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BACKGROUND AND PURPOSE: This study evaluated associations of brain amyloid with 2-year objective and subjective cognitive measures in a trial-ready older general population at risk for dementia. METHODS: Forty-eight participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability underwent 11C-Pittsburgh compound B (PiB) positron emission tomography (PET) scans and assessment of cognition (modified Neuropsychological Test Battery [NTB]) and subjective memory complaints (Prospective and Retrospective Memory Questionnaire). RESULTS: Mean age was 71.4 ± 5.06 years, and 20 participants (42%) had positive baseline PiB-PET scans. Amyloid positivity was associated with lower NTB executive function at baseline and less favorable 2-year NTB total score and memory trajectories, but not with other objective or subjective cognitive measures. Overall, there was little cognitive decline during 2 years. CONCLUSIONS: Amyloid accumulation may affect objective but not necessarily subjective cognition from a very early at-risk stage, although substantial decline likely requires >2 years to occur.
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BACKGROUND: Stimulating activities are associated with a decreased risk of dementia. However, the extent to which this reflects a protective effect of activity or non-participation resulting from dementia is debated. We investigated the association of stimulating leisure-time activity in late adulthood with the risk of dementia across up to two decades' follow-up. METHODS: We used data from five prospective cohort studies from Finland and Sweden. Mental, social, outdoor, consumptive and physical leisure-time activities were self-reported. Incident dementia was ascertained from clinical diagnoses or healthcare and death registers. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Of the 33 263 dementia-free individuals aged ≥50 years at baseline, 1408 had dementia during a mean follow-up of 7.0 years. Active participation in mental (HR: 0.52, 95% CI: 0.41 to 0.65), social (HR: 0.56 95% CI: 0.46 to 0.72), outdoor (HR: 0.70, 95% CI: 0.58 to 0.85), consumptive (HR: 0.67, 95% CI: 0.53 to 0.94) and physical (HR: 0.62, 95% CI: 0.51 to 0.75) activity, as well as variety (HR: 0.54, 95% CI: 0.43 to 0.68) and the overall frequency of activity (HR: 0.41, 95% CI: 0.34 to 0.49) were associated with a reduced risk of dementia in <10 years' follow-up. In ≥10 years' follow-up all associations attenuated toward the null. CONCLUSION: Stimulating leisure-time activities are associated with a reduced risk of dementia in short-term but not long-term follow-up. These findings may reflect a reduction in leisure-time activity following preclinical dementia or dilution of the association over time.
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Demencia , Actividades Recreativas , Humanos , Demencia/epidemiología , Demencia/prevención & control , Demencia/diagnóstico , Demencia/psicología , Masculino , Femenino , Anciano , Suecia/epidemiología , Finlandia/epidemiología , Persona de Mediana Edad , Factores de Riesgo , Estudios Prospectivos , Factores de Tiempo , Factores Protectores , Medición de Riesgo , IncidenciaRESUMEN
Background: Evidence for the beneficial effects of cognitive training on cognitive function and daily living activities is inconclusive. Variable study quality and design does not allow for robust comparisons/meta-analyses of different cognitive training programmes. Fairly low adherence to extended cognitive training interventions in clinical trials has been reported. Aims: The aim of further developing a Cognitive Training Support Programme (CTSP) is to supplement the Computerised Cognitive Training (CCT) intervention component of the multimodal Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), which is adapted to different cultural, regional and economic settings within the Word-Wide FINGERS (WW-FINGERS) Network. The main objectives are to improve adherence to cognitive training through a behaviour change framework and provide information about cognitive stimulation, social engagement and lifestyle risk factors for dementia. Methods: Six CTSP sessions were re-designed covering topics including (1) CCT instructions and tasks, (2) Cognitive domains: episodic memory, executive function and processing speed, (3) Successful ageing and compensatory strategies, (4) Cognitive stimulation and engagement, (5) Wellbeing factors affecting cognition (e.g., sleep and mood), (6) Sensory factors. Session content will be related to everyday life, with participant reflection and behaviour change techniques incorporated, e.g., strategies, goal-setting, active planning to enhance motivation, and adherence to the CCT and in relevant lifestyle changes. Conclusions: Through interactive presentations promoting brain health, the programme provides for personal reflection that may enhance capability, opportunity and motivation for behaviour change. This will support adherence to the CCT within multidomain intervention trials. Efficacy of the programme will be evaluated through participant feedback and adherence metrics.
