Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene.

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

Pro-inflammatory interleukin-18 increases Alzheimer's disease-associated amyloid-ß production in human neuron-like cells.

BACKGROUND: Alzheimer's disease (AD) involves increased accumulation of amyloid-ß (Aß) plaques and neurofibrillary tangles as well as neuronal loss in various regions of the neocortex. Neuroinflammation is also present, but its role in AD is not fully understood. We previously showed increased levels of pro-inflammatory cytokine interleukin-18 (IL-18) in different regions of AD brains, where it co-localized with Aß-plaques, as well as the ability of IL-18 to increase expression of glycogen synthase kinase-3ß (GSK-3ß) and cyclin dependent kinase 5, involved in hyperphosphorylation of tau-protein. Elevated IL-18 has been detected in several risk conditions for AD, including obesity, type-II diabetes, and cardiovascular diseases as well as in stress. METHODS: We differentiated SH-SY5Y neuroblastoma cells as neuron-like and exposed them to IL-18 for various times. We examined the protein levels of amyloid-ß precursor protein (APP) and its processing products, its cleaving enzymes, involved in amyloidogenic processing of APP, and markers of apoptosis. RESULTS: IL-18 increased protein levels of the ß-site APP-cleaving enzyme BACE-1, the N-terminal fragment of presenilin-1 and slightly presenilin enhancer 2, both of which are members of the γ-secretase complex, as well as Fe65, which is a binding protein of the C-terminus of APP and one regulator for GSK-3ß. IL-18 also increased APP expression and phosphorylation, which preceded increased BACE-1 levels. Further, IL-18 altered APP processing, increasing Aß40 production in particular, which was inhibited by IL-18 binding protein. Increased levels of soluble APPß were detected in culture medium after the IL-18 exposure. IL-18 also increased anti-apoptotic bcl-xL levels, which likely counteracted the minor increase of the pro-apoptotic caspase-3. Lactate dehydrogenase activity in culture medium was unaffected. CONCLUSIONS: The IL-18 induction of BACE-1, APP processing, and Aß is likely to be linked to stress-associated adaptations in neurons during the course of normal functioning and development. However, in the course of wider changes in the aging brain, and particularly in AD, the effects of heightened or prolonged levels of IL-18 may contribute to the process of AD, including via increased Aß.

Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS.

Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.

Amyloid and tau proteins in cortical brain biopsy and Alzheimer's disease.

OBJECTIVE: Amyloid-ß(Aß) aggregates are presumed to be found in the brain at an early stage of Alzheimer's disease (AD) but have seldom been assessed by brain biopsy during life in often elderly patients. METHODS: Between 1991 and 2006 we evaluated 468 patients with suspected normal pressure hydrocephalus with intraventricular pressure monitoring and a right frontal cortical biopsy sample immunostained for Aß and hyperphosphorylated tau (HPτ). Adequate samples and the clinical follow-up data until death or the end of 2008, available in 433 cases, were reviewed for the clinical signs of dementia, including AD. Logistic regression analysis was used to analyze whether Aß and/or HPτ in the biopsy samples obtained during life predicted development of cognitive impairment, in particular, AD. RESULTS: Of the 433 frontal cortical samples, 42 (10%) displayed both Aß and HPτ, 144 (33%) Aß only, and 247 (57%) neither Aß nor HPτ. In a median follow-up time of 4.4 years, 94 patients (22%) developed clinical AD. The presence of both Aß and HPτ was strongly associated (odds ratio [OR], 68.2; 95% confidence interval [CI], 22.1-210) and Aß alone significantly associated (OR, 10.8; 95% CI, 4.9-23.8) with the clinical diagnosis of AD. INTERPRETATION: This is the largest follow-up study of patients assessed for the presence of Aß and HPτ in frontal cortical brain biopsy samples. 1) The presence of Aß and HPτ spoke strongly for the presence or later development of clinical AD; 2) Aß alone was suggestive of AD; and 3) the absence of Aß and HPτ spoke against a later clinical diagnosis of AD.

