| 1. |
- de Rojas, I., et al.
(author)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 3. |
- Bellenguez, C, et al.
(author)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Journal article (peer-reviewed)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 6. |
- Neuvonen, E, et al.
(author)
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Associations of Depressive Symptoms and Cognition in the FINGER Trial: A Secondary Analysis of a Randomised Clinical Trial
- 2022
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In: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 11:5
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Journal article (peer-reviewed)abstract
- Depression and cognition are associated, but the role of depressive symptoms in lifestyle interventions to prevent dementia needs further study. We investigated the intervention effect on depressive symptoms and their associations with cognition in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER; NCT01041989), a two-year multidomain lifestyle trial. One thousand two-hundred and sixty individuals (60–77 years) at risk for dementia were randomised into a multidomain intervention (diet, exercise, cognitive training, and vascular/metabolic risk monitoring) or control group (regular health advice). Depressive symptoms (Zung scale) and cognition (modified Neuropsychological Test Battery) were evaluated at baseline, 12, and 24 months. One thousand one-hundred and twenty-five participants had baseline Zung data. Mean Zung score decreased 0.73 (SD 5.6) points in the intervention and 0.36 (5.6) points in the control group, with nonsignificant between-group difference (group × time coefficient −0.006, 95% CI −0.019 to 0.007). Overall, higher baseline Zung score was associated with less improvement in global cognition (−0.140, p = 0.005) and memory (−0.231, p = 0.005). Participants with clinically significant baseline depressive symptoms (Zung ≥ 40 points) had less intervention benefit to executive functioning (group × time × Zung −0.096, 95% CI −0.163 to −0.028). Change in Zung score was not associated with change in cognition. Clinically significant depressive symptoms warrant more attention when designing dementia-prevention interventions.
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| 7. |
- Sindi, S., et al.
(author)
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Baseline telomere length and effects of a multidomain lifestyle intervention on cognition : The FINGER randomized controlled trial
- 2017
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 59:4, s. 1459-1470
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Journal article (peer-reviewed)abstract
- Leukocyte telomere length (LTL) is a biomarker of aging, and it is associated with lifestyle. It is currently unknown whether LTL is associated with the response to lifestyle interventions. The goal is to assess whether baseline LTL modified the cognitive benefits of a 2-year multidomain lifestyle intervention (exploratory analyses). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2-year randomized controlled trial including 1,260 people at risk of cognitive decline, aged 60-77 years identified from the general population. Participants were randomly assigned to the lifestyle intervention (diet, exercise, cognitive training, and vascular risk management) and control (general health advice) groups. Primary outcome was change in cognition (comprehensive neuropsychological test battery). Secondary outcomes were changes in cognitive domains: Memory, executive functioning, and processing speed. 775 participants (392 control, 383 intervention) had baseline LTL (peripheral blood DNA). Mixed effects regression models with maximum likelihood estimation were used to analyze change in cognition as a function of randomization group, time, baseline LTL, and their interaction. Intervention and control groups did not significantly differ at baseline. Shorter LTL was related to less healthy baseline lifestyle. Intervention benefits on executive functioning were more pronounced among those with shorter baseline LTL (p-value for interaction was 0.010 adjusted for age and sex, and 0.007 additionally adjusted for baseline lifestyle factors). The FINGER intervention cognitive benefits were more pronounced with shorter baseline LTL, particularly for executive functioning, indicating that the multidomain lifestyle intervention was especially beneficial among higher-risk individuals.
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| 8. |
- Sindi, S., et al.
