Multimorbidity and functional impairment-bidirectional interplay, synergistic effects and common pathways.

This review discusses the interplay between multimorbidity (i.e. co-occurrence of more than one chronic health condition in an individual) and functional impairment (i.e. limitations in mobility, strength or cognition that may eventually hamper a person's ability to perform everyday tasks). On the one hand, diseases belonging to common patterns of multimorbidity may interact, curtailing compensatory mechanisms and resulting in physical and cognitive decline. On the other hand, physical and cognitive impairment impact the severity and burden of multimorbidity, contributing to the establishment of a vicious circle. The circle may be further exacerbated by people's reduced ability to cope with treatment and care burden and physicians' fragmented view of health problems, which cause suboptimal use of health services and reduced quality of life and survival. Thus, the synergistic effects of medical diagnoses and functional status in adults, particularly older adults, emerge as central to assessing their health and care needs. Furthermore, common pathways seem to underlie multimorbidity, functional impairment and their interplay. For example, older age, obesity, involuntary weight loss and sedentarism can accelerate damage accumulation in organs and physiological systems by fostering inflammatory status. Inappropriate use or overuse of specific medications and drug-drug and drug-disease interactions also contribute to the bidirectional association between multimorbidity and functional impairment. Additionally, psychosocial factors such as low socioeconomic status and the direct or indirect effects of negative life events, weak social networks and an external locus of control may underlie the complex interactions between multimorbidity, functional decline and negative outcomes. Identifying modifiable risk factors and pathways common to multimorbidity and functional impairment could aid in the design of interventions to delay, prevent or alleviate age-related health deterioration; this review provides an overview of knowledge gaps and future directions.

Natural history of prediabetes in older adults from a population-based longitudinal study.

BACKGROUND: The natural history of prediabetes in older adults remains unknown. OBJECTIVES: To assess the rate at which prediabetes progresses to diabetes, leads to death or reverts to normoglycaemia in older adults and to identify prognostic factors related to different outcomes of prediabetes. METHODS: In the Swedish National Study on Aging and Care-Kungsholmen, 2575 diabetes-free participants aged ≥60 years were examined at baseline and followed for up to 12 years. At each wave, diabetes was diagnosed via medical examination, antidiabetic drug use, medical records or glycated haemoglobin (HbA1c) ≥6.5%. Prediabetes was defined as HbA1c ≥5.7% and normoglycaemia as HbA1c <5.7% in diabetes-free participants. Data were analysed with multinomial logistic regression. RESULTS: At baseline, 918 (36%) individuals had prediabetes. Of them, 204 (22%) reverted to normoglycaemia (3.4/100 person-years, 95% CI 5.6-12.3), 119 (13%) developed diabetes (2.0/100 person-years, 95% CI 1.7-2.4) and 215 (23%) died (13.0/100 person-years, 95% CI 11.4-14.9) during the 12-year follow-up. The rates of reversion, progression and mortality were higher in the first 6-year than in the second 6-year follow-up, albeit not statistically significant. Lower systolic blood pressure (SBP), absence of heart diseases and weight loss promoted the reversion from prediabetes to normoglycaemia, whilst obesity accelerated its progression to diabetes. CONCLUSIONS: During a 12-year follow-up, most of older adults with prediabetes remained stable or reverted to normoglycaemia, whereas only one-third developed diabetes or died. Lower SBP, no heart diseases and weight management may promote reversion to normoglycaemia, suggesting possible strategies for achieving normoglycaemia in older adults with prediabetes.

Rapidly developing multimorbidity and disability in older adults: does social background matter?

