Platelet phospholipase A<Subscript>2</Subscript> activity in Alzheimer’s disease and mild cognitive impairment

Summary. Phospholipase A₂ (PLA₂) controls the metabolism of phospholipids in cell membranes. In the brain, PLA₂ influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (A), which are the major components of the senile plaques in Alzheimers disease (AD). Reduced PLA₂ activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA₂ activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA₂ activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA₂). PLA₂ activity was significantly lower in AD than in controls (p<0.001). Mean PLA₂ activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA₂ activity was significantly correlated with a worse cognitive performance both at the MMSE (p=0.001) and the cognitive sub-scale of the CAMDEX inventory (p=0.002). Our data replicate previous findings of reduced platelet PLA₂ activity in AD. Both reduced PLA₂ activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA₂ inhibits the physiological secretion of the APP, a mechanism that increases A formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA₂ values in platelets would be at a higher risk to develop AD during a longitudinal follow up.     

Cerebrospinal fluid biomarkers in Alzheimer’s disease, vascular dementia and ischemic stroke patients: a critical analysis

Vascular factors are thought to contribute to the development of disease pathology in neurodegenerative dementia such as Alzheimer’s disease (AD). Another entity, called vascular dementia (VaD), comprises a less defined group of dementia patients having various vascular diseases that especially emerge in the elderly population and require valid options for examination and differential diagnosis. In the context of a retrospective study, we analyzed the cerebrospinal fluid (CSF) biomarkers t-tau, p-tau and Aß42 of a total of 131 patients with AD (n = 47), mild cognitive impairment (MCI) (n = 22), VaD (n = 44) and stroke (n = 18). We found a remarkable alteration in CSF biomarker profile in AD, VaD and in acute ischemic events. CSF profile in AD patients was altered in a very similar way as in stroke patients, without statistical differences. In stroke, increase depend largely on size and duration after the initial event. Total tau levels were useful to differ between VaD and stroke. Aß42 decreased in a similar way in AD, VaD and stroke and had a trend to lower levels in MCI but not in controls.     

The role of phospholipase A<Subscript>2</Subscript> in neuronal homeostasis and memory formation: implications for the pathogenesis of Alzheimer’s disease

Summary. Phospholipase A₂ (PLA₂) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA₂ activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent ³¹P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA₂ activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA₂ has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA₂ inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA₂ precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA₂ enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA₂ activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD.     

T1rho (T<Subscript>1ρ</Subscript>) MR imaging in Alzheimer’ disease and Parkinson’s disease with and without dementia

In the current study, we aim to measure T1rho (T _1ρ) in the hippocampus in the brain of control, Alzheimer’s disease (AD), Parkinson’s disease (PD), and PD patients with dementia (PDD), and to determine efficacy of T _1ρ in differentiating these cohorts. With informed consent, 53 AD patients, 62 PD patients, 11 PDD patients, and 46 age-matched controls underwent a standardized clinical assessment including mini-mental state examination (MMSE) and brain T _1ρ MRI on a 1.5-T clinical-scanner. T_1ρ maps were generated by fitting each pixel’s intensity as a function of the spin-lock pulse duration. In control, AD, PD and PDD, mean ± SE T _1ρ values in the right hippocampus (RH) were 92.15 ± 2.00, 99.65 ± 1.98, 85.68 ± 1.87, 102.47 ± 4.66 ms while in the left hippocampus (LH) these values were 90.16 ± 1.82, 99.53 ± 1.91, 84.33 ± 2.03, 95.33 ± 4.64 ms. Significant difference for both RH and LH T _1ρ across the groups (p < 0.001) was observed. Both RH and LH T _1ρ were significantly increased in AD compared to control (p = 0.034, p = 0.001) and PD (p < 0.001, p < 0.001). In control, both RH and LH T _1ρ values were significantly increased compared to PD (p = 0.031, p = 0.027) while compared to PDD only the RH T _1ρ value was significantly decreased (p = 0.043). Both RH and LH T _1ρ values in PD were significantly lower than PDD (p = 0.004, p = 0.032). No significant correlation between the T _1ρ and age as well as between T _1ρ and MMSE scores was observed. The serial measurement of T_1ρ in both AD and PD may provide the nature of disease progression and may contribute to their early diagnosis.     