(author)
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Telomere Length Change in a Multidomain Lifestyle Intervention to Prevent Cognitive Decline : A Randomized Clinical Trial
- 2021
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In: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press. - 1079-5006 .- 1758-535X. ; 76:3, s. 491-498
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Journal article (peer-reviewed)abstract
- BACKGROUND: Shorter leukocyte telomere length (LTL) is associated with aging and dementia. Impact of lifestyle changes on LTL, and relation to cognition and genetic susceptibility for dementia, has not been investigated in randomized controlled trials (RCTs). METHODS: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability is a 2-year RCT enrolling 1260 participants at risk for dementia from the general population, aged 60-77 years, randomly assigned (1:1) to multidomain lifestyle intervention or control group. The primary outcome was cognitive change (Neuropsychological Test Battery z-score). Relative LTL was measured using quantitative real-time polymerase chain reaction (trial registration: NCT01041989). RESULTS: This exploratory LTL substudy included 756 participants (377 intervention, 379 control) with baseline and 24-month LTL measurements. The mean annual LTL change (SD) was -0.016 (0.19) in the intervention group and -0.023 (0.17) in the control group. Between-group difference was nonsignificant (unstandardized β-coefficient 0.007, 95% CI -0.015 to 0.030). Interaction analyses indicated better LTL maintenance among apolipoprotein E (APOE)-ε4 carriers versus noncarriers: 0.054 (95% CI 0.007 to 0.102); younger versus older participants: -0.005 (95% CI -0.010 to -0.001); and those with more versus less healthy lifestyle changes: 0.047 (95% CI 0.005 to 0.089). Cognitive intervention benefits were more pronounced among participants with better LTL maintenance for executive functioning (0.227, 95% CI 0.057 to 0.396) and long-term memory (0.257, 95% CI 0.024 to 0.489), with a similar trend for Neuropsychological Test Battery total score (0.127, 95% CI -0.011 to 0.264). CONCLUSIONS: This is the first large RCT showing that a multidomain lifestyle intervention facilitated LTL maintenance among subgroups of older people at risk for dementia, including APOE-ε4 carriers. LTL maintenance was associated with more pronounced cognitive intervention benefits. CLINICAL TRIALS REGISTRATION NUMBER: NCT01041989.
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| 13. |
- Allaouat, S, et al.
(author)
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Long-term exposure to ambient fine particulate matter originating from traffic and residential wood combustion and the prevalence of depression
- 2021
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In: Journal of epidemiology and community health. - : BMJ. - 1470-2738 .- 0143-005X. ; 75:11, s. 1111-1116
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Journal article (peer-reviewed)abstract
- Air pollution has been suggested to be associated with depression. However, current evidence is conflicting, and no study has considered different sources of ambient particulate matter with an aerodynamic diameter below 2.5 µm (PM2.5). We evaluated the associations of long-term exposure to PM2.5 from road traffic and residential wood combustion with the prevalence of depression in the Helsinki region, Finland.MethodsWe conducted a cross-sectional analysis based on the Helsinki Capital Region Environmental Health Survey 2015–2016 (N=5895). Modelled long-term outdoor concentrations of PM2.5 were evaluated using high-resolution emission and dispersion modelling on an urban scale and linked to the home addresses of study participants. The outcome was self-reported doctor-diagnosed or treated depression. We applied logistic regression and calculated the OR for 1 μg/m3 increase in PM2.5, with 95% CI. Models were adjusted for potential confounders, including traffic noise and urban green space.ResultsOf the participants, 377 reported to have been diagnosed or treated for depression by a doctor. Long-term exposure to PM2.5 from road traffic (OR=1.23, 95% CI 0.86 to 1.73; n=5895) or residential wood combustion (OR=0.78, 95% CI 0.43 to 1.41; n=5895) was not associated with the prevalence of depression. The estimates for PM2.5 from road traffic were elevated, but statistically non-significant, for non-smokers (OR=1.38, 95% CI 0.94 to 2.01; n=4716).ConclusionsWe found no convincing evidence of an effect of long-term exposure to PM2.5 from road traffic or residential wood combustion on depression.
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| 20. |
- Kulmala, J., et al.
(author)
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Association between mid- to late life physical fitness and dementia : evidence from the CAIDE study
- 2014
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 276:3, s. 296-307
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Journal article (peer-reviewed)abstract
- Objectives. This study investigated the association between perceived physical fitness at midlife, changes in perceived fitness during the three decades from mid-to late life and dementia risk. Design. Prospective cohort study. Setting. Cardiovascular risk factors, ageing and incidence of dementia (CAIDE) study. Subjects. Subjects were selected from four independent, random samples of population-based cardiovascular surveys and were first examined in 1972, 1977, 1982 or 1987, when they were on average 50 years old. The CAIDE target population included 3559 individuals. A random sample of 2000 individuals still alive in 1997 was drawn for re-examinations (performed in 1998 and 2005-2008) that consisted of cognitive assessments, with 1511 subjects participating in at least one re-examination. Dementia diagnoses were also confirmed from national registers for the entire target population. Main outcome measure. All-cause dementia. Results. Poor physical fitness at midlife was associated with increased dementia risk in the entire target population [hazard ratio (HR), 1.5; 95% confidence interval (CI), 1.1-2.0]. In participants, odds ratio (OR) was 2.0 (95% CI, 0.9-4.0). This association was significant in apolipoprotein E epsilon 4 allele (APO epsilon 4) noncarriers (OR, 4.3; 95% CI, 1.4-13.3), men (HR, 1.8; 95% CI, 1.1-3.0) and people with chronic conditions (HR, 2.9; 95% CI, 1.3-6.6). A decline in fitness after midlife was also associated with dementia (OR, 3.0; 95% CI, 1.7-5.1), which was significant amongst both men and women and more pronounced in APOE epsilon 4 carriers (OR, 4.4; 95% CI, 2.1-9.1). Conclusions. Perceived poor physical fitness reflects a combination of biological and lifestyle-related factors that can increase dementia risk. A simple question about perceived physical fitness may reveal at-risk individuals who could benefit from preventive interventions.
