Journal of Alzheimer's Disease - Volume 33, issue s1

Authors: Braskie, Meredith N. | Toga, Arthur W. | Thompson, Paul M.

Article Type: Review Article

Abstract: Advances in brain imaging technology in the past five years have contributed greatly to the understanding of Alzheimer's disease (AD). Here, we review recent research related to amyloid imaging, new methods for magnetic resonance imaging analyses, and statistical methods. We also review research that evaluates AD risk factors and brain imaging, in the context of AD prediction and progression. We selected a variety of illustrative studies, describing how they advanced the field and are leading AD research in promising new directions.

Keywords: Alzheimer's disease, amyloid, imaging, magnetic resonance imaging, methods, positron emission tomography, prediction, progression, risk factors

DOI: 10.3233/JAD-2012-129016

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S313-S327, 2013

Authors: Teipel, Stefan J. | Sabri, Osama | Grothe, Michel | Barthel, Henryk | Prvulovic, David | Buerger, Katharina | Bokde, Arun L.W. | Ewers, Michael | Hoffmann, Wolfgang | Hampel, Harald

Article Type: Review Article

Abstract: The diagnosis of Alzheimer's disease (AD) is presently going through a paradigm shift from disease categories to dimensions and toward the implementation of biomarkers to support identification of predementia and even preclinical asymptomatic stages of the disease. We outline the methodological basis of presently available biomarkers and technological methodologies in AD, including exploratory and hypothesis-based plasma and blood candidates, cerebrospinal fluid markers of amyloid load and axonal destruction, and imaging markers of amyloid deposition, synaptic dysfunction, cortical functional and structural disconnection, and regional atrophy. We integrate biomarker findings into a comprehensive model of AD pathogenesis from healthy aging to cognitive …decline, the resilience to cerebral amyloid load (RECAL) matrix. The RECAL framework integrates factors of risk and resilience to cerebral amyloid load for individual risk prediction. We show the clinical consequences when the RECAL matrix is operationalized into a diagnostic algorithm both for individual counseling of subjects and for the identification of at risk samples for primary and secondary preventive trials. We discuss the implication of biomarkers for the identification of prodromal AD for the primary care system that seems presently not even prepared to cope with the increasing number of subjects afflicted with late stage AD dementia, let alone future cohorts of subjects searching counseling or treatment of predementia and asymptomatic stages of AD. The paradigm shift in AD diagnosis and its operationalization into a diagnostic framework will have major implications for our understanding of disease pathogenesis. Now, for the first time, we have access to in vivo markers of key events in AD pathogenesis integrated into a heuristic framework that makes strong predictions on pattern of multimodal biomarkers in different stages of AD. Critical testing of these predictions will help us to modify or even falsify the currently hold assumptions on the pathogenesis of AD based on in vivo evidence in humans. Show more

Keywords: Alzheimer's disease, amyloid, atrophy, biomarker, blood, cerebrospinal fluid, diagnosis, diffusion tensor imaging, hippocampus, mild cognitive impairment, neurodegeneration, neuroimaging, pathophysiology, positron emission tomography, prognosis, resting state functional magnetic resonance imaging, tau, therapy

DOI: 10.3233/JAD-2012-129030

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S329-S347, 2013

Authors: Villemagne, Victor L. | Rowe, Christopher C.

