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.

Background: Neuroimaging measures and chemical biomarkers may be important indices of clini-

Mild cognitive impairment is associated with an increased risk of death and incident AD, and a greater rate of decline in selected cognitive abilities.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

The authors examined change in cognitive abilities in older Catholic clergy members. For up to 6 years, participants underwent annual clinical evaluations, which included a battery of tests from which summary measures of 7 abilities were derived. On average, decline occurred in each ability and was more rapid in older persons than in younger persons. However, wide individual differences were evident at all ages. Rate of change in a given domain was not strongly related to baseline level of function in that domain but was moderately associated with rates of change in other cognitive domains. The results suggest that change in cognitive function in old age primarily reflects person-specific factors rather than an inevitable developmental process.

With the increasing life expectancy in developed countries, the incidence of Alzheimer's disease (AD) and thus its socioeconomic impact are growing. Increasing knowledge over the last years about the pathomechanisms involved in AD allow for the development of specific treatment strategies aimed at slowing down or even preventing neuronal death in AD. However, this requires also that (1) AD can be diagnosed with high accuracy, because non-AD dementias would not benefit from an AD-specific treatment; (2) AD can be diagnosed in very early stages when any intervention would be most effective; and (3) treatment efficacy can be reliably and meaningfully monitored. Although there currently is no ideal biomarker that would fulfill all these requirements, there is increasing evidence that a combination of currently existing neuroimaging and cerebrospinal fluid (CSF) and blood biomarkers can provide important complementary information and thus contribute to a more accurate and earlier diagnosis of AD. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is exploring which combinations of these biomarkers are the most powerful for diagnosis of AD and monitoring of treatment effects.

Alzheimer's disease: the way to an effective treatmentWith increasing life expectancy in developed countries, diseases typically associated with old age are becoming more frequent and, thus, increasingly gain in socioeconomic importance. Age is a major risk factor for almost all neurodegenerative diseases, in particular dementia. Currently, more than 4 million people in the United States suffer from dementia, the majority of them from Alzheimer's disease (AD). The cost of dementia to the United States economy is now well over $100 billion per year. It is expected, however, that the incidence of dementia will double during the next 20 years [1] and that its cost will exceed $380 billion per year. Therefore, there is considerable effort to unravel the pathophysiologic mechanisms of AD [2], allowing for the development of effective treatment strategies. Pathologic studies show that neurodegeneration in AD starts in the entorhinal cortex but in later stages also involves the hippocampus, the limbic system, and neocortical regions. It is characterized by accumulations of β-amyloid plaques and neurofibrillary tangles [2-6], which exert direct and indirect neurotoxic effects by promoting oxidative stress [7,8] and inflammation. In the rare forms of early-onset familial AD, mutations of the amyloid precursor protein and the presenilin genes are identified, which are associated with increased amyloid production and deposition, whereas in late-onset AD, intensive research has led to the identification of several risk factors associated with increased amyloid deposition (eg, allele producing the ε4 type of apolipoprotein E [APOE*E4], hyper-homocysteinemia, hyperlipidemia, and disturbances of the neuronal insulin signal transduction pathway) [9]. This increasing knowledge about the mechanisms in AD facilitates the development of treatments aimed at modifying the disease process [10,11] (eg, anti-inflammatory drugs, statins, antioxidants, acetylcho-linesterase inhibitors, γ-and β-

The Alzheimer's Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year re-search project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer's disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)/blood biomarkers as predictors and outcomes for use in clinical trials of