Neuropsychiatric symptoms and quality of life in patients with very mild and mild Alzheimer's disease.

BACKGROUND: Neuropsychiatric symptoms (NPS) are common manifestations of Alzheimer' s disease (AD). OBJECTIVE: To examine the prevalence and significance of NPS in very mild and mild AD patients with emphasis on their influence on the well-being of the patients and their caregivers. METHODS: The participants were 240 patient-caregiver dyads who participated in a prospective, controlled rehabilitation study (ALSOVA). Three Quality of Life (QoL) instruments were used; generic 15D, disease-specific QoL-AD and Visual Analog Scale (VAS). The disease-specific QoL-AD was both self-rated and caregiver rated. Other scales used were Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), ADCS-ADL, Neuropsychiatric Inventory (NPI) and Beck Depression Inventory (BDI). RESULTS: NPS were present in 76.5% of patients with very mild AD (CDR 0.5) and in 84.9% of patients with mild to moderate AD (CDR 1). The most frequent symptoms were apathy, depression, irritability, and agitation. The strongest predictor of self-reported QoL-AD scores was depressive symptoms whereas functional decline and presence of NPS predicted poor caregiver ratings of patients' QoL. However, caregiver depression also influenced significantly their ratings. CONCLUSION: NPS are common even in the early stages of AD. NPS were significantly associated with caregiver assessment of the patient's QoL but not with patients' self-assessed QoL. Depression decreases QoL, but may remain unrecognized in AD patients, emphasizing the need for careful and structured assessment of NPS before deciding on the appropriate treatment.

An update on clinical proteomics in Alzheimer's research.

Alzheimer's disease (AD) is a pathologically complex and aetiologically multifactorial dementing disorder affecting millions of people worldwide. The pathological brain changes are assumed to occur decades prior to the onset of clinical symptoms. The diagnosis of early AD remains problematic and is mainly based on clinical and neuropsychological findings after the onset of symptoms. Currently available drugs are able to delay the symptom progression of the disease but not to attenuate the progression of pathological brain changes. Many studies exploring AD proteomes have been conducted as the middle of 1990s as a consequence of recent advances in the development of both gel-based and gel-free proteomics approaches. It is hoped that proteomics can contribute to improving the understanding, diagnosis, and follow-up of the progression of AD. In this review, we summarise the present status of proteome alterations, with emphasis on quantitative approaches, in AD brain, CSF and blood, and their relevance to dementia research.

[Update on current care guidelines: diagnostics, treatment and rehabilitation of multiple sclerosis]. / MS-taudin diagnoosi, lääkehoito ja kuntoutus.

Treatment is initiated when the McDonald criteria for relapsing-remitting multiple sclerosis (RRMS) are fulfilled. High-risk patients with clinically isolated syndrome are followed using magnetic resonance imaging for one year after the first imaging. Interferon-beta or glatiramer acetate are the first-line immunomodulating drugs (IMD) for RRMS. MxA protein is measured 12 and 24 months after initiation of Interferon-beta to evaluate possible development of neutralizing antibodies. If MxA protein may not be detected repeatedly interferon-beta treatment is discontinued. If the disease is active in spite of treatment with first-line IMD, natalizumab may be considered as a second-line therapy. IMD is stopped when the transition to secondary progressive phase has occurred (or upon transition to secondary progressive phase).

[Early detection of cognitive changes in memory diseases: new cut-off scores for the Finnish version of CERAD neuropsychological battery]. / Muistisairauksien tiedonkäsittelymuutosten varhainen toteaminen uudistetulla CERAD-tehtäväsarjalla.