Article Type: Review Article

Abstract: The introduction of radiotracers for the non-invasive in vivo quantification of amyloid-β (Aβ) burden in the brain has revolutionized the approach to the evaluation of Alzheimer's disease (AD). Aβ burden as measured by positron emission tomography (PET) matches histopathological reports of Aβ distribution in aging and dementia. It appears more accurate than FDG for the diagnosis of AD, and is an excellent aid in the differential diagnosis of AD from frontotemporal lobar degeneration. Apolipoprotein E ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non-ε4 carriers. As new therapies enter clinical trials, the role of …Aβ imaging in vivo is becoming increasingly crucial. Aβ imaging allows the in vivo assessment of brain Aβ pathology and its changes over time, providing highly accurate, reliable, and reproducible quantitative statements of regional or global Aβ burden in the brain, essential for therapeutic trial recruitment and for the evaluation of anti-Aβ treatments. Although Aβ burden as assessed by PET does not strongly correlate with cognitive impairment in AD, it does correlate with memory impairment and a higher risk for cognitive decline in the aging population and mild cognitive impairment (MCI) subjects. This correlation with memory impairment, one of the earliest symptoms of AD, suggests that Aβ deposition is not part of normal aging, supporting the hypothesis that Aβ deposition occurs well before the onset of symptoms and likely represents preclinical AD in asymptomatic individuals and prodromal AD in MCI. Further longitudinal observations, coupled with different disease-specific biomarkers to assess potential downstream effects of Aβ, are required to confirm this hypothesis and further elucidate the role of Aβ deposition in the course of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, brain imaging, dementia, positron emission tomography

DOI: 10.3233/JAD-2012-129034

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S349-S359, 2013

Authors: Zetterberg, Henrik | Blennow, Kaj

Article Type: Review Article

Abstract: The past decades have witnessed an enormous expansion of the literature on cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD). It is now clear that a triplet of CSF biomarkers (total-tau, phospho-tau, and the 42 amino acid fragment of amyloid-β) reflects core neuropathological features of AD and contributes diagnostically relevant information if measured in a proper manner. Here, we discuss what is needed for these biomarkers to become generally implemented in the clinical routine. We also discuss novel CSF biomarkers, the challenge of differential diagnosis-making in diseases with shared pathologies, and if CSF biomarkers will survive in the long run, …given the advancements in molecular neuroimaging and ultra-sensitive blood tests. Show more

Keywords: Alzheimer's disease, amyloid, biomarkers, cerebrospinal fluid, tau

DOI: 10.3233/JAD-2012-129035

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S361-S369, 2013

Authors: Quinn, Joseph F.

Article Type: Review Article

Abstract: The indolent nature of Alzheimer's disease, coupled with burgeoning interest in a “presymptomatic” stage of disease, has motivated efforts to identify, validate, and exploit surrogate disease markers for trials of disease-modifying or preventive strategies. Many of these efforts have been productive, and biomarkers are now routinely applied in selection of study subjects and evaluation of outcomes in clinical trials. On the other hand, biomarkers also have the capacity to lead to bad therapeutic outcomes when they determine “go- no go” decisions in early drug development. This paper reviews several reports of biomarker studies which illustrate the great potential, for both …good and ill, of biomarkers of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, biomarkers, clinical trials

DOI: 10.3233/JAD-2012-129022

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S371-S376, 2013

Authors: Grossman, Murray

Article Type: Review Article

Abstract: Here we provide a brief description of our program to improve diagnostic accuracy in cases with phenotypically similar presentations that are due to distinct histopathologic abnormalities. We propose a staged approach to diagnosis, beginning with a screening assessment of specific, quantitative neuropsychological measures, and followed by assessments of imaging and biofluid biomarkers. Our goal is to determine the specific histopathologic abnormalities contributing to an individual's neurodegenerative condition.

Keywords: Amyotrophic lateral sclerosis, biomarker, corticobasal degeneration, frontotemporal degeneration

DOI: 10.3233/JAD-2012-129002

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S379-S383, 2013

Authors: Brayne, Carol | Barker, Roger A. | Harold, Denise | Ince, Paul G. | Savva, George M. | Williams, Julie | Williams-Gray, Caroline H. | Wharton, Stephen B.