Muscle profile and cognition in patients with Alzheimer’s disease dementia

Introduction

Neurodegenerative disease is one of the main contributing factors affecting muscle atrophy. However, this intriguing brain-muscle axis has been explained by the unsubstantial mechanisms. Although there have been several studies that have evaluated the muscle profile and its relation to cognition in patients with dementia, there is still lack of data using standardized methods and only few published studies on Korean populations. The objective of this study is to evaluate the relationship of muscle mass and strength to cognition in patients with Alzheimer’s disease dementia (AD).

Methods

We recruited 91 patients with probable AD without weakness. We assessed patients’ basic demographic characteristics, vascular risk, body mass index, and global cognitive assessment scores. Muscle mass was measured using body dual-energy X-ray absorptiometry. Muscle strength was assessed by isokinetic knee extensor using an isokinetic device at an angular velocity of 60°/s in nm/kg.

Results

The muscle mass and strength were not related to each other in both male and female groups. Only muscle strength, but not muscle mass, was negatively related to cognition. After adjusting for covariates, the relationship between muscle strength and cognition still remained in the male group, however, was attenuated in the female group.

Conclusions

In patients with AD dementia, abundant muscle mass did not mean strong power. The simple lower-extremity muscle strength assessment is more effective in predicting cognition than a muscle mass measure in male patients.

     

Influence of controlled encoding and retrieval facilitation on memory performance of patients with subcortical ischemic vascular dementia and Alzheimer’s disease

Journal of Neurology - Patients with subcortical ischemic vascular dementia (SIVD) perform better than Alzheimer’s disease patients (AD) on the Free and Cued Recall Selective Reminding test...     

Increased infections with β-blocker use in ischemic stroke,a β<Subscript>2</Subscript>-receptor mediated process?

Strokes promote immunosuppression, partially from increased sympathetic activity. Altering sympathetic drive with β-blockers has variably been shown to improve stroke outcomes. This study adds to this literature using propensity score matching to limit confounding and by examining the effects of selective and non-selective β-blockers. Prospective data from acute ischemic stroke admissions at a single center from July 2010–June 2015 were analyzed. Outcomes included infection (urinary tract infection [UTI], pneumonia, or bacteremia), discharge modified Rankin Score (mRS), and in-hospital death. Any selective and non-selective β-blocker use during the first 3 days of admission were investigated with propensity score matching. A sensitivity analysis was also performed. This study included 1431 admissions. Any β-blocker use was associated with increased infections (16.4 vs. 10.7%, p = 0.030). Non-selective β-blocker use was associated with increased infections (18.9 vs. 9.7%, p = 0.005) and UTIs (13.0 vs. 5.5%, p = 0.009). Selective β-blocker use was not associated with infection. There were no associations between β-blocker use and in-hospital death or discharge mRS. In the sensitivity analysis, the association between non-selective β-blocker use and urinary tract infections persisted (12.5 vs. 4.2%, p = 0.044). No associations with death or mRS were found. Early β-blocker use after ischemic stroke may increase the risk of infection but did not change disability or mortality risk. The mechanism may be mediated by β₂-adrenergic receptor antagonism given the different effects seen with selective versus non-selective β-blocker use.     

Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies

The aim of this study was to characterize myelin loss as one of the features of white matter abnormalities across three common dementing disorders. We evaluated post-mortem brain tissue from frontal and temporal lobes from 20 vascular dementia (VaD), 19 Alzheimer’s disease (AD) and 31 dementia with Lewy bodies (DLB) cases and 12 comparable age controls. Images of sections stained with conventional luxol fast blue were analysed to estimate myelin attenuation by optical density. Serial adjacent sections were then immunostained for degraded myelin basic protein (dMBP) and the mean percentage area containing dMBP (%dMBP) was determined as an indicator of myelin degeneration. We further assessed the relationship between dMBP and glutathione S-transferase (a marker of mature oligodendrocytes) immunoreactivities. Pathological diagnosis significantly affected the frontal but not temporal lobe myelin attenuation: myelin density was most reduced in VaD compared to AD and DLB, which still significantly exhibited lower myelin density compared to ageing controls. Consistent with this, the degree of myelin loss was correlated with greater %dMBP, with the highest %dMBP in VaD compared to the other groups. The %dMBP was inversely correlated with the mean size of oligodendrocytes in VaD, whereas it was positively correlated with their density in AD. A two-tier regression model analysis confirmed that the type of disorder (VaD or AD) determines the relationship between %dMBP and the size or density of oligodendrocytes across the cases. Our findings, attested by the use of three markers, suggest that myelin loss may evolve in parallel with shrunken oligodendrocytes in VaD but their increased density in AD, highlighting partially different mechanisms are associated with myelin degeneration, which could originate from hypoxic–ischaemic damage to oligodendrocytes in VaD whereas secondary to axonal degeneration in AD.     

