Alzheimer disease (AD), which is characterized by progressive cognitive and behavioral deficit, is the most common form of dementia. The incidence of AD is increasing at an alarming rate, and has become a major public health concern in many countries. It is well known that the onset of AD is preceded by a long preclinical period. It is thus critical to establish diagnostic biomarkers that can predict the risk of developing AD prior to clinical manifestation of dementia, for effective prevention and early intervention. With the emergence of potential promising approaches to treat AD targeting the β-amyloid (Aβ) pathway, such as gamma-secretase inhibitors and vaccine therapy, there is an urgent need for such diagnostic markers. Although cerebrospinal fluid (CSF) Aβ and tau protein levels are candidate biomarkers for AD, the invasive sampling procedure with associated complications limits their use in routine clinical practice. Plasma Aβ has been suggested as an inexpensive and non-invasive biomarker for AD. Although most previous cross-sectional studies on plasma Aβ level in humans failed to show a significant difference between individuals with AD compared to healthy older adults, many strategies are under investigation to improve the diagnostic potential of plasma Aβ. One promising approach is to modify the plasma Aβ level using some potential modulators. It is possible that a difference in plasma Aβ level might be unmasked by evaluating the response to stimulation by a modulator. Anti-Aβ antibody and Aβ binding proteins have been reported to be such modulators of plasma Aβ. In addition, the glucometabolic or hormonal status appears to modulate the plasma Aβ level. Our recent study has shown the possibility that glucose loading could be a novel simple strategy to modulate the plasma Aβ level, making it better suited for early diagnosis. This review summarizes the utility and limitations of current biomarkers of AD and discusses future strategies to improve the diagnostic potential of plasma Aβ.
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