS: A cognitive assessment was executed with the CERAD test battery and the Trail Making Test A on average 13 years after baseline. Lifestyle measurements included annual clinical measurements, food records, and exercise questionnaires during both the intervention and follow-up phase. RESULTS: Lower intake of total fat (p=0.021) and saturated fatty acids (p=0.010), and frequent physical activity (p=0.040) during the whole study period were associated with better cognitive performance. Higher BMI (p=0.012) and waist circumference (p=0.012) were also associated with worse performance, but weight reduction prior to the cognition assessment predicted worse performance as well (decrease vs. increase, p=0.008 for BMI and p=0.002 for waist). CONCLUSIONS: Long-term dietary fat intake, BMI, and waist circumference have an inverse association with cognitive function in later life among people with IGT. However, decreases in BMI and waist prior to cognitive assessment are associated with worse cognitive performance, which could be explained by reverse causality.