The evaluation of cognitive functions by using CERAD (Consortium to Establish a Registry for Alzheimer's Disease) is recommended as a tool in basic health care for screening of memory diseases. The reliability of this method, adopted in Finland in 1999, has been impaired by the fact that there have been no comprehensive Finnish norms to serve as the basis for the cut-off limits of the test tasks. This article presents the new, revised cut-off values for the CERAD procedure, based on the comparison of Finnish population-based normative data with those of persons having very mild or mild Alzheimer's disease.

[Update on current care guidelines. The diagnosis and medical treatment of memory disorders]. / Muistisairauksien diagnostiikka ja lääkehoito.

Any complaints from a patient about their memory should be examined. Diagnosis is based on international criteria. The basic evaluation consists of the medical history, clinical evaluation, cognitive tests and brain imaging, especially using MRI. When a diagnosis of Alzheimer's disease, AD with cerebrovascular disease or with Lewy Body disease, or Dementia associated with Parkinson's disease or LBD is made, evidence based medical therapy is indicated as part of comprehensive care. An acetylcholinesterase inhibitor or memantine can be used. These drugs are ineffective in the case of frontotemporal degenerations. For severe behavioural disorders, other psychoactive medications can be applied.

Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study.

BACKGROUND: Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS: Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS: The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION: AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING: European Commission; Ana Aslan International Foundation.

No evidence for shared etiology in two demyelinative disorders, MS and PLOSL.

Loss-of-function mutations of DAP12 and TREM2 cause a recessively inherited disease PLOSL, manifesting in brain white matter. The genes of the DAP12-TREM2 signaling receptor are located on 19q13.12 and 6p21.1, to which linkage has been observed also in families affected by another immune-mediated demyelinating disease, MS. We have tested if allelic variation in DAP12 or TREM2 predisposes also to MS by monitoring carrier frequency of the Finnish PLOSL mutation in Finnish MS cases and by studying DAP12 and TREM2 in MS by linkage and association. To conclude, the DAP12-TREM2 complex unlikely has a role in genetic susceptibility of MS.

Treatment with galantamine and time to nursing home placement in Alzheimer's disease patients with and without cerebrovascular disease.

OBJECTIVE: This study evaluated patient and treatment (galantamine and other acetylcholinesterase inhibitors (AChEIs)) factors associated with the time until nursing home placement (NHP) in patients with Alzheimer's disease (AD) with and without cerebrovascular disease (CVD). METHODS: Re-contact follow-up study conducted in 2004 of 548 patients who had previously participated in RCTs with galantamine. Time to NHP was analyzed using Kaplan-Meier estimates and Cox regression analysed factors associated with NHP. RESULTS: There were 57% of female subjects and the mean age (SE) was 73.6 (+/-0.33) years. Within this cohort 78% of patients had AD, and 22% had AD with CVD. Overall, 59% of subjects had a NHP (median 42.4 months 95%CI: 38.0-48.0). The Cox regression model identified higher baseline Disability Assessment in Dementia (DAD) and Mini Mental State Examination (MMSE) scores, diagnosis (AD with CVD vs AD), living with caregiver, country, and treatment duration with galantamine or other AChEIs as factors associated with a reduced risk of institutionalization (p < 0.05). For each year of treatment with galantamine or other AChEI, the risk of being admitted to a nursing home within a given period was reduced by 31% (galantamine) and 29% (other AChEI). CONCLUSIONS: Long-term treatment with galantamine or other AChEIs appears to be associated with a significant delay in the time to NHP in patients with AD and AD with CVD. Further prospective studies are needed to confirm these findings.

Caregiver depression is associated with a low sense of coherence and health-related quality of life.