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BACKGROUND: Multimodal lifestyle interventions can benefit overall health, including cognition, in populations at-risk for dementia. However, little is known about the effect of lifestyle interventions in patients with prodromal Alzheimer's disease (AD). Even less is known about dietary intake and adherence to dietary recommendations within this population making it difficult to design tailored interventions for them. METHOD: A 6-month MIND-ADmini pilot randomized controlled trial (RCT) was conducted among 93 participants with prodromal AD in Sweden, Finland, Germany, and France. Three arms were included in the RCT: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management, and social stimulation); 2) multimodal lifestyle intervention + medical food product; and 3) regular health advice (control group). Adherence to dietary advice was assessed with a brief food intake questionnaire by using the Healthy Diet Index (HDI) and Mediterranean Diet Adherence Screener (MEDAS). The intake of macro- and micronutrients were analyzed on a subsample using 3-day food records. RESULTS: The dietary quality in the intervention groups, pooled together, improved compared to that of the control group at the end of the study, as measured with by HDI (p = 0.026) and MEDAS (p = 0.008). The lifestyle-only group improved significantly more in MEDAS (p = 0.046) and almost significantly in HDI (p = 0.052) compared to the control group, while the lifestyle + medical food group improved in both HDI (p = 0.042) and MEDAS (p = 0.007) during the study. There were no changes in macro- or micronutrient intake for the intervention groups at follow-up; however, the intakes in the control group declined in several vitamins and minerals when adjusted for energy intake. CONCLUSION: These results suggest that dietary intervention as part of multimodal lifestyle interventions is feasible and results in improved dietary quality in a population with prodromal AD. Nutrient intakes remained unchanged in the intervention groups while the control group showed a decreasing nutrient density. TRIAL REGISTRATION: ClinicalTrials.gov NCT03249688, 2017-07-08.
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Enfermedad de Alzheimer , Síntomas Prodrómicos , Humanos , Enfermedad de Alzheimer/dietoterapia , Enfermedad de Alzheimer/prevención & control , Masculino , Femenino , Anciano , Proyectos Piloto , Estilo de Vida , Dieta Mediterránea , Ejercicio Físico , Dieta/métodos , Terapia Combinada , Persona de Mediana Edad , Dieta Saludable/métodosRESUMEN
INTRODUCTION: Evidence has emerged that cardiometabolic multimorbidity (CMM) is associated with dementia, but the underlying mechanisms are poorly understood. METHODS: This population-based study included 5704 older adults. Of these, data were available in 1439 persons for plasma amyloid-ß (Aß), total tau, and neurofilament light chain (NfL) and in 1809 persons for serum cytokines. We defined CMM following two common definitions used in previous studies. Data were analyzed using general linear, logistic, and mediation models. RESULTS: The presence of CMM was significantly associated with an increased likelihood of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) (p < 0.05). CMM was significantly associated with increased plasma Aß40, Aß42, and NfL, whereas CMM that included visceral obesity was associated with increased serum cytokines. The mediation analysis suggested that plasma NfL significantly mediated the association of CMM with AD. DISCUSSION: CMM is associated with dementia, AD, and VaD in older adults. The neurodegenerative pathway is involved in the association of CMM with AD. HIGHLIGHTS: The presence of CMM was associated with increased likelihoods of dementia, AD, and VaD in older adults. CMM was associated with increased AD-related plasma biomarkers and serum inflammatory cytokines. Neurodegenerative pathway was partly involved in the association of CMM with AD.
