Carrillo, María C.

Abstract Introduction A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. Methods Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web‐based quantitative survey regarding symptom frequency and the conceptualization of PCA. Results A three‐level classification framework for PCA is described comprising both syndrome‐ and disease‐level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico‐radiological syndrome. Classification level 2 (PCA‐pure, PCA‐plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA‐AD], Lewy body disease [PCA‐LBD], corticobasal degeneration [PCA‐CBD], prion disease [PCA‐prion]) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome‐level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum. Discussion There was strong agreement regarding the definition of the core clinico‐radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single‐center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.

AbstractRecent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer's disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened a one‐day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations, and partnerships for future action.

Abstract More than 5 million Americans are living with Alzheimer's disease (AD) today, and nearly two‐thirds of Americans with AD are women. This sex difference may be due to the higher longevity women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimer's Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex‐ and gender‐related disparities of risk for AD.

Abstract Dementia is often characterized as being caused by one of several major diseases, such as Alzheimer's disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist. How overlapping pathologic findings affect the diagnosis and treatment of clinical AD and other dementia phenotypes was the topic taken up by the Alzheimer's Association's Research Roundtable in October 2014. This review will cover the neuropathologic basis of dementia, provide clinical perspectives on multiple pathologies, and discuss therapeutics and biomarkers targeting overlapping pathologies and how these issues impact clinical trials.High prevalence of multiple pathologic findings among individuals with clinical diagnosis of AD suggests that new treatment strategies may be needed to effectively treat AD and other dementing illnesses.

Abstract Alzheimer's disease research has often focused on the molecular brain changes that promote memory loss and other dementia‐related cognitive impairments. Many studies, for example, have used positron emission tomography (PET) imaging to measure brain levels of the beta‐amyloid protein, a key molecular suspect in Alzheimer's. In recent years, PET scans have become more prominent in clinical settings. Clinicians may use a positive PET scan—that is, a significant presence of beta‐amyloid plaques in the brain—to help determine a diagnosis of Alzheimer's disease. Yet, because beta‐amyloid PET remains a fairly new diagnostic tool, physicians and patients still have many basic questions about how and why it is used. This article addresses some of those questions. It explains what PET scans actually show, how they are employed in research and clinical trials, and when they should and should not be used to help diagnose Alzheimer's in everyday patients. The article also discusses whether cognitively healthy people should request PET scans to assess their risk for developing dementia. Information in the text will be updated in future years, as diagnostic imaging techniques for Alzheimer's disease continue to evolve.

Abstract During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this “silent” stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

AbstractIntroductionThe genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.MethodsWe genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome‐wide association study.ResultsWe confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome‐wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]).DiscussionWe provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

Abstract Scientific evidence continues to demonstrate the linkage of vascular contributions to cognitive impairment and dementia such as Alzheimer's disease. In December, 2013, the Alzheimer's Association, with scientific input from the National Institute of Neurological Disorders and Stroke and the National Heart, Lung and Blood Institute from the National Institutes of Health, convened scientific experts to discuss the research gaps in our understanding of how vascular factors contribute to Alzheimer's disease and related dementia. This manuscript summarizes the meeting and the resultant discussion, including an outline of next steps needed to move this area of research forward.