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| 21. |
- Kulmala, J, et al.
(author)
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Leisure-Time and Occupational Physical Activity in Early and Late Adulthood in Relation to Later Life Physical Functioning
- 2016
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In: Journal of physical activity & health. - : Human Kinetics. - 1543-5474 .- 1543-3080. ; 13:10, s. 1079-1087
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Journal article (peer-reviewed)abstract
- Physical activity (PA) has beneficial effects on older age physical functioning, but longitudinal studies with follow-ups extending up to decades are few. We investigated the association between leisure-time PA (LTPA) and occupational PA (OPA) from early to late adulthood in relation to later life performance-based physical functioning.Methods:The study involved 1260 people aged 60 to 79 years who took part in assessments of physical functioning (Short Physical Performance Battery [SPPB] test, 10-m maximal walking test, and grip strength test). Participants’ data on earlier life LTPA/OPA (age range 25 to 74 years) were received from the previous studies (average follow-up 13.4 years). Logistic, linear, and censored regression models were used to assess the associations between LTPA/OPA earlier in life and subsequent physical functioning.Results:A high level of LTPA earlier in life was associated with a lower risk of having difficulties on the SPPB test (odds ratio [OR]: 0.37; 95% confidence interval [CI], 0.24–0.58) and especially on the chair rise test (OR: 0.42; 95% CI, 0.27–0.64) in old age. Heavy manual work predicted difficulties on SPPB (OR: 1.91; 95% CI, 1.22–2.98) and the chair rise test (OR: 1.75; 95% CI, 1.14–2.69) and poorer walking speed (β = .10, P = .005).Conclusions:This study highlights the importance of LTPA on later life functioning, but also indicates the inverse effects that may be caused by heavy manual work.
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| 30. |
- Alenius, M, et al.
(author)
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Cognitive Performance among Cognitively Healthy Adults Aged 30-100 Years
- 2019
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In: Dementia and geriatric cognitive disorders extra. - : S. Karger AG. - 1664-5464. ; 9:1, s. 11-23
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Journal article (peer-reviewed)abstract
- <b><i>Background/Aims:</i></b> To detect cognitive decline in older adults, measures of verbal fluency and verbal memory are widely used. Less is known about performance in these measures in younger persons or according to education level and gender. We investigated cognitive performance according to age, education and gender among cognitively healthy adults aged 30–100 years. <b><i>Methods:</i></b> The study population comprised 4,174 cognitively healthy persons participating in the nationally representative Finnish Health 2011 survey. Cognitive assessment included verbal fluency, word list memory, word list recall and word list savings from the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery. <b><i>Results:</i></b> Total variance in the cognitive test performance explained by age, education and gender varied from 12.3 to 31.2%. A decreasing trend in cognitive performance existed in all subtests by advancing age, with differences appearing between 50 and 55 years. Persons with the highest-education level performed best for all measures. For the participants < 55 years, education explained part of the variance, while age and gender did not. <b><i>Conclusions:</i></b> When assessing cognition, age and education should be accounted for in more detail in research and clinical practice. Additionally, the cohort effect and its potential impact on the renewal cycle of future normative values for cognitive tests should be considered.
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| 31. |
- Alenius, M, et al.