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BACKGROUND: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) showed cognitive benefits from a multidomain lifestyle intervention in at-risk older people. The LipiDiDiet trial highlighted benefits of medical food in prodromal Alzheimer's disease (AD). However, the feasibility and impact of multimodal interventions combining lifestyle with medical food in prodromal AD is unclear. METHODS: MIND-ADmini was a 6-month multinational (Sweden, Finland, Germany, France) proof-of-concept randomized controlled trial (RCT). Participants were 60-85 years old, had prodromal AD (International Working Group-1 criteria), and vascular/lifestyle risk factors. The parallel-group RCT had three arms: multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); multimodal lifestyle intervention + medical food (Fortasyn Connect); and regular health advice/care (control). Participants were randomized 1:1:1 (computer-generated allocation at each site). Outcome evaluators were blinded to randomization. Primary outcome was feasibility of the multimodal intervention, evaluated by recruitment rate during a 6-month recruitment phase, overall adherence in each intervention arm, and 6-month retention rate. Successful adherence was pre-specified as attending ≥ 40% of sessions/domain in ≥ 2/4 domains (lifestyle intervention), and consuming ≥ 60% of the medical food (lifestyle intervention + medical food). The secondary outcomes included adherence/participation to each intervention component and overall adherence to healthy lifestyle changes, measured using a composite score for healthy lifestyle. Cognitive assessments were included as exploratory outcomes, e.g. Clinical Dementia Rating scale. RESULTS: During September 2017-May 2019, 93 individuals were randomized (32 lifestyle intervention, 31 lifestyle + medical food, and 30 control group). Overall recruitment rate was 76.2% (64.8% during the first 6 months). Overall 6-month retention rate was 91.4% (lifestyle intervention 87.5%; lifestyle + medical food 90.3%; control 96.7%). Domain-specific adherence in the lifestyle intervention group was 71.9% to cognitive training, 78.1% exercise, 68.8% nutritional guidance, and 81.3% vascular risk management; and in the lifestyle + medical food group, 90.3% to cognitive training, 87.1% exercise, 80.7% nutritional guidance, 87.1% vascular risk management, and 87.1% medical food. Compared with control, both intervention arms showed healthy diet improvements (ßLifestyle×Time = 1.11, P = 0.038; ßLifestyle+medical food×Time = 1.43, P = 0.007); the lifestyle + medical food group also showed vascular risk reduction (P = 0.043) and less cognitive-functional decline (P < 0.05, exploratory analysis). There were 5 serious adverse events (control group: 1; lifestyle intervention: 3; lifestyle + medical food: 1) unrelated to interventions. CONCLUSIONS: The multidomain lifestyle intervention, alone or combined with medical food, had good feasibility and adherence in prodromal AD. Longer-term cognitive and other health benefits should be further investigated in a larger-scale trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03249688.
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Enfermedad de Alzheimer , Estilo de Vida , Humanos , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/psicología , Femenino , Masculino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Síntomas Prodrómicos , Terapia Combinada/métodos , Ejercicio Físico/fisiología , Disfunción Cognitiva/terapia , Disfunción Cognitiva/prevención & controlRESUMEN
INTRODUCTION: We assessed a genetic risk score for Alzheimer's disease (AD-GRS) and apolipoprotein E (APOE4) in an exploratory neuroimaging substudy of the FINGER trial. METHODS: 1260 at-risk older individuals without dementia were randomized to multidomain lifestyle intervention or health advice. N = 126 participants underwent magnetic resonance imaging (MRI), and N = 47 positron emission tomography (PET) scans (Pittsburgh Compund B [PiB], Fluorodeoxyglucose) at baseline; N = 107 and N = 38 had repeated 2-year scans. RESULTS: The APOE4 allele, but not AD-GRS, was associated with baseline lower hippocampus volume (ß = -0.27, p = 0.001), greater amyloid deposition (ß = 0.48, p = 0.001), 2-year decline in hippocampus (ß = -0.27, p = 0.01), total gray matter volume (ß = -0.25, p = 0.01), and cortical thickness (ß = -0.28, p = 0.003). In analyses stratified by AD-GRS (below vs above median), the PiB composite score increased less in intervention versus control in the higher AD-GRS group (ß = -0.60, p = 0.03). DISCUSSION: AD-GRS and APOE4 may have different impacts on potential intervention effects on amyloid, that is, less accumulation in the higher-risk group (AD-GRS) versus lower-risk group (APOE). HIGHLIGHTS: First study of neuroimaging and AD genetics in a multidomain lifestyle intervention. Possible intervention effect on brain amyloid deposition may rely on genetic risk. AD-GRS and APOE4 allele may have different impacts on amyloid during intervention.