BACKGROUND: Multimorbidity is among the most disabling geriatric conditions. In this study, we explored whether a rapid development of multimorbidity potentiates its impact on the functional independence of older adults, and whether different sociodemographic factors play a role beyond the rate of chronic disease accumulation. METHODS: A random sample of persons aged ≥60 years (n = 2387) from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K) was followed over 6 years. The speed of multimorbidity development was estimated as the rate of chronic disease accumulation (linear mixed models) and further dichotomized into the upper versus the three lower rate quartiles. Binomial negative mixed models were used to analyse the association between speed of multimorbidity development and disability (impaired basic and instrumental activities of daily living), expressed as the incidence rate ratio (IRR). The effect of sociodemographic factors, including sex, education, occupation and social network, was investigated. RESULTS: The risk of new activity impairment was higher among participants who developed multimorbidity faster (IRR 2.4, 95% CI 1.9-3.1) compared with those who accumulated diseases more slowly overtime, even after considering the baseline number of chronic conditions. Only female sex (IRR for women vs. men 1.6, 95% CI 1.2-2.0) and social network (IRR for poor vs. rich social network 1.7, 95% CI 1.3-2.2) showed an effect on disability beyond the rate of chronic disease accumulation. CONCLUSIONS: Rapidly developing multimorbidity is a negative prognostic factor for disability. However, sociodemographic factors such as sex and social network may determine older adults' reserves of functional ability, helping them to live independently despite the rapid accumulation of chronic conditions.

Work-related psychosocial stress and the risk of type 2 diabetes in later life.

OBJECTIVES: Although work-related psychosocial stress and type 2 diabetes mellitus (T2DM) have been investigated, the association between lifelong work stress and T2DM in later life remains unclear. This study examined whether high work stress increased the risk of T2DM risk in later life, accounting also for other sources of stress outside work, such as burden from household chores. METHODS: From the population-based prospective study SNAC-K, 2719 diabetes-free participants aged ≥60 years were identified and followed up for 6 years. T2DM was ascertained by glycated haemoglobin level, self-report, hypoglycaemic medication use and clinical records. Levels of job control and demands over the whole working life were assessed by a validated matrix. Household chores load was assessed by hours spent on such chores. Multivariate logistic regression models were used to estimate the association between job strain and T2DM. RESULTS: During the 6-year follow-up, 154 incident cases of T2DM were identified. High job strain was associated with T2DM occurrence amongst the 60-year-old cohort (OR = 3.14, 95% CI: 1.27-7.77), and only amongst women (OR = 6.18, 95% CI: 1.22-31.26), but not in men. When taking into account household chores load, a more pronounced risk of T2DM was associated with high job strain in combination with heavy household chores load in women aged 60 years at baseline (OR = 9.45, 95% CI: 1.17-76.53). CONCLUSION: Work-related psychosocial stress may increase the risk of T2DM only amongst women in their early 60s. The risk can be amplified by high household chores load.

The influence of negative life events on hippocampal and amygdala volumes in old age: a life-course perspective.

BACKGROUND: Psychosocial stress has been related to changes in the nervous system, with both adaptive and maladaptive consequences. The aim of this study was to examine the relationship of negative events experienced throughout the entire lifespan and hippocampal and amygdala volumes in older adults. METHOD: In 466 non-demented old adults (age range 60-96 years, 58% female), hippocampal and amygdala volumes were segmented using Freesurfer. Negative life events and the age at which these events occurred were assessed by means of a structured questionnaire. Using generalized linear models, hippocampal and amygdala volumes were estimated with life events as independent variables. The statistical analyses were adjusted for age, gender, intracranial volume, lifestyle factors, cardiovascular risk factors, depressive symptoms, and cognitive functioning. RESULTS: Total number of negative life events and of late-life events, but not of early-life, early-adulthood, or middle-adulthood events, was related to larger amygdala volume. There were interactions of early-life events with age and gender. Participants who reported two or more early-life events had significantly smaller amygdala and hippocampal volumes with increasing age. Furthermore, smaller hippocampal volume was found in men who reported two or more early-life events, but not in women. CONCLUSIONS: These results suggest that the effect of negative life events on the brain depends on the time when the events occurred, with the strongest effects observed during the critical time periods of early and late life.

Mild cognitive impairment: a concept in evolution.

The construct of mild cognitive impairment (MCI) has evolved over the past 10 years since the publication of the new MCI definition at the Key Symposium in 2003, but the core criteria have remained unchanged. The construct has been extensively used worldwide, both in clinical and in research settings, to define the grey area between intact cognitive functioning and clinical dementia. A rich set of data regarding occurrence, risk factors and progression of MCI has been generated. Discrepancies between studies can be mostly explained by differences in the operationalization of the criteria, differences in the setting where the criteria have been applied, selection of subjects and length of follow-up in longitudinal studies. Major controversial issues that remain to be further explored are algorithmic versus clinical classification, reliability of clinical judgment, temporal changes in cognitive performances and predictivity of putative biomarkers. Some suggestions to further develop the MCI construct include the tailoring of the clinical criteria to specific populations and to specific contexts. The addition of biomarkers to the clinical phenotypes is promising but requires deeper investigation. Translation of findings from the specialty clinic to the population setting, although challenging, will enhance uniformity of outcomes. More longitudinal population-based studies on cognitive ageing and MCI need to be performed to clarify all these issues.