(author)
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Cognitive Performance at Time of AD Diagnosis: A Clinically Augmented Register-Based Study
- 2022
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In: Frontiers in psychology. - : Frontiers Media SA. - 1664-1078. ; 13, s. 901945-
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Journal article (peer-reviewed)abstract
- We aimed to evaluate the feasibility of using real-world register data for identifying persons with mild Alzheimer’s disease (AD) and to describe their cognitive performance at the time of diagnosis. Patients diagnosed with AD during 2010–2013 (aged 60–81 years) were identified from the Finnish national health registers and enlarged with a smaller private sector sample (total n = 1,268). Patients with other disorders impacting cognition were excluded. Detailed clinical and cognitive screening data (the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery [CERAD-nb]) were obtained from local health records. Adequate cognitive data were available for 389 patients with mild AD (31%) of the entire AD group. The main reasons for not including patients in analyses of cognitive performance were AD diagnosis at a moderate/severe stage (n = 266, 21%), AD diagnosis given before full register coverage (n = 152, 12%), and missing CERAD-nb data (n = 139, 11%). The cognitive performance of persons with late-onset AD (n = 284), mixed cerebrovascular disease and AD (n = 51), and other AD subtypes (n = 54) was compared with that of a non-demented sample (n = 1980) from the general population. Compared with the other AD groups, patients with late-onset AD performed the worst in word list recognition, while patients with mixed cerebrovascular disease and AD performed the worst in constructional praxis and clock drawing tests. A combination of national registers and local health records can be used to collect data relevant for cognitive screening; today, the process is laborious, but it could be improved in the future with refined search algorithms and electronic data.
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| 32. |
- Alenius, M, et al.
(author)
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Education-Based Cutoffs for Cognitive Screening of Alzheimer's Disease
- 2022
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In: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 51:1, s. 42-55
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Journal article (peer-reviewed)abstract
- <b><i>Introduction:</i></b> The educational background and size of the elderly population are undergoing significant changes in Finland during the 2020s. A similar process is likely to occur also in several European countries. For cognitive screening of early Alzheimer’s disease (AD), using outdated norms and cutoff scores may negatively affect clinical accuracy. The aim of the present study was to examine the effects of education, age, and gender on the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery (CERAD-nb) in a large register-based, clinical sample of patients with mild AD and nondemented at-risk persons from the general population (controls) and to examine whether corrected cutoff scores would increase the accuracy of differentiation between the 2 groups. <b><i>Methods:</i></b> CERAD-nb scores were obtained from AD patients (<i>n</i> = 389, 58% women, mean age 74.0 years) and from controls (<i>n</i> = 1,980, 52% women, mean age 68.5 years). The differences in CERAD-nb performance were evaluated by univariate GLM. Differentiation between the 2 groups was evaluated using a receiver operating characteristic (ROC) curve, where a larger area under the ROC curve represents better discrimination. Youden’s J was calculated for the overall performance and accuracy of each of the measures. <b><i>Results:</i></b> Of the demographic factors, education was the strongest predictor of CERAD-nb performance, explaining more variation than age or gender in both the AD patients and the controls. Education corrected cutoff scores had better diagnostic accuracy in discriminating between the AD patients and controls than existing uncorrected scores. The highest level of discrimination between the 2 groups overall was found for two CERAD-nb total scores. <b><i>Conclusions:</i></b> Education-corrected cutoff scores were superior to uncorrected scores in differentiating between controls and AD patients especially for the highest level of education and should therefore be used in clinical cognitive screening, also as the proportion of the educated elderly is increasing substantially during the 2020s. Our results also indicate that total scores of the CERAD-nb are better at discriminating AD patients from controls than any single subtest score. A digital tool for calculating the total scores and comparing education-based cutoffs would increase the efficiency and usability of the test.
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| 39. |
- Sindi, S., et al.
(author)
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Midlife improvements in financial situation are associated with a reduced dementia risk later in life : the CAIDE 30-year study
- 2020
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In: International psychogeriatrics. - : Cambridge University Press. - 1041-6102 .- 1741-203X. ; 32:11, s. 1317-1324
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Journal article (peer-reviewed)abstract
- 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.
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| 40. |
- Sindi, S., et al.
(author)
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Multimodal Preventive Trial for Alzheimer’s Disease : MIND-ADmini Pilot Trial Study Design and Progress
- 2022
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In: The Journal of Prevention of Alzheimer's Disease. - : Serdi-Editions. - 2274-5807 .- 2426-0266. ; 9:1, s. 30-39
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Journal article (peer-reviewed)abstract
- 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).
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| 41. |
- Solomon, A., et al.
(author)
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Self-rated physical fitness and estimated maximal oxygen uptake in relation to all-cause and cause-specific mortality
- 2018
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In: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 28:2, s. 532-540
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Journal article (peer-reviewed)abstract
- 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 59741 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 38years. 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.
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