Article Type: Review Article

Abstract: Six papers based on studies with particular epidemiological designs are presented here which have been selected on the basis of their visibility in the literature. The designs are intended to provide robust evidence on risk, natural history, and underpinning neurobiology and outcomes relevant to aging populations. There is a large case control study (the Late Onset Alzheimer's Disease study), a case cohort study of Parkinson's Disease (the CamPaIGN study), and the Medical Research Council Cognitive Function and Ageing Study. Each study has included genetic investigation and risk, and the latter two include investigation of the clinical syndromes and their natural …histories in relation to underlying pathology. Each aimed to provide results which were as generalizable to usual older populations as possible and each has produced findings which have contributed to current understanding of genetic risk, the heterogeneity of the syndrome of Parkinson's disease, and the underlying neuropathology of dementia in older population. They have influenced thinking about future directions, and the cohorts on which the findings are based will continue to provide an important resource for novel areas of research and future health care planning. Show more

Keywords: Alzheimer's disease, dementia, epidemiology, genetics, pathology

DOI: 10.3233/JAD-2012-129006

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S385-S396, 2013

Authors: Bennett, David A. | Wilson, Robert S. | Arvanitakis, Zoe | Boyle, Patricia A. | de Toledo-Morrell, Leyla | Schneider, Julie A.

Article Type: Review Article

Abstract: The Religious Orders Study and the Rush Memory and Aging Project are both cohort studies of aging and dementia that include organ donation at death. Together, more than 2,700 persons have agreed to annual clinical evaluation and brain donation at death. A subset of participants also participated in a substudy that included ante-mortem imaging. We highlight recent findings that have been highly cited over the past five years. The findings fall into three general categories. The first relates to the neuropathology of probable Alzheimer's disease, mild cognitive impairment, and those without dementia or mild cognitive impairment. The second relates to …risk factors for Alzheimer's disease and neuropathology. The third are clinical and imaging studies of mild cognitive impairment. The findings illustrate the range of insights that can be gained into cognitive aging by incorporating neuropathologic indices into well designed, prospective cohort studies. Show more

Keywords: Clinical-pathology, mild cognitive impairment, risk factors

DOI: 10.3233/JAD-2012-129007

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S397-S403, 2013

Authors: Caselli, Richard J. | Reiman, Eric M.

Article Type: Review Article

Abstract: Studies of asymptomatic carriers of genes that are known to predispose to Alzheimer's disease (AD) have facilitated the characterization of preclinical AD. The most prevalent genetic risk factor is the ε4 allele of apolipoprotein E (APOE). Neuropathological studies of young deceased ε4 carriers have shown modest but abnormal amounts of neocortical amyloid and medial temporal neurofibrillary tangles that is also reflected in cerebrospinal fluid (CSF) biomarkers, amyloid-β, and phospho-tau in particular. MRI studies have shown progressive hippocampal and gray matter atrophy with the advent of mild cognitive impairment (MCI), and fluorodeoxyglucose PET scans show reduced cerebral metabolism in posterior cingulate …and related AD regions evident even in 30 year olds. Cerebral amyloidosis disclosed by more recent amyloid ligand PET studies in asymptomatic 60 year olds increases in parallel with ε4 gene dose. Longitudinal neuropsychological studies have revealed accelerated memory decline in ε4 carriers beginning around age 55–60 years whose severity again parallels ε4 gene dose. The clinico-pathological correlation of declining memory and AD-like neuropathological change defines preclinical AD and has set the stage for the accelerated evaluation of presymptomatic AD treatments. In this article, we briefly consider some of the earliest detectable changes associated with the predisposition to AD, and some of the prevention trial strategies that have been proposed to help find treatments to reduce the risk, postpone the onset of, or completely prevent AD symptoms as soon as possible. Show more

Keywords: APOE, normal aging, preclinical, prevention

DOI: 10.3233/JAD-2012-129026

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S405-S416, 2013

Authors: DeCarli, Charles

Article Type: Review Article

Abstract: Cerebrovascular risk factors and stroke are highly prevalent with advancing age, and stroke may be more common than Alzheimer's disease, particularly among older men. While stroke mortality continues to decline, the prevalence of individuals with various vascular risk factors continues to rise and many are undiagnosed or undertreated. Asymptomatic cerebrovascular brain injury that includes asymptomatic brain infarction and white matter hyperintensities as well as accelerated brain atrophy is even more frequent than clinical stroke. Moreover, the impact of cerebrovascular risk factors on brain injury appears to begin in middle life and additively increases the likelihood of later life dementia. This …review focuses on the use of neuroimaging and genetics to understand the impact of asymptomatic vascular risk factors on the trajectories of cognitive aging as well as incident cognitive impairment, stroke, and mortality. Results of this review emphasize the need for early detection and treatment of vascular risk factors to improve the cognitive health of our rapidly aging population. Show more

