Alzheimer’s Disease is Associated with Decreased Risk of Cancer-Specific Mortality

J Alzheimers Dis. 2014 Jan 1;40(2):465-73. doi: 10.3233/JAD-132048.

Alzheimer’s Disease is Associated with Decreased Risk of Cancer-Specific Mortality: A Prospective Study (NEDICES).

Romero JP1Benito-León J2Louis ED3Bermejo-Pareja F2.

Abstract

Previous studies have shown that Alzheimer’s disease (AD) is associated with a reduced risk of cancer. However, most studies exclude those with undiagnosed dementia.

The only way to overcome this methodological issue is to examine all the participants or to screen the population for symptoms of dementia with a validated instrument and confirm any suspected dementia patients with a clinical examination (i.e., a two-phase investigation method).

We used this methodology to estimate whether cancer-specific mortality is associated with AD and other types of dementia in a prospective population-based study (NEDICES) involving 5,278 elderly people. Community-dwelling subjects with and without dementia were identified and followed for a median of 12.5 years, after which the death certificates of those who deceased were examined. A total of 1,976 (47.1%) died, including 277 who had possible or probable AD and 126 with non-AD dementia.

Cancer was reported significantly less often in those with possible or probable AD (5.8%) or non-AD dementia (6.3%) than in those without dementia (26.5%). In an unadjusted Cox model, hazard ratio (HR) of cancer-specific mortality in participants with AD = 0.45 (p = 0.002) and HR in participants with non-AD dementia = 0.62 (p = 0.179) when compared to the non-demented group.

In a Cox model that adjusted for a variety of demographic factors and co-morbidities, HRs of cancer-specific mortality in participants with AD = 0.50 (p = 0.028) and 0.97 (p = 0.942) in non-AD dementia. This study provides further evidence of an inverse association between cancer and AD.

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No Evidence of AD-Associated Changes in Adolescents Carrying Genetic Risk Factors

(Journal of Alzheimer’s Disease) Two studies published in the Journal of Alzheimer’s Disease indicate that some of the pathologic changes associated with Alzheimer’s disease in older individuals are not apparent in young people who carry the apolipoprotein (APOE) genetic risk factor for developing the disease. In the first study, no differences were found in hippocampal volume or asymmetry between cognitively normal adolescent carriers and non-carriers of the ApoE ɛ4 or ɛ2 allelles. The second study reports no differences in plasma concentrations of amyloid-β peptides among young adult ɛ4, ɛ3 or ɛ2 carriers.

Carriers of the apolipoprotein (ApoE) ɛ4 allele are at greater risk for developing late-onset Alzheimer’s disease (AD), develop AD at an earlier age, and experience a more severe cognitive decline and shorter survival times. The ɛ4 allele has also been linked to the severity of hippocampal atrophy and pathological alterations in the neocortex. The ɛ2 allele is thought to exert protection against the disease.

“Atrophy of the hippocampus, a region of the brain crucial for memory, is a common feature of AD, although it may also be detected in asymptomatic individuals as well as healthy adult carriers of the ApoE ɛ4 allele,” explained Andy Simmons, PhD, of the Department of Neuroimaging of the Institute of Psychiatry of King’s College London. “Whether young people genetically at risk for AD manifest early changes is an important question for those interested in interventions or treatments designed to slow or stop the progression of the disease.”

To address the question, 1412 adolescents underwent MRI imaging and had blood samples tested for DNA analysis in order to determine their ApoE status.

“Contrary to some recent studies, no hippocampal volume differences were observed between carriers and non-carriers of the ApoE ɛ4 allelle,” said Dr. Simmons. The investigators also looked for other potential changes, such as hippocampal asymmetry or gene dose-dependent effects on volume, but could find no associations with genetic status.

In addition to structural changes in the brain, patients with AD typically show an increase in the brain load of amyloid-β (Aβ) peptides and a decrease in cerebrospinal fluid (CSF) concentration of Aβ peptides. Similar changes are found in almost all persons with mild cognitive impairment at risk of conversion to AD.

“These changes represent the earliest diagnostic tools in AD,” explains Professor Dr. med.

Piotr Lewczuk, head of the Lab for Clinical Neurochemistry and Neurochemical Dementia Diagnostics, at the Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg. Since to some extent alterations of the concentrations of Aβ peptides are also observed in the blood, his research group explored differences in plasma levels of Aβ peptides among young adult ε4, ε3 or ε2 carriers.

