The concept of cognitive impairment intervening between normal ageing and very early dementia has been in the literature for many years. Recently, the construct of mild cognitive impairment (MCI) has been proposed to designate an early, but abnormal, state of cognitive impairment. MCI has generated a great deal of research from both clinical and research perspectives. Numerous epidemiological studies have documented the accelerated rate of progression to dementia and Alzheimer's disease (AD) in MCI subjects and certain predictor variables appear valid. However, there has been controversy regarding the precise definition of the concept and its implementation in various clinical settings. Clinical subtypes of MCI have been proposed to broaden the concept and include prodromal forms of a variety of dementias. It is suggested that the diagnosis of MCI can be made in a fashion similar to the clinical diagnoses of dementia and AD. An algorithm is presented to assist the clinician in identifying subjects and subclassifying them into the various types of MCI. By refining the criteria for MCI, clinical trials can be designed with appropriate inclusion and exclusion restrictions to allow for the investigation of therapeutics tailored for specific targets and populations.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2796.2004.01388.x

Mild cognitive impairment as a diagnostic entity

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

/pdf/toward-defining-the-preclinical-stages-of-alzheimer-s-4a348i45fl.pdf

Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

/pdf/nia-aa-research-framework-toward-a-biological-definition-of-1sjt6cvmd3.pdf

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

2016 Alzheimer's disease facts and figures

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Racial/ethnic disparities in anti‐dementia medications use in longitudinally followed research participants are unclear.

Racial/ethnic disparities in initiation and persistent use of anti‐dementia medications

Tomm40 ‘523 variant and cognitive decline in community based older persons with apoe e3/3 genotype

Brain Disorders in Critical Illness: Cognitive reserve

To the Editor—We thank Drs Itzhaki and Klapper for their interest in and comments regarding our study [1], which examined the relationship between cytomegalovirus (CMV) infection and risk of Alzheimer's disease (AD). We found that CMV seropositivity was associated with a 2-fold increase in risk of AD and a faster rate of cognitive decline. The results were robust to a number of covariates, including herpes simplex virus type 1 (HSV-1). In addition, our findings support earlier cohort studies that have examined the association between CMV and cognitive function [2, 3]. Together, these studies suggest a potential role for CMV as a factor that may influence cognition and risk of AD in older ages.

As Itzhaki and Klapper state, one must use assays of equivalent sensitivity when comparing serological evidence of past exposure to HSV-1 with that of CMV. We agree. Although the assays used for immunoglobin G antibodies to CMV and HSV-1 were different in antigenic composition, both have been widely used in epidemiologic studies in different populations. We reported that rates of positivity for HSV-1 in our sample were much lower than for CMV, and that this discrepancy might be a reason for the lack of associations with HSV-1. Few large epidemiologic studies with older adults have specifically addressed HSV-1 [4]. Nonetheless, the lack of an association between HSV-1 antibodies and AD in our study does not preclude a role for HSV-1 in some cases of AD, using more sensitive immunological or virologic methods.

The authors state that our findings contrast with others who have found a relationship between HSV-1 and cognitive decline. However, the studies cited are cross-sectional rather than longitudinal, which is needed to document cognitive decline, and most were small case-control studies of HSV-1 in the brain. Thus, the association of HSV-1 and incident AD remains unknown at this time. Overall, the evidence points to a role for herpesvirus infections in some cases of AD. Indeed, identifying an association between CMV and AD supports the hypothesis that herpesviruses may play an important role in disease risk, and does not negate a potential role for other pathogens in AD. A better understanding of the role of individual infectious agents or their combination will require large-scale studies involving different populations and, ultimately, intervention studies using specific prevention and treatment modalities.

Lisa L. Barnes

Papers

Racial/ethnic disparities in initiation and persistent use of anti‐dementia medications

Tomm40 ‘523 variant and cognitive decline in community based older persons with apoe e3/3 genotype

Brain Disorders in Critical Illness: Cognitive reserve

Reply to Itzhaki

Associations of deformation-based brain morphometry with cognitive level and decline within older Blacks without dementia