Advances in the prevention of Alzheimer's disease and dementia.

BACKGROUND: Definitions and diagnostic criteria for all medical conditions are regularly subjected to reviews and revisions as knowledge advances. In the field of Alzheimer's disease (AD) research, it has taken almost three decades for diagnostic nomenclature to undergo major re-examination. The shift towards presymptomatic and pre-dementia stages of AD has brought prevention and treatment trials much closer to each other than before. METHODS: Here we discuss: (i) the impact of diagnostic reliability on the possibilities for developing preventive strategies for AD; (ii) the scientific evidence to support moving from observation to action; (iii) ongoing intervention studies; and (iv) the methodological issues and prospects for balancing strategies for high-risk individuals with those for broad population-based prevention. RESULTS: The associations between neuropathology and cognition are still not entirely clear. In addition, the risk factors for AD dementia and the neuropathological hallmarks of AD may not necessarily be the same. Cognitive impairment has a clearer clinical significance and should therefore remain the main focus of prevention. Risk/protective factors for dementia/AD need to be studied from a life-course perspective. New approaches in prevention trials include enrichment strategies based on genetic risk factors or beta-amyloid biomarkers (at least four ongoing pharmacological trials), and multidomain interventions simultaneously targeting various vascular and lifestyle-related risk factors (at least three ongoing trials). Experience from prevention programmes in other chronic diseases can provide additional methodological improvements. CONCLUSIONS: Building infrastructures for international collaborations is necessary for managing the worldwide public health problem of AD and dementia. The International Database on Aging and Dementia (IDAD) and the European Dementia Prevention Initiative (EDPI) are examples of ongoing international efforts aiming to improve the methodology of preventive studies and provide the basis for larger intervention trials.

Cognitive deficits in unipolar old-age depression: a population-based study.

BACKGROUND: There is substantial variability in the degree of cognitive impairment among older depressed persons. Inconsistencies in previous findings may be due to differences in clinical and demographic characteristics across study samples. We assessed the influence of unipolar depression and severity of depression on cognitive performance in a population-based sample of elderly persons aged ⩾60 years. METHOD: Eighty-nine persons fulfilled ICD-10 criteria for unipolar depression (mild, n = 48; moderate, n = 38; severe, n = 3) after thorough screening for dementia (DSM-IV criteria), psychiatric co-morbidities and antidepressant pharmacotherapy. Participants (n = 2486) were administered an extensive cognitive test battery. RESULTS: Moderate/severe unipolar depression was associated with poorer performance on tasks assessing processing speed, attention, executive function, verbal fluency, episodic memory and vocabulary. Mild depression was associated with poorer performance in processing speed, and few differences between mild and moderate/severe depression were observed. No association between depression and short-term memory, general knowledge or spatial ability was observed. Increasing age did not exacerbate the depression-related cognitive deficits, and the deficits remained largely unchanged after excluding persons in a preclinical phase of dementia. Furthermore, depression-related cognitive deficits were not associated with other pharmacological treatments that may affect cognitive performance. CONCLUSIONS: Cognitive deficits in unipolar old-age depression involve a range of domains and the cognitive deficits seem to follow the spectrum of depression severity. The finding that mild depression was also associated with poorer cognitive functioning underscores the importance of detecting mild depression in elderly persons.

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Estimating the burden of early onset dementia; systematic review of disease prevalence.