To see whether these changes associated with AD are present at an early age, before clinical symptoms are apparent, investigators measured Aβ peptide concentrations in the plasma of 175 cognitively normal young adults. 40 individuals (22.9%) had at least one ε4 allele and were considered “at risk” for AD, 111 (63.4%) had the ε3/ε3 genotype and were considered “neutral,” and 24 (13.7%) in the “protective: group had at least one ε2 allele.

The investigators measured four Aβ peptides and found that no significant differences in plasma levels of any of the Aβ peptides were found among the three genetic groups.

“The lack of differences of the Aβ concentrations reported in this study between the groups with and without increased genetic risk of AD does not mean that ongoing pre-clinical neurodegeneration can be fully excluded in all young subjects,” says Dr. Lewczuk.

He also notes that around 40% of AD patients are not carriers of the ε4 allele. However, he believes that both Dr. Simmons’ findings concerning hippocampal volume and his study on plasma Aβ concentrations suggest that the AD-suggestive alterations begin perhaps 20-30 years before the onset of clinical symptoms, but most probably not earlier.

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Leisure-time Physical Activity from Mid- to Late Life, Body Mass Index, and Risk of Dementia

Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association – 09 April 2014 (10.1016/j.jalz.2014.01.008)

Leisure-time physical activity from mid- to late life, body mass index, and risk of dementia

Anna-Maija Tolppanen, Alina Solomon, Jenni Kulmala, Ingemar Kåreholt, Tiia Ngandu, Minna Rusanen, Tiina Laatikainen, Hilkka Soininen, Miia Kivipelto

Abstract

Background

Physical activity may be beneficial for cognition, but the effect may vary depending on personal characteristics.

Methods

We investigated the associations between leisure-time physical activity (LTPA) from mid- to late life, the risk of dementia, and the role of body mass index, sex, and APOE in the CAIDE study during 28-year follow-up. Cognitive function of a random subsample was assessed at a mean age of 78.8 years (n = 1511), and dementia/Alzheimer’s disease (AD) diagnoses were identified from national registers for the entire target population (n = 3559).

Results

Moderate (hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.08–1.99) and low levels of midlife LTPA (HR, 1.39; 95% CI, 0.99–1.95) were associated with higher risk of dementia in comparison with the most active category. The benefits were more pronounced among men, overweight individuals, and APOE ε4 noncarriers. Maintaining high LTPA (HR, 0.16; 95% CI, 0.06–0.41) or increasing LTPA (HR, 0.19; 95% CI, 0.09–0.40) after midlife was associated with lower dementia risk. Similar results were observed for AD.

Conclusions

The window of opportunity for preventive physical activity interventions may extend from midlife to older ages.

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Huperzine A in the Treatment of Alzheimer’s Disease

Neurobiol Aging. 2014 May;35(5):1045-54. doi: 10.1016/j.neurobiolaging.2013.11.004. Epub 2013 Nov 13.

Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer’s disease.

Huang XT1Qian ZM2He X3Gong Q3Wu KC3Jiang LR4Lu LN3Zhu ZJ3Zhang HY5Yung WH3Ke Y6.

Author information

Abstract

Huperzine A (HupA), a natural inhibitor of acetylcholinesterase derived from a plant, is a licensed anti-Alzheimer’s disease (AD) drug in China and a nutraceutical in the United States. In addition to acting as an acetylcholinesterase inhibitor, HupA possesses neuroprotective properties. However, the relevant mechanism is unknown.

Here, we showed that the neuroprotective effect of HupA was derived from a novel action on brain iron regulation.

HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/PS1dE9 transgenic AD mice.

Also, HupA decreased beta amyloid oligomers and amyloid precursor protein levels, and increased A Disintegrin And Metalloprotease Domain 10 (ADAM10) expression in these treated AD mice. However, these beneficial effects of HupA were largely abolished by feeding the animals with a high iron diet.

In parallel, we found that HupA decreased iron content in the brain and demonstrated that HupA also has a role to reduce the expression of transferrin-receptor 1 as well as the transferrin-bound iron uptake in cultured neurons. The findings implied that reducing iron in the brain is a novel mechanism of HupA in the treatment of Alzheimer’s disease.

