Advances on biological markers in early diagnosis of Alzheimer disease

Alzheimer disease (AD) represents the most common neurodegenerative disease worldwide, accounting for 60%-70% of cases of progressive cognitive impairment in elderly patients. The prevalence of dementia of the Alzheimer type (DAT) doubles every 5 years after the age of 60 years, increasing from a prevalence of 1% among those 60-64 years old up to 40% of those aged 85 years and older [1, 2]. The disease is more common among women than men by a ratio of 1.2 to 1.5. Dementia patients have a substantially shortened life expectancy; the average survival is 8 years from diagnosis. The characteristic findings at the microscopic level are degeneration of the neurons and their synapses, together with extensive amounts of senile plaques and neurofibrillary tangles [3]. Extensive exploration of possible risk factors for AD has been somewhat disappointing so far. Age, dementia in a close family member, and apolipoprotein E (APOE) ε4 allele are the only confirmed risk factors for the disease [4]. Female sex, herpes infection, low serum levels of folate and vitamin B12, elevated plasma and total homocysteine levels, low lipid plasma concentrations, a history of head trauma, and the protective effect of hormonal replacement therapy are all factors that likely bimodally interact with APOE genotype to modify relative risk [5]. Several other possible risk factors for AD such as exposure to anesthetic agents, diabetes mellitus, and the protective effects of antiinflammatory drugs, smoking, and alcohol are being reevaluated, using improving methodologies [5]. Having more education and an active lifestyle have been associated with low rates of AD, which could be at least partly attributable to compensatory strategies that delay detection of the disease. The introduction of acetylcholine esterase inhibitors as symptomatic treatment has highlighted the importance of diagnostic markers for AD [6, 7]. The awareness in the population of the availability of drug treatment has also made patients seek medical advice at an earlier stage of the disease. This has increased the diagnostic challenge for physicians, because the characteristic clinical picture of AD with slowly progressive memory disturbances combined with parietal lobe symptoms is rather subtle in the early stage and can be barely noticeable. Accordingly, there is no clinical method to accurately identify AD in the very early phase and to determine which at-risk cases will progress to DAT, except for having a very long clinical follow-up period [8]. During the so-called preclinical phase of AD, the neuronal degeneration proceeds and the amount of plaques and tangles increase, and at a certain threshold, the first symptoms-most often including impairment of episodic memory-appear. This preclinical period probably starts 20-30 years before the first clinical symptoms appear [9]. According to current diagnostic criteria, AD cannot be diagnosed clinically before the disease has progressed so far that dementia is present. This means that the symptoms must be severe enough to significantly interfere with work and social activities or relations. Thus, new diagnostic tools to aid the diagnosis of early AD and to identify incipient AD in at-risk cases would be of great importance. Such diagnostic markers would be of even higher significance if new drugs, with the promise of disease-arresting effects, prove to have clinical effect. Such drugs will probably be more effective in the earlier stages of the disease, before neurodegeneration is too severe and widespread. Our goal with this review concerns early recognition of AD, focusing on the use of biological markers in identifying, among individuals at risk, those who will progress to DAT. In particular we will review the contribution of biological markers in early diagnosis of AD. "Early diagnosis" refers to the capability to diagnose AD at a very early stage, before symptoms and clinical signs have reached the stage at which a diagnosis of clinically probable DAT can be made according to currently recommended criteria. Accordingly, in this review AD is conceptualized as a chronic degenerative disease clinically characterized by a long presymptomatic phase followed by a prodromal transitional stage, hereby termed mild cognitive impairment (MCI) which is subsided by the ultimate stage of dementia, more properly called DAT [10]. The goal of research in this area is to develop highly specific and sensitive tools capable of identifying, among at-risk subjects either in the preclinical or in the prodromal stage, those who will eventually progress to DAT. Before beginning this review, a brief account of some aspects of AD instrumental to understand the topic of this review are given.