Dementia is more common in older age but a number of people develop symptoms at a younger age and are said to have early onset dementia (EOD). Those with EOD face different challenges to those with onset later in life. It has been difficult to quantify this disease burden. This is a systematic review of papers reporting on the prevalence of EOD. A search of Medline and Embase was performed. This was followed by a hand search of the references of these papers. Eleven suitable studies were included. All of the data was from more economically developed countries. The studies were heterogeneous in their design hindering direct comparison. The majority of the papers looked at all types of dementia although many gave a breakdown of the prevalence of different subgroups. A variety of diagnostic criteria was employed. Figures of 38 to 260 per 100,000 are quoted by papers looking at various different types of dementia together with an onset of between 30 and 64 or up to 420 per 100,000 for those aged 55-64. Prevalence rises as age approaches 65. Epidemiological data for prevalence rates for EOD are sparse. EOD remains a rare condition with low case numbers. Assimilation and comparison of results from existing studies is difficult due to methodological heterogeneity. Cross-national standardization of methodology should be a priority for future research in this area.

Do cardiovascular risk factors explain the link between white matter hyperintensities and brain volumes in old age? A population-based study.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) and brain atrophy frequently coexist in older people. However, it is unclear whether the association between these two brain lesions is dependent on the aging process, a vascular mechanism or genetic susceptibility. It was therefore investigated whether the association between load of WMHs and brain atrophy measures is related to age, vascular risk factors (VRFs) or the APOE-ε4 allele. METHODS: This population-based study included 492 participants (age ≥60 years, 59.6% women) free of dementia and stroke. Data on demographics, VRFs and APOE genotypes were collected through interviews, clinical examination and laboratory tests. WMHs on magnetic resonance images were assessed using manual visual rating and automatic volumetric segmentation. Hippocampal and ventricular volumes were manually delineated, whereas total gray matter (GM) volume was measured by automatic segmentation. Data were analyzed with multivariate linear regression models. RESULTS: More global WMHs, assessed using either a visual rating scale or a volumetric approach, were significantly associated with lower GM volume and higher ventricular volume; the associations remained significant after adjusting for age, VRFs and the APOE-ε4 allele. In contrast, the association between global WMHs and hippocampal volume was no longer significant after adjusting for age, whereas adjustment for VRFs and APOE-ε4 had no influential effect. CONCLUSION: The association of global WMHs with lower GM volume and higher ventricular volume is independent of age, VRFs and APOE-ε4 allele, suggesting that the process of cerebral microvascular disease and neurodegeneration are associated independently of the normal aging process, vascular mechanisms or genetic susceptibility.

Lifestyle factors related to mortality and survival: a mini-review.

As the world's population ages, elderly people are becoming an increasingly important group that merits special attention with regard to health and social issues. Lifestyles affect health and survival at all ages, but the consequences of poor lifestyle behaviors may be different for elderly people than for younger adults. They can also be heavily dependent on exposure earlier in life. Our current state of knowledge is based predominantly on studies conducted among middle-aged adults or young elderly people. Moreover, studies are sparse throughout the entire older age spectrum, from 65 to 90 years. This article summarizes the evidence regarding the impact of lifestyle behaviors on mortality among elderly people. It focuses on behaviors modifiable by individual actions and public health interventions, such as smoking, obesity and sedentary behavior, which predispose numerous people to diseases that rank among the leading causes of death, including heart disease, cancer, stroke, diabetes and dementia. These factors not only shorten life but, when they occur together, also have a major impact on survival beyond that associated with each single lifestyle factor. We propose an integrated life course model to guide research on longevity to answer questions that remain open and to find new strategies to ensure a longer and healthier life for future generations.

Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations.

BACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research. OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer's disease (AD) using cohort studies. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model. RESULTS: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project. CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.

Undertreatment of osteoporosis in persons with dementia? A population-based study.

UNLABELLED: In this population-based study of more than 2,600 elderly, people with dementia received less preventive treatment for osteoporosis compared to people without dementia, although osteoporotic fractures were more common in patients with dementia. Thus, our results indicate an undertreatment of osteoporosis in dementia. INTRODUCTION: This study compares the use of osteoporosis drugs in elderly with and without dementia, taking into account osteoporotic fractures and type of housing. METHODS: We analyzed data from the baseline examination (2001-2004) of The Swedish National Study on Aging and Care- Kungsholmen (SNAC-K), Stockholm, Sweden. Participants were aged ≥ 66 years (n = 2610). We analysed the use of bisphosphonates, raloxifene, and calcium/vitamin D combinations in relation to clinically based dementia diagnosis. Information about osteoporotic fractures during the previous 4 years was obtained from the Swedish National Patient Register. We used logistic regression to analyze the association between dementia status and use of osteoporosis drugs. RESULTS: Osteoporosis drugs (mainly calcium/vitamin D combinations) were used by 5% of the persons with dementia and 12% of the persons without dementia. Furthermore, 25% of the persons with dementia and 7% of the persons without dementia had had at least one osteoporotic fracture during the past 4 years. After controlling for age, sex, osteoporotic fractures, and type of housing (own home or institution), persons with dementia were less likely to use osteoporosis drugs than persons without dementia (OR = 0.34; 95% CI, 0.19-0.59). CONCLUSIONS: Our results indicate an undertreatment of osteoporosis in persons with dementia, although osteoporotic fractures are common among these patients.