Different mechanisms of corpus callosum atrophy in Alzheimer’s disease and vascular dementia

Abstract. Previous neuroimaging studies have indicated that corpus callosum atrophy in Alzheimers disease (AD) and large vessel occlusive disease (LVOD) is caused by interhemispheric disconnection, namely Wallerian degeneration of interhemispheric commissural nerve fibers originating from pyramidal neurons in the cerebral cortex. However, this hypothesis has not been tested from a neuropathological viewpoint. In the present study, 22 brains with AD (presenile onset, 9; senile onset, 13), 6 brains with Binswangers disease (BD), a form of vascular dementia and 3 brains with LVOD were compared with 6 non-neurological control brains.White matter lesions in the deep white matter and corpus callosum were quantified as a fiber density score by image analysis of myelin-stained sections. Axonal damage and astrogliosis were assessed by immunohistochemistry for amyloid precursor protein and glial fibrillary acidic protein, respectively.The corpus callosum thickness at the anterior part of the body was decreased in AD and LVOD,but not in BD significantly, as compared with the controls. The corpus callosum thickness correlated roughly with brain weight in AD (R = 0.50),and with the severity of deep white matter lesions in BD (R = 0.81). Atrophy of the brain and corpus callosum was more marked in presenile onset AD than in senile onset AD. With immunohistochemistry, the corpus callosum showed axonal damage and gliosis with a decreased fiber density score in BD and LVOD, but not in AD. Thus, corpus callosum atrophy was correlated with brain atrophy in AD, which is relevant to the mechanism of interhemispheric disconnection,whereas corpus callosum lesions in BD were secondary to deep white matter lesions. Corpus callosum atrophy in LVOD may indicate interhemispheric disconnection, but focal ischemic injuries may also be involved.     

Selective loss of P2Y<Subscript>2</Subscript> nucleotide receptor immunoreactivity is associated with Alzheimer’s disease neuropathology

The uridine nucleotide-activated P2Y(2), P2Y(4) and P2Y(6) receptors are widely expressed in the brain and are involved in many CNS processes, including those which malfunction in Alzheimer's disease (AD). However, the status of these receptors in the AD neocortex, as well as their putative roles in the pathogenesis of neuritic plaques and neurofibrillary tangles, remain unclear. In this study, we used immunoblotting to measure P2Y(2), P2Y(4) and P2Y(6) receptors in two regions of the postmortem neocortex of neuropathologically assessed AD patients and aged controls. P2Y(2) immunoreactivity was found to be selectively reduced in the AD parietal cortex, while P2Y(4) and P2Y(6) levels were unchanged. In contrast, all three receptors were preserved in the occipital cortex, which is known to be minimally affected by AD neuropathology. Furthermore, reductions in parietal P2Y(2) immunoreactivity correlated both with neuropathologic scores and markers of synapse loss. These results provide a basis for considering P2Y(2) receptor changes as a neurochemical substrate of AD, and point towards uridine nucleotide-activated P2Y receptors as novel targets for disease-modifying AD pharmacotherapeutic strategies.     

Evaluation of CSF-Chlamydia pneumoniae,CSF-tau,and CSF-Abeta42 in Alzheimer’s disease and vascular dementia

The potential role of microbiological factors such as Chlamydia pneumoniae (ChP) in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) and vascular dementia (VD), has been suggested, but the correctness of this hypothesis still needs to be tested. In this study the appearance of ChP in the cerebrospinal fluid (CSF) of 57 AD and 21 VD patients and in 47 controls (CG) as well as the influence of ChP on the levels of tau protein and Abeta42 were investigated. The frequency of ChP occurrence in the AD patient group (43.9%) was significantly higher (p < 0.001) than in the control group (10.6%). In the case of VD patients, 9.5% of this group was positive for ChP. The presence of ChP DNA in the CSF of patients with AD significantly increases the occurrence of this disease (odds ratio = 7.21). Cerebrospinal fluid Abeta42 levels were significantly lower in patients with AD than in the CG (p < 0.001). Cerebrospinal tau protein was significantly higher in AD vs. CG (p = 0.007). However, no relationships between the presence of the bacterium in CSF and the level of either tau or Abeta42 protein were observed. In conclusion, we may suspect that testing for the presence of ChP in CSF, along with the tau and Abeta42 markers, may be used in the clinic diagnosis of AD.     