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Enfermedad de Alzheimer , Apolipoproteína E4 , Estilo de Vida , Imagen por Resonancia Magnética , Neuroimagen , Tomografía de Emisión de Positrones , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico por imagen , Masculino , Femenino , Anciano , Apolipoproteína E4/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Predisposición Genética a la Enfermedad , Persona de Mediana Edad , Factores de Riesgo , Puntuación de Riesgo GenéticoRESUMEN
AIM: Emerging evidence suggests association of tooth loss with impaired cognition. However, the differential effects of anterior versus posterior tooth loss, occlusal support loss and chewing ability are not considered comprehensively. MATERIALS AND METHODS: We conducted cross-sectional (N = 4036) and longitudinal analyses (N = 2787) on data from Health 2000 and 2011 Surveys for associations of posterior occlusal support loss, anterior versus posterior tooth loss, and chewing ability with baseline cognition and 11-year cognitive decline. Additionally, 15-year incident dementia risk was investigated (N = 4073). RESULTS: After considering relevant confounders and potential reverse causality bias, posterior occlusal support loss significantly increased dementia risk across all categories indicative of posterior occlusal support loss (hazard ratios [HRs] between 1.99 and 2.89). Bilateral inadequate posterior occlusal support was associated with 11-year decline in overall cognition (odds ratio [OR] = 1.48:1.00-2.19), and unilateral inadequate posterior occlusal support with total immediate (OR = 1.62:1.14-2.30) and delayed recall decline (OR = 1.45:1.03-2.05). Moreover, posterior tooth loss was associated with dementia (HR = 2.23:1.27-3.91) and chewing ability with total immediate decline (OR = 1.80:1.04-3.13). CONCLUSIONS: Posterior tooth and occlusal support loss significantly increases dementia risk. The impact of posterior occlusal support loss appears to be dose-dependent, and this effect is distinct from that of dentures. Dental healthcare services should be particularly attentive to the state of posterior dentition. Further studies exploring possible mechanisms are warranted.
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BACKGROUND AND PURPOSE: The complex aetiology of Alzheimer's disease suggests prevention potential. Risk scores have potential as risk stratification tools and surrogate outcomes in multimodal interventions targeting specific at-risk populations. The Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) was tested in relation to cognition and its suitability as a surrogate outcome in a multidomain lifestyle randomized controlled trial, in older adults at risk of dementia. METHODS: In this post hoc analysis of the Finnish Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), ANU-ADRI was calculated at baseline, 12, and 24 months (n = 1174). The association between ANU-ADRI and cognition (at baseline and over time), the intervention effect on changes in ANU-ADRI, and the potential impact of baseline ANU-ADRI on the intervention effect on changes in cognition were assessed using linear mixed models with maximum likelihood estimation. RESULTS: A higher ANU-ADRI was significantly related to worse cognition, at baseline (e.g., estimate for global cognition [95% confidence interval] was -0.028 [-0.032 to -0.025]) and over the 2-year study (e.g., estimate for 2-year changes in ANU-ADRI and per-year changes in global cognition [95% confidence interval] was -0.068 [-0.026 to -0.108]). No significant beneficial intervention effect was reported for ANU-ADRI, and baseline ANU-ADRI did not significantly affect the response to the intervention on changes in cognition. CONCLUSIONS: The ANU-ADRI was effective for the risk prediction of cognitive decline. Risk scores may be crucial for the success of novel dementia prevention strategies, but their algorithm, the target population, and the intervention design should be carefully considered when choosing the appropriate tool for each context.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/epidemiología , Australia/epidemiología , Universidades , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Disfunción Cognitiva/prevención & control , Estilo de Vida , Cognición/fisiologíaRESUMEN
BACKGROUND: Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60-79 years) at increased risk of dementia. METHODS: MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. CONCLUSION: MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05109169).