Keywords: Cerebrovascular disease, magnetic resonance imaging, pathophysiology, white matter hyperintensities

DOI: 10.3233/JAD-2012-129004

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S417-S426, 2013

Authors: Lopez, Oscar L. | Becker, James T. | Kuller, Lewis H.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most frequent form of dementia in elderly individuals and its incidence and prevalence increases with age. This risk of AD is increased in the presence of genetic and demographic factors including apolipoprotein E 4 allele, lower education, and family history of AD. There are medical risk modifiers including systemic hypertension, diabetes mellitus, cardiovascular disease, and cerebrovascular disease that increase the vulnerability for AD. By contrast, there are lifestyle risk modifiers that reduce the effects of AD risk factors include diet and physical and cognitive activity. Our research has consistently shown that it is the interactions …among these risk factors with the pathobiological cascade of AD that determine the likelihood of a clinical expression of AD—either as dementia or mild cognitive impairment. However, the association between “vulnerability” and “protective” factors varies with age, since the effects of these factors on the risk for AD may differ in younger (age < 80) versus older (age > 80) individuals. The understanding of the dynamic of these factors at different age periods will be essential for the implementation of primary prevention treatments for AD. Show more

Keywords: Alzheimer's disease, cardiovascular disease, cerebrovascular disease, mild cognitive impairment

DOI: 10.3233/JAD-2012-129015

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S427-S438, 2013

Authors: Weinstein, Galit | Wolf, Philip A. | Beiser, Alexa S. | Au, Rhoda | Seshadri, Sudha

Article Type: Review Article

Abstract: The study of Alzheimer's disease (AD) in the Framingham Heart Study (FHS), a multi-generational, community-based population study, began nearly four decades ago. In this overview, we highlight findings from seven prior publications that examined lifetime risk estimates for AD, environmental risk factors for AD, circulating and imaging markers of aging-related brain injury, and explorations on the genetics underlying AD. First, we describe estimations of the lifetime risk of AD. These estimates are distinguished from other measures of disease burden and have substantial public health implications. We then describe prospective studies of environmental AD risk factors: one examined the association between …plasma levels of omega-3 fatty-acid and risk of incident AD, the other explored the association of diabetes to this risk in subsamples with specific characteristics. With evidence of inflammation as an underlying mechanism, we also describe findings from a study that compared the effects of serum cytokines and spontaneous production of peripheral blood mononuclear cell cytokines on AD risk. Investigating AD related endophenotypes increases sensitivity in identifying risk factors and can be used to explore pathophysiologic pathways between a risk factor and the disease. We describe findings of an association between large volume of white matter hyperintensities and a specific pattern of cognitive deficits in non-demented participants. Finally, we summarize our findings from two genetic studies: The first used genome-wide association (GWA) and family-based association methods to explore the genetic basis of cognitive and structural brain traits. The second is a large meta-analysis GWA study of AD, in which novel loci of AD susceptibility were found. Together, these findings demonstrate the FHS multi-directional efforts in investigating dementia and AD. Show more

Keywords: Alzheimer's disease, cerebrovascular disorders, cohort studies, genetic variation, risk factors

DOI: 10.3233/JAD-2012-129040

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S439-S445, 2013

Authors: Devanand, Devangere | Lee, Joseph | Luchsinger, Jose | Manly, Jennifer | Marder, Karen | Mayeux, Richard | Scarmeas, Nikolaos | Schupf, Nicole | Stern, Yaakov