OBJECTIVES: The main objective is to examine the sense of coherence (SOC) of spouse caregivers. The aim was further investigate the association of SOC, health-related quality of life (HRQoL), depressive symptoms, distress and how severity of Alzheimer's disease (AD) affects SOC. METHOD: 17O patient-spouse caregiver dyads in which the patient has recently diagnosed mild AD. Caregivers completed SOC scale (SOC-29), HRQoL (15D), Beck depression and general health questionnaire scale. The assessment of AD-related symptoms was made using mini mental state examination, clinical dementia rating, neuropsychiatric inventory and functional performance using activities of daily living (ADCS-ADL) scale. RESULTS: Male caregivers' SOC was significantly higher than female caregivers. The main predictor for low SOC was depression, with 37% of spousal caregivers reporting depressive symptoms. Women reported more depressive symptoms and distress. Caregivers' HRQoL was as high as 0.8714, and a significant correlation was found between SOC and depression, r = -0.632 and distress r = -0.579. Furthermore, significant correlations were found between HRQoL and depression (r = -0.572) and distress (r = -0.568). The main predictors for high HRQoL were female gender and low distress. CONCLUSION: Spouse caregivers with low SOC seem to be a vulnerable group of caregivers. The many negative effects of perceived health accumulate in these caregivers during the very early phases of the caregiving process. Vulnerable caregivers need to be recognized at the time of AD diagnosis so that they can receive psychological support and counselling in addition to prevent morbidity in these caregivers.

CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.

CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.

[Use of CSF biomarkers in the diagnostics of memory diseases]. / Alzheimerin taudin merkkitekijöiden käyttö muistisairauksien diagnostiikassa.

Alzheimer's disease is the most common cause of dementia. Early diagnosis of diseases leading to dementia is cost-effective. However, early diagnosis of Alzheimer's disease may be difficult and should not be based on exclusion of other reasons for dementia. A decreased CSF amyloid beta-peptide-42 level together with elevated tau or phosphorylated tau levels can differentiate patients with AD from control subjects or patients with other neurologic conditions with relatively high accuracy. We evaluated the use of these biomarkers in 452 patient cohort during 2005-2007 in clinical practice. Cerebrospinal fluid biomarkers seem to be useful especially to confirm Alzheimer's disease diagnosis.

A multi-metabolite analysis of serum by 1H NMR spectroscopy: early systemic signs of Alzheimer's disease.

A three-molecular-window approach for (1)H NMR spectroscopy of serum is presented to obtain specific molecular data on lipoproteins, various low-molecular-weight metabolites, and individual lipid molecules together with their degree of (poly)(un)saturation. The multiple data were analysed with self-organising maps, illustrating the strength of the approach as a holistic metabonomics framework in solely data-driven metabolic phenotyping. We studied 180 serum samples of which 30% were related to mild cognitive impairment (MCI), a neuropsychological diagnosis with severely increased risk for Alzheimer's disease (AD). The results underline the association between MCI and the metabolic syndrome (MetS). Additionally, the low relativeamount of omega-3 fatty acids appears more indicative of MCI than low serum omega-3 or polyunsaturated fatty acid concentration as such. The analyses also feature the role of elevated glycoproteins in the risk for AD, supporting the view that coexistence of inflammation and the MetS forms a high risk condition for cognitive decline.

Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells.

Inflammatory cytokines, produced mainly by activated microglia in the brain, can enhance neuronal degeneration and the amyloid-beta-plaque production involved in Alzheimer's disease (AD). We previously demonstrated that the expression of the pro-inflammatory cytokine interleukin-18 (IL-18) colocalizes with plaques and hyperphoshorylated tau containing neurons in AD patients. Here we exposed neuron-like, differentiated SH-SY5Y neuroblastomas to IL-18 and observed that the protein levels of p35, Cdk5, GSK-3beta, and Ser15-phosphorylated p53 increased during 6 h-24 h. Tau phosphorylation and expression of cyclin G1, involved in neuronal regeneration, increased at 72 h. In vivo, over-expression of IL-18 may induce hyperphosphorylation of tau and induce cell cycle activators.

CSF Abeta42, tau and phosphorylated tau correlate with medial temporal lobe atrophy.