Medial temporal lobe is vulnerable to vascular risk factors in men: a population-based study.

BACKGROUND AND PURPOSE: Vascular risk factors (VRFs) are known to cause cerebral microvascular disease, but evidence supporting an effect of VRFs on regional brain atrophy is mixed. We investigate whether an aggregation of VRFs is associated with volume of hippocampus and entorhinal cortex in elderly people living in the community. METHODS: This cross-sectional study consists of 523 participants (age ≥60 years, 59.3% women) of the SNAC-K Study in central Stockholm, Sweden, who were free of clinical stroke and cognitive impairment. We collected data on VRFs through interviews, clinical examination and inpatient register system. Hippocampal and entorhinal cortex volume was manually measured on magnetic resonance images. Data were analysed with general linear regression models controlling for demographics and total intracranial volume. RESULTS: In men, high total cholesterol and diabetes were significantly or marginally associated with smaller hippocampus and entorhinal cortex; when current smoking, binge alcohol drinking, high cholesterol and diabetes were aggregated, an increasing number of VRFs were significantly associated with decreasing volume of hippocampus and entorhinal cortex (P for linear trend <0.01). In women, none of individual VRFs or their aggregation was significantly associated with the volume of these brain regions, except former smoking that was significantly associated with a larger volume of these regions. CONCLUSIONS: Aggregation of VRFs is associated with reduced hippocampal and entorhinal cortex volume in apparently healthy elderly men, but not in women. This implies that in men, the medial temporal lobe is vulnerable to cardiovascular risk factors.

The symptom of low mood in the prodromal stage of mild cognitive impairment and dementia: a cohort study of a community dwelling elderly population.

OBJECTIVE: To investigate the symptom of low mood as a predictor of mild cognitive impairment (MCI) and its progression to dementia, taking into account: (i) MCI severity, (ii) time of assessment and (iii) interaction with other factors. METHODS: 764 cognitively healthy elderly subjects living in the community, from the Kungsholmen Project. Participants were assessed by direct interview to detect low mood. Subjects were then followed for 6 years to identify those who developed MCI. People with incident MCI were followed for a further 3 years to assess progression to dementia. RESULTS: People with low mood at baseline had a 2.7-fold (95% CI 1.9 to 3.7) increased risk of developing MCI at follow-up. The association was stronger for amnestic MCI (aMCI: HR 5.8; 95% CI 3.1 to 10.9) compared with global cognitive impairment (other cognitive impairment no dementia, oCIND: HR 2.2; 95% CI 1.5 to 3.3). ApoE-ε4 interacted with low mood in a synergistic fashion, increasing the risk of aMCI, while no interaction with psychiatric, vascular, frailty related or psychosocial factors was observed. Low mood at baseline, as opposed to low mood co-occurring with MCI, was associated with a 5.3-fold (95% CI 1.2 to 23.3) increased risk of progression to dementia in aMCI. In contrast, no association was found in oCIND. CONCLUSION: Low mood was more strongly associated with aMCI than with global cognitive impairment. Progression towards dementia was predicted only by low mood manifest in the prodromal stage of MCI. These findings indicate that low mood is particularly prominent in the very early stages of cognitive decline.

Epidemiological studies of cognitive impairment and dementia across Eastern and Middle European countries (epidemiology of dementia in Eastern and Middle European Countries).

