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 (original) (raw)

Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals

BMC Medicine, 2012

Since the first description of the case of Auguste Deter, presented in Tübingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controver...

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria

Alzheimer's & dementia : the journal of the Alzheimer's Association, 2016

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.

Age, Alzheimer's disease, and the big picture

International Psychogeriatrics, 2011

The recently published revised National Institute on Aging/Alzheimer's Association clinical diagnostic criteria for Alzheimer's disease (AD) (Albert et al., 2011; Jack et al., 2011; McKhann et al., 2011; Sperling et al., 2011) have been hailed for incorporating a number of timely and important advances. They reflect new understanding that has been gained since the previous criteria were published in 1984 (McKhann et al., 1984). They include recognition of the state of mild cognitive impairment that is present before the threshold is crossed into dementia; they recognize the potential role of biomarkers in enhancing the specificity of diagnosis; they also address emerging work in the preclinical stage of AD that could help in understanding the sequence and stages of the core pathology before symptoms emerge. Among the previously listed diagnostic features that have disappeared was the requirement that onset of dementia occur before the age of 90 years. Meanwhile, the Neurocog...

Characterizing the preclinical stages of Alzheimer's disease and the prospect of presymptomatic intervention

Journal of Alzheimer's disease : JAD, 2013

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 decl...

Early risk assessment for Alzheimer's disease

Alzheimers & Dementia, 2009

The purpose of the Alzheimer's Association Research Roundtable meeting was to discuss the potential of finding diagnostic tools to determine the earliest risk factors for Alzheimer's disease (AD). Currently, drugs approved for AD address symptoms which are generally manifest after the disease is already well-established, but there is a growing pipeline of drugs that may alter the underlying pathology and therefore slow or halt progression of the disease. As these drugs become available, it will become increasingly imperative that those at risk for AD be detected and possibly treated early, especially given recent indications that the disease process may start decades before the first clinical symptoms are recognized. Early detection must go hand-in-hand with qualified tools to determine the efficacy of drugs in people who may be asymptomatic or who have only very mild symptoms of the disease. Devising strategies and screening tools to identify and monitor those at risk in order to perform ''prevention'' trials is seen by many as a top public-health priority, made all the more urgent by an impending growth in the elderly population worldwide.

Prediction of preclinical Alzheimer's disease: longitudinal rates of change in cognition

Journal of Alzheimer's disease : JAD, 2011

Preclinical Alzheimer's disease (pAD) reflects neuropathological findings of AD in cognitively normal subjects. The present study represents an effort to determine if differences could be identified in the longitudinal patterns of cognitive performance in persons classified as pAD compared to those who did not meet criteria for AD at autopsy. We included 121 subjects who were cognitively normal from baseline through their last assessment before death and who underwent autopsy. Participants were classified into two groups: pathologically normal (PN; NIA-Reagan low or no-likelihood of AD, n = 89) and preclinical AD (pAD; NIA-Reagan criteria of intermediate or high-likelihood of AD in the absence of clinical dementia symptoms, n = 32) followed for a mean 7.5 years prior to death. Longitudinal rates and patterns of change in scores on a standard cognitive battery were compared between these two groups. While cognitive results at baseline and last evaluations revealed no clear cross ...

Diagnosis of Preclinical Alzheimers Disease in a Clinical Setting

International Psychogeriatrics, 2001

Introduction. The aim of the study was to investigate whether the preclinical stage of Alzheimer's disease (AD) can be diagnosed in a clinical setting. To this end we investigated whether subjects with preclinical AD could be differentiated from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia. Methods.

A methodological critique of the National Institute of Aging and Alzheimer’s Association Guidelines for Alzheimer’s disease, dementia, and mild cognitive impairments

In 2011, the U.S. National Institute on Aging published guidelines for clinical diagnostics for Alzheimer’s disease dementia. These guidelines define a continuum with three stages—an early, pre-clinical stage with no symptoms, followed by mild cognitive impairment, and a final stage of Alzheimer’s disease dementia. This methodological critique examines the validity of this continuum. No studies exist showing the progression of these biomarkers to Alzheimer’s disease. There is also a lack of empirical evidence showing how biomarkers determine mild cognitive impairment, which has multiple etiologies. The guidelines fail to explain anomalies where there are biomarkers but no expression of Alzheimer’s disease.