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Enfermedad de Alzheimer , Disfunción Cognitiva , Diabetes Mellitus Tipo 2 , Metformina , Anciano , Humanos , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Reposicionamiento de Medicamentos , Estilo de Vida , Metformina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Persona de Mediana EdadRESUMEN
INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies.
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Disfunción Cognitiva , Humanos , Anciano , Disfunción Cognitiva/psicología , Estilo de Vida , Cognición , Ejercicio Físico , EncéfaloRESUMEN
INTRODUCTION: To examine the burden and clusters of multimorbidity in association with mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD)-related plasma biomarkers among older adults. METHODS: This population-based study included 5432 participants (age ≥60 years); of these, plasma amyloid beta (Aß), total tau, and neurofilament light chain (NfL) were measured in a subsample (n = 1412). We used hierarchical clustering to generate five multimorbidity clusters from 23 chronic diseases. We diagnosed dementia and MCI following international criteria. Data were analyzed using logistic and linear regression models. RESULTS: The number of chronic diseases was associated with dementia (multivariable-adjusted odds ratio = 1.22; 95% confidence interval [CI] = 1.11 to 1.33), AD (1.13; 1.01 to 1.26), vascular dementia (VaD) (1.44; 1.25 to 1.64), and non-amnestic MCI (1.25; 1.13 to 1.37). Metabolic cluster was associated with VaD and non-amnestic MCI, whereas degenerative ocular cluster was associated with AD (p < 0.05). The number of chronic diseases was associated with increased plasma Aß and NfL (p < 0.05). DISCUSSION: Multimorbidity burden and clusters are differentially associated with subtypes of dementia and MCI and AD-related plasma biomarkers in older adults. HIGHLIGHTS: We used hierarchical clustering to generate five clusters of multimorbidity. The presence and load of multimorbidity were associated with dementia and mild cognitive impairment. Multimorbidity clusters were differentially associated with subtypes of dementia and Alzheimer's disease plasma biomarkers.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia Vascular , Humanos , Anciano , Persona de Mediana Edad , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Multimorbilidad , Progresión de la Enfermedad , Biomarcadores , Disfunción Cognitiva/diagnóstico , Fenotipo , Enfermedad Crónica , Cognición , Proteínas tauRESUMEN
BACKGROUND: Prior studies suggest that physical activity lowers circulating C-reactive protein (CRP) levels. However, little is known about the association between regular active commuting, i.e. walking or cycling to work, and CRP concentrations. This study examines whether active commuting is associated with lower CRP. METHODS: We conducted a cross-sectional study using population-based FINRISK data from 1997, 2002, 2007 and 2012. Participants were working adults living in Finland (n = 6208; mean age = 44 years; 53.6% women). We used linear and additive models adjusted for potential confounders to analyze whether daily active commuting, defined as the time spent walking or cycling to work, was associated with lower high-sensitivity (hs-) CRP serum concentrations compared with passive commuting. RESULTS: We observed that daily active commuting for 45 min or more (vs. none) was associated with lower hs-CRP [% mean difference in the main model: -16.8%; 95% confidence interval (CI) -25.6% to -7.0%), and results were robust to adjustment for leisure-time and occupational physical activity, as well as diet. Similarly, active commuting for 15-29 min daily was associated with lower hs-CRP in the main model (-7.4; 95% CI -14.1 to -0.2), but the association attenuated to null after further adjustments. In subgroup analyses, associations were only observed for women. CONCLUSIONS: Active commuting for at least 45 min a day was associated with lower levels of low-grade inflammation. Promoting active modes of transport may lead not only to reduced emissions from motorized traffic but also to population-level health benefits.