Follow-up investigations in cerebrospinal fluid of patients with dementia with Lewy bodies and Alzheimer’s disease

Summary. Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimers disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), A42, A40 and S-100B protein, using a set of commercially available assays.Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. A42 and A40 remained relatively stable during follow-up but we found a slight increase of the median A42 level in DLB, whereas in AD, A42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases.The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD.Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases.     

Tomm40 polymorphisms in Italian Alzheimer’s disease and frontotemporal dementia patients

Chromosome 19 is one of the several prominent chromosomes related to the risk of developing late-onset Alzheimer’s disease (LOAD) and frontotemporal lobar degeneration (FTLD). However, only Apolipoprotein E (APOE) has been confirmed as a risk factor for both disorders. The aim of this study was to investigate a set of polymorphisms in the translocase of the outer mitochondrial membrane 40 (TOMM40) gene, located in close proximity to APOE, to clarify if the TOMM40 gene may be considered a risk factor for AD and FTLD, independently of APOE status. We performed a case–control study in a dataset of Italian LOAD and FTLD patients, analyzing the following three single-nucleotide polymorphisms (SNPs): rs157580, rs2075650 and rs157581. The analysis was made in 710 Italian subjects: 282 LOAD patients, 156 FTLD patients and 272 healthy subjects. Our results confirm the presence of an association between TOMM40 SNPs and LOAD in our Italian population, suggesting that genetic variations proximate to APOE contributes to the LOAD risk. Genotype and allele distribution of the TOMM40 polymorphisms between the FTLD group and controls did not show any statistical difference. When we analyzed haplotype distribution of the SNPs, taking into account the presence of the APOE allele, we observed a strong association between the ε4 allele and the GAC haplotype both in LOAD and FTLD patients. In contrast, this association did not hold for ε3/GAC. These results demonstrate that the TOMM40 gene does not have an APOE-independent role in the risk of developing LOAD and FTLD.     

Differentiating Alzheimer’s disease from subcortical vascular dementia with the FAB test

Background The frontal assessment battery (FAB) test is a composite tool for assessing executive functions related to the frontal lobe. Neuropsychological and blood-flow studies indicate distinct patterns of deterioration of anterior and posterior cortical function in Alzheimer’s disease (AD) and subcortical vascular dementia (VD) patients. We predict that the FAB score may be useful for discriminating VD from AD. Objective To evaluate the clinical usefulness of the FAB test for differential diagnosis of AD and VD. Methods We compared FAB scores in 25 patients with AD, 27 patients with VD, and 80 age-matched normal control subjects. The AD group was matched for age, education and MMSE score with the VD group. The subtest scores in FAB were also compared among the three groups. Results The FAB scores were significantly decreased in both the AD and VD groups compared to the control group, and the reduction were greater in the VD group. Among the FAB subtests, mental flexibility (phonological verbal fluency) was the only subtest that significantly discriminated VD from the other two groups. Conclusions The FAB test can provide useful information for differentiating AD and VD at the bedside. Received in revised form: 20 January 2006     

Assessment of sleep satisfaction in patients with dementia due to Alzheimer’s disease