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Groundbreaking Research: Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults

JAMA Neurol. Published online March 31, 2014. doi:10.1001/jamaneurol.2014.186

Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults

Timothy M. Hughes, PhD, MPH; Lewis H. Kuller, MD, DrPH; Emma J. M. Barinas-Mitchell, PhD; Eric M. McDade, DO; William E. Klunk, MD, PhD; Ann D. Cohen, PhD; Chester A. Mathis, PhD; Steven T. DeKosky, MD; Julie C. Price, PhD; Oscar L. Lopez, MD

Abstract

Importance

Recent studies show that cerebral β-amyloid (Aβ) deposition is associated with blood pressure and measures of arterial stiffness in nondemented individuals.

Objective

To examine the association between measures of arterial stiffness and change in Aβ deposition over time.

Design, Setting, and Participants

Deposition of Aβ was determined in a longitudinal observational study of aging by positron emission tomography using the Pittsburgh compound B twice 2 years apart in 81 nondemented individuals 83 years and older. Arterial stiffness was measured with a noninvasive and automated waveform analyzer at the time closest to the second positron emission tomography scan. All measures were performed under standardized conditions. Pulse wave velocity (PWV) was measured in the central (carotid-femoral and heart-femoral PWV), peripheral (femoral-ankle PWV), and mixed (brachial-ankle PWV) vascular beds.

Main Outcomes and Measures  The change in Aβ deposition over 2 years was calculated from the 81 individuals with repeat Aβ–positron emission tomography.

Results

The proportion of Aβ-positive individuals increased from 48% at baseline to 75% at follow-up. Brachial-ankle PWV was significantly higher among Aβ-positive participants at baseline and follow-up. Femoral-ankle PWV was only higher among Aβ-positive participants at follow-up. Measures of central stiffness and blood pressure were not associated with Aβ status at baseline or follow-up, but central stiffness was associated with a change in Aβ deposition over time. Each standard deviation increase in central stiffness (carotid-femoral PWV, P = .001; heart-femoral PWV,P = .004) was linked with increases in Aβ deposition over 2 years.

Conclusions and Relevance

This study showed that Aβ deposition increases with age in nondemented individuals and that arterial stiffness is strongly associated with the progressive deposition of Aβ in the brain, especially in this age group. The association between Aβ deposition changes over time and generalized arterial stiffness indicated a relationship between the severity of subclinical vascular disease and progressive cerebral Aβ deposition.

Hypertension is linked to cognitive impairment and the pathologic features of Alzheimer disease (AD), including neurofibrillary tangles and β-amyloid (Aβ) plaques,1 as well as cerebrovascular disease and white matter hyperintensities (WMHs) in the brain.2 Arterial stiffness appears to play a major role in the relationship between hypertension and its consequences in the brain. Mounting evidence implicates arterial stiffness in the pathogenesis of brain aging,3 cerebrovascular disease,3impaired cognitive function, and dementia in the elderly.4

Recent studies using radiolabeled Aβ ligands (eg, Pittsburgh compound B) in positron emission tomography (PET) imaging demonstrated that more than half of nondemented adults older than 80 years have significant fibrillar Aβ deposition.5 With the exception of the apolipoprotein E4 (ApoE4) genotype and aging, the risk factors and determinants of Aβ deposition in the brain are poorly understood. Recent studies report that brain Aβ deposition is associated with blood pressure6,7and that arterial stiffness may play a central role. We recently showed that greater arterial stiffness (measured as higher pulse wave velocities [PWVs]) was associated with the amount of Aβ deposition in the brain.8 Interestingly, this association was independent of standard covariates and systolic blood pressure. However, it is unknown if arterial stiffness or other modifiable vascular factors are associated with the accumulation of Aβ deposition in the brain over time.

In this study, we evaluated the relationship between arterial stiffness and change in Aβ deposition, measured twice, 2 years apart, in a longitudinal observational study of nondemented older adults. We hypothesized that greater systemic arterial stiffness would be associated with the extent of Aβ accumulation in the brain during 2 years of follow-up.

Citation

 

Predictors of Institutionalization in Dementia: A Three Year Longitudinal Study

Journal of Alzheimer’s Disease, Volume 40, Number 1 / 2014 / 221-226

Predictors of Institutionalization in Dementia: A Three Year Longitudinal Study

Henry Brodaty, Michael H. Connors, Jing Xu, Michael Woodward, David Ames

Abstract

Patients with dementia often require institutionalization when they can no longer care for themselves. The study examined demographic and clinical variables that predict the time until institutionalization in patients with dementia attending memory clinics.