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Proteína C-Reactiva , Ejercicio Físico , Adulto , Humanos , Femenino , Masculino , Estudios Transversales , Caminata , Transportes/métodos , Ciclismo , Inflamación/epidemiologíaRESUMEN
AIM: To evaluate whether tooth loss is associated with cognitive decline and incident dementia. MATERIALS AND METHODS: We analysed data from the Finnish population-based Health 2000 and follow-up Health 2011 surveys (participants aged ≥30 years and without dementia at baseline; N = 5506 at baseline and 3426 at 11-year follow-up). Dementia diagnoses until 2015 were ascertained from national registers (N = 5542). Tooth count was dichotomized as adequate (≥20) versus tooth loss (<20). Tooth loss was further stratified into 10-19 teeth, 1-9 teeth and edentulism. Upper and lower jaws were also considered separately. Baseline cognitive test scores were dichotomized by median as high versus low, and 11-year change as decline versus no decline. RESULTS: Tooth loss (<20) was associated with lower baseline overall cognition (odds ratio [OR] = 1.21, 95% confidence interval [CI] = 1.03-1.43), 11-year cognitive decline (OR = 1.30, 95% CI = 1.05-1.70) and higher 15-year dementia risk (hazard ratio = 1.52, 95% CI = 1.15-2.02) after adjusting for multiple confounders. After adjustment for dentures, associations became non-significant, except for 10-19 teeth remaining and dementia. Results were similar after considering reverse causality bias; however, 10-19 teeth remaining was significantly associated with 11-year cognitive decline even after adjustment for dentures. No jaw-specific differences were observed. CONCLUSIONS: Tooth loss adversely impacts the risk of cognitive decline and dementia. The role of dentures should be further explored.
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Disfunción Cognitiva , Demencia , Pérdida de Diente , Humanos , Adulto , Pérdida de Diente/epidemiología , Pérdida de Diente/complicaciones , Finlandia/epidemiología , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/complicaciones , Cognición , Demencia/epidemiología , Demencia/etiología , Demencia/psicologíaRESUMEN
Background: Roughly 80% of total energy intake (TEI) in most human diets originates from digestible carbohydrates (eCarb) and fat (eFat), but the impact of their proportions on cognitive performance is poorly understood. Objectives: Our primary aim was to investigate estimates of global cognition in relation to macronutrient intake, with the log-ratio eCarb/eFat (CFr) as the primary predictor variable of interest. Secondary predictors were protein and the saturated/total fat ratio. Exploratory comparisons of CFr with eCarb and eFat as separate predictors were an additional aim. Methods: The observations were made on panel data (years 0, 1, 2) from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, n = 1251; age 60-77 y; 47% females; selected by risk factors for dementia. Self-reported diet was assessed by 3-d food records. Global cognition was measured using a modified Neuropsychological Test Battery. A mixed linear regression model was used, adjusted for age, sex, education, body-mass index, cholesterol-lowering drugs, TEI, time, time × intervention/control group, with study site and subject as random factors. Estimates were standardized (mean = 0; SD = 1) with 95% CI. Results: CFr had a negative estimate to global cognition (ß = -0.022, CI: -0.039, -0.005; P = 0.011). The point estimate for protein was ß = 0.013 (P = 0.41), and for the saturated/total fat ratio, associations with cognition were nonlinear. CFr correlated highly with eCarb (Pearson's r = 0.92) and eFat (r = -0.94). The point estimate for CFr fell between eCarb (ß = -0.026, P < 0.001) and (inversely) eFat (ß = 0.017, P = 0.090). Conclusions: A lower CFr was associated with better global cognition among older adults at risk for dementia. Because this is an important target group for preventive interventions, clinical trials are warranted to further investigate the impact of macronutritional composition on cognitive health. The potential role of CFr as a predictor for cognitive health should be further studied.