Sleep length and architecture are potential markers of progressive cognitive impairment, while neuropsychiatric symptoms and APOE4− haplotypes have been associated with more sleep complaints in patients with dementia due to Alzheimer’s disease (AD). In this cross-sectional study, we sought to investigate which factors might be related to sleep satisfaction in patients with AD. A total of 217 consecutive patients with AD were assessed for demographic features, neuropsychiatric symptoms, cognitive decline, functional impairment for activities of daily living, caregiver burden, APOE haplotypes, self-reported sleep satisfaction and length of sleep. Statistical comparisons were conducted with significance at p < 0.05. Concerning sleep complaints, 179 patients (82.5%) reported satisfactory sleep, while 38 (17.5%) were unsatisfied, with no relation to age, sex, APOE haplotypes, obesity, education, marital status, alcohol consumption or smoking found. Length of sleep (p = 0.011) and behavioural symptoms (p = 0.009) had significant associations with sleep satisfaction. Length of sleep was positively correlated with apathy (p = 0.014) and scores on the Clock Drawing Test (p = 0.015), and inversely correlated with anxiety (p = 0.015) and independence for instrumental activities of daily living (p = 0.003). Patients who were treated with memantine (p = 0.02) or anti-psychotics (p < 0.01) had longer duration of sleep. In conclusion, behavioural symptoms had strong associations with sleep satisfaction, which is highly correlated with length of sleep in patients with AD. Functional independence, apathy, anxiety, use of memantine or anti-psychotics, and scores on the Clock Drawing Test were significantly associated with length of sleep in this sample.     

Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models

The interstitial fluid (ISF) drainage pathway has been hypothesized to underlie the clearance of solutes and metabolites from the brain. Previous work has implicated the perivascular spaces along arteries as the likely route for ISF clearance; however, it has never been demonstrated directly. The accumulation of amyloid β (Aβ) peptides in brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD), and it is likely related to an imbalance between production and clearance of the peptide. Aβ drainage along perivascular spaces has been postulated to be one of the mechanisms that mediate the peptide clearance from the brain. We therefore devised a novel method to visualize solute clearance in real time in the living mouse brain using laser guided bolus dye injections and multiphoton imaging. This methodology allows high spatial and temporal resolution and revealed the kinetics of ISF clearance. We found that the ISF drains along perivascular spaces of arteries and capillaries but not veins, and its clearance exhibits a bi-exponential profile. ISF drainage requires a functional vasculature, as solute clearance decreased when perfusion was impaired. In addition, reduced solute clearance was observed in transgenic mice with significant vascular amyloid deposition; we suggest the existence of a feed-forward mechanism, by which amyloid deposition promotes further amyloid deposition. This important finding provides a mechanistic link between cerebrovascular disease and Alzheimer disease and suggests that facilitation of Aβ clearance along the perivascular pathway should be considered as a new target for therapeutic approaches to Alzheimer disease and cerebral amyloid angiopathy.     

Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies

Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a subpopulation of patients with other dementia disorders, including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36–56%) and in DLB (53–60%) than previously reported. Of the TDP-43-positive cases, about 20–30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and α-synuclein.     

Reduced 25-hydroxyvitamin D and risk of Alzheimer’s disease and vascular dementia

BackgroundVitamin D deficiency has been implicated as a risk factor for dementia in several cross-sectional studies. We tested the hypothesis that reduced plasma 25-hydroxyvitamin D (25[OH]D) is associated with increased risk of Alzheimer’s disease (AD) and vascular dementia in the general population.MethodsWe measured baseline plasma 25(OH)D in 10,186 white individuals from the Danish general population.ResultsDuring 30 years of follow-up, 418 participants developed AD and 92 developed vascular dementia. Multivariable adjusted hazard ratios for AD were 1.25 (95% confidence interval [CI], 0.95–1.64) for 25(OH)D less than 25 nmol/L vs. greater than or equal to 50 nmol/L, and 1.29 (95% CI, 1.01–1.66) for less than the 25th seasonally adjusted 25(OH)D percentile vs. more than the 50th seasonally adjusted 25(OH)D percentile. Multivariable adjusted hazard ratios for vascular dementia were 1.22 (95% CI, 0.77–1.91) for 25(OH)D less than 50 nmol/L vs. greater than or equal to 50 nmol/L, and 1.22 (95% CI, 0.79–1.87) for less than or equal to the 50th vs. more than the 50th seasonally adjusted 25(OH)D percentile. Last, multivariable adjusted hazard ratios for the combined end point were 1.28 (95% CI, 1.00–1.64) for 25(OH)D less than 25 nmol/L vs. greater than or equal to 50 nmol/L, and 1.27 (95% CI, 1.01–1.60) for less than the 25th vs. more than the 50th seasonally adjusted 25(OH)D.ConclusionsWe observed an association of reduced plasma 25(OH)D with increased risk of the combined end point of AD and vascular dementia in this prospective cohort study of the general population.