Of 970 patients recruited from nine memory clinics around Australia, 779 patients had dementia at baseline.

Measures of dementia severity, cognition, functional ability, neuropsychiatric symptoms, caregiver burden, and medication use were completed for all patients. Patients were followed for three years.

Overall, 197 (25.3%) of the patients with dementia were institutionalized within three years.

Lower cognitive ability, lower functional ability, and more neuropsychiatric symptoms at baseline predicted a shorter time until institutionalization, as did use of antipsychotic medication.

In addition, greater deterioration in cognitive ability, functional ability, and neuropsychiatric symptoms over the initial three months predicted a shorter time to institutionalization.

The findings confirm that clinical features of dementia at baseline predict the time to institutionalization, as do greater changes in symptoms over three months independent of baseline levels.

Citation

 

Can a Novel Computerized Cognitive Screening Test Provide Additional Information for Early Detection of Alzheimer’s Disease?

Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

20 March 2014 (Article in Press DOI: 10.1016/j.jalz.2014.01.002)

Can a novel computerized cognitive screening test provide additional information for early detection of Alzheimer’s disease?

Ioannis Tarnanas, Magda Tsolaki, Tobias Nef, René M. Müri, Urs P. Mosimann

Abstract

Background

Virtual reality testing of everyday activities is a novel type of computerized assessment that measures cognitive, executive, and motor performance as a screening tool for early dementia. This study used a virtual reality day-out task (VR-DOT) environment to evaluate its predictive value in patients with mild cognitive impairment (MCI).

Methods

One hundred thirty-four patients with MCI were selected and compared with 75 healthy control subjects. Participants received an initial assessment that included VR-DOT, a neuropsychological evaluation, magnetic resonance imaging (MRI) scan, and event-related potentials (ERPs). After 12 months, participants were assessed again with MRI, ERP, VR-DOT, and neuropsychological tests.

Results

At the end of the study, we differentiated two subgroups of patients with MCI according to their clinical evolution from baseline to follow-up: 56 MCI progressors and 78 MCI nonprogressors. VR-DOT performance profiles correlated strongly with existing predictive biomarkers, especially the ERP and MRI biomarkers of cortical thickness.

Conclusions

Compared with ERP, MRI, or neuropsychological tests alone, the VR-DOT could provide additional predictive information in a low-cost, computerized, and noninvasive way.

Citation

 

Ferric Iron and the Alzheimer’s Disease Peptide β-amyloid (1–42)

Journal of the Royal Society Interface, 6 June 2014 vol. 11 no. 9520140165

Published 26 March 2014 doi: 10.1098/​rsif.2014.0165

J. Everett, E. Céspedes, L. R. Shelford, C. Exley, J. F. Collingwood, J. Dobson,, G. van der Laan, C. A. Jenkins, E. Arenholz and N. D. Telling

Abstract

For decades, a link between increased levels of iron and areas of Alzheimer’s disease (AD) pathology has been recognized, including AD lesions comprised of the peptide β-amyloid (Aβ). Despite many observations of this association, the relationship between Aβ and iron is poorly understood.

Using X-ray microspectroscopy, X-ray absorption spectroscopy, electron microscopy and spectrophotometric iron(II) quantification techniques, we examine the interaction between Aβ(1–42) and synthetic iron(III), reminiscent of ferric iron stores in the brain.

We report Aβ to be capable of accumulating iron(III) within amyloid aggregates, with this process resulting in Aβ-mediated reduction of iron(III) to a redox-active iron(II) phase. Additionally, we show that the presence of aluminium increases the reductive capacity of Aβ, enabling the redox cycling of the iron.

These results demonstrate the ability of Aβ to accumulate iron, offering an explanation for previously observed local increases in iron concentration associated with AD lesions. Furthermore, the ability of iron to form redox-active iron phases from ferric precursors provides an origin both for the redox-active iron previously witnessed in AD tissue, and the increased levels of oxidative stress characteristic of AD.

These interactions between Aβ and iron deliver valuable insights into the process of AD progression, which may ultimately provide targets for disease therapies.

Citation