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INTRODUCTION: Mechanisms underlying the positive association between occupational mental demands and late-life cognition are poorly understood. The objective of this study was to assess whether the association between occupational complexity and cognition is related to and moderated by brain integrity in individuals at risk for dementia. Brain integrity was appraised throughout structural measures (magnetic resonance imaging, MRI) and amyloid accumulation (Pittsburgh compound B (PiB)-positron emission tomography, PiB-PET). METHODS: Participants from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) neuroimaging sample - MRI (N = 126), PiB-PET (N = 41) - were included in a post hoc cross-sectional analysis. Neuroimaging parameters comprised the Alzheimer's disease signature (ADS) cortical thickness (FreeSurfer 5.3), medial temporal atrophy (MTA), and amyloid accumulation (PiB-PET). Cognition was assessed using the neuropsychological test battery. Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. Linear regression models included cognition as dependent variable, and occupational complexity, measures of brain integrity, and their interaction terms as predictors. RESULTS: Occupational complexity with data and substantive complexity were associated with better cognition (overall cognition, executive function) when adjusting for ADS and MTA (independent association). Significant interaction effects between occupational complexity and brain integrity were also found, indicating that, for some indicators of brain integrity and cognition (e.g., overall cognition, processing speed), the positive association between occupational complexity and cognition occurred only among persons with higher brain integrity (moderated association). CONCLUSIONS: Among individuals at risk for dementia, occupational complexity does not seem to contribute toward resilience against neuropathology. These exploratory findings require validation in larger populations.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Estudios Transversales , Encéfalo/patología , Cognición , Disfunción Cognitiva/psicología , Enfermedad de Alzheimer/psicología , Imagen por Resonancia Magnética , Amiloide/metabolismo , Pruebas Neuropsicológicas , Péptidos beta-Amiloides/metabolismoRESUMEN
Introduction: Population-based studies have rarely explored the associations of the triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, with dementia and plasma biomarkers for amyloid beta (Aß) and neurodegeneration. Methods: This population-based study included 5199 participants (age ≥ 65 years); of these, plasma Aß, total tau, and neurofilament light chain (NfL) were measured in 1287 persons. Dementia and subtypes were diagnosed following the international criteria. TyG index was calculated as ln(fasting triglyceride(mg/dL) × fasting glucose[mg/dL]/2). Data were analyzed using logistic and general linear regression models. Results: Dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were diagnosed in 301, 195, and 95 individuals, respectively. A high TyG index was significantly associated with increased likelihoods of dementia and AD; the significant association with dementia remained among participants without cardiovascular disease or diabetes. In the biomarker subsample, a high TyG index was correlated with elevated plasma Aß, but not with total tau or NfL. Discussion: High TyG index is associated with dementia, possibly via Aß pathology.
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The rare A673T variant was the first variant found within the amyloid precursor protein (APP) gene conferring protection against Alzheimer's disease (AD). Thereafter, different studies have discovered that the carriers of the APP A673T variant show reduced levels of amyloid beta (Aß) in the plasma and better cognitive performance at high age. Here, we analyzed cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using a mass spectrometry-based proteomics approach to identify differentially regulated targets in an unbiased manner. Furthermore, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models together with the pathogenic APP Swedish and London mutations. Consequently, we now report for the first time the protective effects of the APP A673T variant against AD-related alterations in the CSF, plasma, and brain biopsy samples from the frontal cortex. The CSF levels of soluble APPß (sAPPß) and Aß42 were significantly decreased on average 9-26% among three APP A673T carriers as compared to three well-matched controls not carrying the protective variant. Consistent with these CSF findings, immunohistochemical assessment of cortical biopsy samples from the same APP A673T carriers did not reveal Aß, phospho-tau, or p62 pathologies. We identified differentially regulated targets involved in protein phosphorylation, inflammation, and mitochondrial function in the CSF and plasma samples of APP A673T carriers. Some of the identified targets showed inverse levels in AD brain tissue with respect to increased AD-associated neurofibrillary pathology. In 2D and 3D neuronal cell culture models expressing APP with the Swedish and London mutations, the introduction of the APP A673T variant resulted in lower sAPPß levels. Concomitantly, the levels of sAPPα were increased, while decreased levels of CTFß and Aß42 were detected in some of these models. Our findings emphasize the important role of APP-derived peptides in the pathogenesis of AD and demonstrate the effectiveness of the protective APP A673T variant to shift APP processing towards the non-amyloidogenic pathway in vitro even in the presence of two pathogenic mutations.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Humanos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Heterocigoto , Encéfalo/metabolismoRESUMEN
Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.