OBJECTIVE: To determine the availability and the consistency of prevalence findings of epidemiological studies on cognitive impairment and dementia conducted in Eastern and Middle Europe. METHODS: We adopted a stepwise multimethod study approach consisting of iterative literature searches for epidemiological articles published between 1990 and 2006 and subsequent data analyses of published material, reanalyses of existing accessible epidemiological data sets and expert inquiries in Eastern and Middle European countries. Systematic computer-assisted searches used the keywords: "dementia", "Alzheimer", "cognitive impairment", "incidence", "prevalence", "epidemiology" in combination with the name of the relevant countries or "Europe" in English and Polish language. We supplemented the literature search with a review of the references in the articles that were identified during the initial search. RESULTS: We were able to find few regional and country-specific epidemiological studies of various kinds (population-based, cohort, cross-sectional studies) and conducted on different restricted population groups of patients (from neurological units, out-patients units, residential homes). No studies were identified from most of the countries taken under consideration and the ones we found were characterized by an immense diversity with a considerable degree of clinical and methodological variations. The few studies that there are suggest prevalence rates of dementia in Eastern Europe similar to those in Western Europe. CONCLUSIONS: There is strong need for epidemiological studies in Eastern and Middle Europe, as well as for greater coordination and standardization of methods to improve the quality and comparability of epidemiological data to determine the prevalences' rates of dementia in all the EU countries.

The influence of vascular disease on cognitive performance in the preclinical and early phases of Alzheimer's disease.

BACKGROUND/AIM: Alzheimer's disease (AD) is one of the most important causes of old-age cognitive impairment. We aimed to examine the influence of history of vascular disease on cognition in preclinical and early AD. METHODS: Participants from a population-based study were assessed twice with a test of global cognition. The study sample was nondemented at baseline. Three years later, 138 persons were diagnosed with AD and 783 persons remained nondemented. History of vascular disease (heart disease, cerebrovascular disease) was assessed at both occasions. RESULTS: Analyses of covariance revealed significant main effects of group (AD; comparison group) and vascular disease (present; absent) at baseline and follow-up (p < 0.01). At follow-up, a significant interaction indicated that the AD group was more negatively affected by vascular disease (p < 0.01). The fastest rate of cognitive decline was observed for those persons with preclinical AD who had new recordings of vascular disease. CONCLUSIONS: History of vascular disease has a negative impact on cognition in old age. This effect is most pronounced in persons in the earliest clinical phases of AD. Treatment of vascular risk factors in early AD might postpone time of diagnosis and slow down dementia progression.

Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study.

AIMS/HYPOTHESIS: Diabetes has been related to Alzheimer's disease with inconsistent findings. We aimed to clarify the association of diabetes with different dementing disorders taking into account glycaemic control, and to explore the link between glucose dysregulation and neurodegeneration. METHODS: A dementia-free cohort (n = 1,248) aged >or=75 years was longitudinally examined to detect dementia, Alzheimer's disease and vascular dementia (VaD) cases (Diagnostic and Statistical Manual of Mental Disorders, revised third edition [DSM-III-R] criteria). The Alzheimer's disease diagnoses were subdivided into Alzheimer's disease with stroke and Alzheimer's disease without hypertension, heart disease and stroke. Diabetes was ascertained based on medical history, or hypoglycaemic medication use, or a random blood glucose level >or=11.0 mmol/l, which included undiagnosed diabetes when neither a history of diabetes nor hypoglycaemic drugs use was present. Uncontrolled diabetes was classified as a random blood glucose level >or=11.0 mmol/l in diabetic patients. Borderline diabetes was defined as a random blood glucose level of 7.8-11.0 mmol/l in diabetes-free individuals. Cox models were used to estimate HRs. RESULTS: During the 9 year follow-up, 420 individuals developed dementia, including 47 with VaD and 320 with Alzheimer's disease (of the 320 Alzheimer's disease cases, 78 had previous, temporally unrelated stroke, and 137 had no major vascular comorbidities). Overall diabetes was only related to VaD (HR 3.21, 95% CI 1.20-8.63). Undiagnosed diabetes led to an HR of 3.29 (95% CI 1.20-9.01) for Alzheimer's disease. Diabetic patients with random blood glucose levels <7.8 mmol/l showed no increased dementia risk. Uncontrolled and borderline diabetes were further associated with Alzheimer's disease without vascular comorbidities. CONCLUSIONS/INTERPRETATION: Uncontrolled diabetes increases the risk of Alzheimer's disease and VaD. Our findings suggest a direct link between glucose dysregulation and neurodegeneration.