Cerebrospinal fluid (CSF) biomarkers and medial temporal lobe (MTL) atrophy predict the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). We investigated the association between the CSF biomarkers and MTL atrophy and the ability of these measures to predict AD in MCI patients in the same study population. The study included 21 MCI patients of whom eight progressed to AD during the study. CSF biomarkers were measured by using ELISA method and volumes of MTL structures were assessed by magnetic resonance imaging (MRI). Abeta42 levels were lower and tau and phospho-tau levels were higher in progressive subjects. The progressive subjects had lower volumes in all MRI measures. Tau and phospho-tau correlated inversely with hippocampal volumes and left entorhinal cortex volume in the whole study group. In the stable group, tau correlated with hippocampal volumes. Phospho-tau [corrected] had a negative correlation whereas Abeta42 [corrected] exhibited a positive correlation with left hippocampal volume in the progressive group. These results indicate that both measures may reflect the ongoing neurodegenerative process in the progressive MCI patients. However, the order of the changes in the CSF biomarkers and MTL atrophy remain unclear due to a small number of studied subjects and study design.

Systematic appraisal using immunohistochemistry of brain pathology in aged and demented subjects.

BACKGROUND/AIMS: Abnormal processing of hyperphosphorylated tau (HPtau), amyloid-beta (Abeta) and alpha-synuclein (alphaS) proteins is considered as causative with regard to the clinical symptoms in age-related neurodegenerative diseases. METHODS: In this retrospective, postmortem study applying immunohistochemical methodology, we assessed Alzheimer's-disease (AD)-related HPtau and Abeta pathology in 178 subjects with alphaS pathology. RESULTS: These pathologies were frequently seen concomitantly, i.e. HPtau in 83% and Abeta in 62% of the alphaS-positive cases. Furthermore, the striatum was frequently involved, particularly in subjects with cognitive impairment (65%). The predictive value of widespread HPtau pathology, i.e. stages V-VI, with respect to cognitive impairment was high, since all 18 subjects presenting with this stage were demented. In contrast, the predictive value of widespread alphaS pathology, i.e. stages 5-6 according to Braak's Parkinson disease staging, was debatable. Fifty-three percent of the subjects with widespread alphaS pathology and no or mild AD-related HPtau pathology were cognitively unimpaired. It is noteworthy that striatal Abeta pathology was more often seen in demented subjects independently of HPtau and/or alphaS status. CONCLUSION: The causative pathology in subjects with clinically diagnosed dementia with Lewy bodies needs to be clarified in future studies.

Atrial fibrillation, stroke, and cognition: a longitudinal population-based study of people aged 85 and older.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the association between atrial fibrillation (AF), stroke, dementia, and their correlation with brain pathology in subjects aged 85 years or older. METHODS: This is a prospective 9-year follow-up population based study in Vantaa, a town in Southern Finland; 553 subjects (92% of the total population) aged 85 years or older were clinically examined by a neurologist. The presence of AF was collected from the medical records or examined by ECG or ambulatory ECG. Neuropathological examination was conducted in more than half of the clinically examined subjects. RESULTS: AF was significantly associated with stroke at baseline; 32% of patients with AF had clinical evidence of stroke compared with 16.7% of those without such evidence (P<0.001). Dementia at baseline was significantly associated with age, clinical stroke, and the presence of apolipoprotein E epsilon4 allele, but not with sex, education, or vascular risk factors. Multiple regression analysis including neuropathological results showed that dementia was significantly associated with education (OR, 0.89; 95% CI, 0.80 to 0.98; P=0.019), the beta-amyloid load in the brain (OR, 1.26; 95% CI, 1.13 to 1.39; P<0.001) and with the vascular pathology (OR, 2.03; 95% CI, 1.14 to 3.62; P=0.016), but not with sex, age at death, apolipoprotein E epsilon4 allele, or vascular risk factors. CONCLUSIONS: AF is a significant and preventable risk factor for stroke but not for dementia in the very old. The etiology of dementia syndrome in the very old is multifactorial. Both Alzheimer disease pathology and vascular pathology, particularly multiple small infarcts, contribute to cognitive decline.