Article Type: Review Article

Abstract: This review summarizes the findings and importance of 12 articles from research at Columbia University in New York City that were among the most cited in the literature between 2006 and 2011. The 12 articles summarized in this review made important contributions to the field of Alzheimer's disease in the last 5 years. Four of the articles established the Mediterranean diet as a food consumption pattern that may prevent Alzheimer's disease in addition to physical activity. Two of the articles advanced our knowledge of predictors of conversion from mild cognitive impairment to dementia. Four of the articles provided important knowledge …of risk factors for the progression of Alzheimer's disease and its complications. Lastly, one of the articles laid the theoretical framework for the study of cognitive reserve, an important modifier of the manifestation of Alzheimer's disease. These studies have advanced our knowledge about risk factors, modifiers, and progression of late onset Alzheimer's disease. Show more

Keywords: Alzheimer's disease, conversion, diet, cognitive reserve, epidemiology, genes, mild cognitive impairment, predictors, progression, risk factors

DOI: 10.3233/JAD-2012-129041

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S447-S455, 2013

Authors: Barberger-Gateau, Pascale | Lambert, Jean-Charles | Féart, Catherine | Pérès, Karine | Ritchie, Karen | Dartigues, Jean-François | Alpérovitch, Annick

Article Type: Review Article

Abstract: Late-life dementia results from non-modifiable risk factors such as age and genetics, modulated by deleterious and protective environmental factors among which nutrition may play a major role. This paper highlights five major recent contributions of the French Three-City (3C) and PAQUID epidemiological studies to Alzheimer's disease (AD) knowledge, targeting genetic and dietary risk factors, and the impact of cognitive decline in daily living. The 3C study contributed to a large genome-wide association study to identify new genetic risk factors for AD. In addition to apolipoprotein E (APOE), two loci gave replicated evidence of association: one within CLU, encoding clusterin or …apolipoprotein J, and the other within CR1, encoding the complement component receptor 1. Although the attributable fraction of risk for these polymorphisms is moderate, genetic studies provide significant insights into the molecular bases of AD. Regarding dietary data, findings from 3C suggest that healthy diets associating sources of both omega 3 fatty acids (fish) and antioxidants (fruits and vegetables) such as the Mediterranean diet, and caffeine could be associated with decreased risk for AD. However, the protective effect of omega3 fatty acids might be limited to APOE4 non-carriers. Future research should focus on gene-nutrient interactions. Regarding the functional impact of prodromal AD, the PAQUID study showed that taking into account mild functional limitations considerably increases the predictive value of neuropsychological tests for conversion to dementia. Research should focus on sensitive instruments to capture early functional decline to improve the identification of elderly patients at high risk of conversion to dementia. Show more

Keywords: Activities of daily living, Alzheimer's disease, caffeine, cohort studies, dementia, epidemiology, genome-wide association study, Mediterranean diet

DOI: 10.3233/JAD-2012-129019

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S457-S463, 2013

Authors: Solomon, Alina | Kivipelto, Miia | Soininen, Hilkka

Article Type: Review Article

Abstract: This is a brief summary of experiences from Finland related to Alzheimer's disease (AD) prevention research. The first signals that AD may have vascular modifiable risk factors came from studies on cardiovascular conditions and diabetes. Cardiovascular prevention projects such as North Karelia Project and WHO-MONICA in the 1970–1980 s were focused on younger populations, which led to the idea of looking for risk factors as far back as middle age. Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) is one of the few studies in the world focusing on late-life cognition with a large and representative population-based cohort, baseline …examination at midlife, and follow-up time up to three decades. Since 1998, it has identified several modifiable risk factors for cognitive impairment/dementia, and produced the first risk score for estimating dementia risk based on midlife profiles. The CAIDE Dementia Risk Score has been used to select participants in the Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER). FINGER is an ongoing multicenter RCT involving 1,200 participants aged 60–77 years, and testing the effects of a two-year multi-domain intervention targeting several risk factors simultaneously. It started in September 2009 and will be completed at the end of 2013. The FINGER study is at the forefront of international collaborative efforts to solve the clinical and public health problems of early identification of individuals at increased risk of late-life cognitive impairment, and of developing intervention strategies to prevent or delay the onset of cognitive impairment and dementia. Show more

Keywords: Alzheimer's disease cognitive impairment, epidemiology, prevention, randomized controlled trials

DOI: 10.3233/JAD-2012-129021

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S465-S469, 2013