Expert Rev Neurother. 2009 Nov;9(11):1623-33.

Alzheimer’s disease (AD) is the leading cause of dementia in elderly populations throughout the world and its incidence is on the rise. Current clinical diagnosis of AD requires intensive examination that includes neuropsychological testing and costly brain imaging techniques, and a definitive diagnosis can only be made upon postmortem neuropathological examination. Additionally, antemortem clinical AD diagnosis is typically administered following onset of cognitive and behavioral symptoms. As these symptoms emerge relatively late in disease progression, therapeutic intervention occurs after significant neurodegeneration, thereby limiting efficacy. The identification of noninvasive diagnostic biomarkers of AD is becoming increasingly important to make diagnosis more widely available to clinics with limited access to neuropsychological testing or state-of-the-art brain imaging, reduce the cost of clinical diagnosis, provide a biological measure to track the course of therapeutic intervention, and most importantly, allow for earlier diagnosis–possibly even during the prodromal phase–with hopes of therapeutic intervention prior to appreciable neurodegeneration. Circulating leukocytes are attractive candidate AD biomarkers as they can be obtained in a minimally invasive manner and are easily analyzed by widely available flow cytometry techniques. In this review, we critically analyze the potential utility of peripheral leukocytes as biological markers for AD.

Ann N Y Acad Sci. 2009 Oct;1180:75-96

Late-onset Alzheimer’s disease (LOAD) is the most common cause of late-onset dementia in western societies. Despite remarkable achievements in human genetics throughout the years, in particular technological advances in gene mapping and in statistical methods that relate genetic variants to disease, to date only a small proportion of the genetic contribution to LOAD can be explained leaving several remaining genetic risk factors to be identified. A possible explanation for the difficulty in gene identification is that LOAD is a multifactorial complex disorder with both genetic and environmental components. Multiple genes with small effects each (“quantitative trait loci”[QTLs]) are likely to contribute to the quantitative traits associated with the disease, such as memory performance, amyloid/tau pathology, or hippocampal atrophy. The motivation for identifying the genetics of LOAD is clear. Not only could it shed light on disease pathogenesis, but it may also provide potential targets for effective treatment, screening, and prevention. Here, we review the usefulness of genetic variation as diagnostic tools and biomarkers in LOAD and discuss the potentials and difficulties researchers face in designing appropriate studies for gene discovery.

Protein sorting as a key mechanism in Alzheimer’s cell biology. (A) A&B (red bar) is liberated from its parent protein, APP (multicolor bar), in two enzymatic steps. In the first &B-cleavage step, BACE (blue bar) splits full-length APP into an sAPP&B fragment (brown bar) and a C-terminal fragment (CTF&B, red/green bar). Then, in the &B-cleavage step, the &B-secretase (star) splits CTF&B into A&B (red bar) and amyloid intracellular domain (AICD, green bar). &B-cleavage is the committed step in APP processing and may be upregulated in LOAD. (B) Both APP (red bar) and BACE (blue bar) are type-I transmembrane proteins that are sorted through multiple membranous compartments of the cell. The sorting triangle that interconnects the trans-Golgi network (TGN), cell surface, and the endosome is critically important for APP and BACE sorting. As indicated, clathrin is the coat complex that regulates transport from the cell surface and the TGN to the endosome, whereas the retromer is the coat complex that regulates transport from the endosome back to the TGN. APP and BACE interact within the membranes of the endosomal system, initiating the amyloidogenic pathway. (Illustration adapted from Small and Gandy.75) (In color in Annals online.)

Mol Neurodegener. 2009 Jun 26;4:27.

Extensive genetic, biochemical, and histological evidence has implicated the amyloid-&豪 peptide (A&豪) in Alzheimer’s disease pathogenesis, and several mechanisms have been suggested, such as metal binding, reactive oxygen species production, and membrane pore formation. However, recent evidence argues for an additional role for signaling mediated by the amyloid precursor protein, APP, in part via the caspase cleavage of APP at aspartate 664. Here we review the effects and implications of this cleavage event, and propose a model of Alzheimer’s disease that focuses on the critical nature of this cleavage and its downstream effects.

Exp Biol Med 232:323–335, 2007

In this review, we point out that natural selection does not act to lessen human diseases after the reproductive and caregiving period and that normal levels of iron and copper that may be healthy during the reproductive years appear to be contributing to diseases of aging and possibly the aging process itself. It is clear that oxidant damage contributes to many of the diseases of aging, such as atherosclerosis, Alzheimer’s disease, Parkinson’s diseases, diabetes, diseases of inflammation, diseases of fibrosis, diseases of autoimmunity, and so on. It is equally clear that both iron and copper can contribute to excess production of damaging reactive oxygen species through Fenton chemistry. Here, we examine the evidence that “normal” levels of iron and copper contribute to various diseases of aging.