Unravelling the disease process

Abstract

Alois Alzheimer’s original description of the clinical features and neuropathology of Alzheimer’s disease in 1907 was an outstanding piece of work. Despite nearly a century of further investigation, his report still accurately describes the clinical and pathological features of this highly prevalent disease. Over the past two decades, as the importance of Alzheimer’s disease as a public-health problem has become clear, increased scientific efforts have been devoted to understanding its epidemiology, genetics, and biochemical pathogenesis. Clues from three areas of research are especially noteworthy, and provide realistic hope for effective treatments. The first advance has been in understanding some of the genetic causes of the disease. Results of molecular and epidemiological studies show that four genes are associated with increased risk for Alzheimer’s disease—APP (amyloid precursor protein); PS1 (presenilin 1); PS2 (presenilin 2); and APOE (apolipoprotein E). Although these genes account for only about 50% of the genetic risk for Alzheimer’s disease, they have already helped to unravel the disease process. These genes, and the other Alzheimersusceptibility genes, which are the focus of continuing research, are also clinically useful in that they allow the identification and prophylactic treatment of individuals at increased risk for the disease. The second area that has advanced is that of the molecular and cellular biology of this disease. Results of studies have revealed that the amyloid -peptide (A ) is the principal component of the extracellular amyloid plaque in the brains of patients with Alzheimer’s disease, and that tau, a microtubule-associated protein, is the principal component of the intracellular neurofibrillary tangle. The metabolic pathways that generate A by the proteolytic cleavage of APP have been defined, and we have learned that A can aggregate into fibrils and cause long-term neuronal injury. There are still holes in our knowledge, though. For instance, we are not sure how the accumulation of A leads to the assembly of tau in neurofibrillary tangles. Nevertheless, even this partial knowledge of the amyloid cascade has led to the identification of several molecules as potential therapeutic targets, including A itself. For example, A might be removed by immune-mediated mechanisms induced by vaccination, or its accumulation into toxic fibrils could be inhibited by “amyloid chainbusting” compounds. Alternatively, the synthesis of A could be blocked by inhibition of either or both of the enzymes involved in the cleavage of A from APP ( secretase and presenilin-dependent -secretase; figure). Another, less explored strategy would be to target APP through the other non-amyloidogenic proteolytic pathway in which APP is cleaved by -secretase through the A domain, thereby preventing the formation of A . Finally, the degradation of A could be accelerated by increasing the activity of one of the two putative A -degrading enzymes (insulin-degrading enzyme and neprilysin). Of these potential therapeutic avenues, efforts to develop a vaccine and presenilin-dependent -secretase inhibitors are the most advanced, and will probably enter clinical trials in the next 1–2 years. Efforts to develop a -secretase inhibitor are also progressing in a pre-clinical stage. Finally, advances have taken place in the generation of partial models of Alzheimer’s disease in transgenic mice that express mutant APP, PS1, or tau transgenes. Although these models do not produce an exact replica of human Alzheimer’s disease, selected features of the behavioural and neuropathological phenotypes in these mice do closely resemble those seen in people. Transgenic models offer a simple but relevant preclinical screening paradigm for new treatments and diagnostic tools. In the next few years, several different therapeutic approaches will be tested in patients. These studies will allow us to compare their efficacy and toxicity, determine whether they might have additive effects—eg, cocktails of -secretase inhibitors and -secretase inhibitors together with vaccination—and also examine potential interactions with other putative adjunctive therapies such as oestrogen replacement, non-steroidal anti-inflammatory agents, and antioxidants. One area that will be of importance in the future is the ability to detect individuals with early, subclinical Alzheimer’s disease. Results of pathological studies indicate that biochemical and pathological attributes of the disease can exist for many years prior to the onset of overt dementia. Identification of these individuals will become a clinical and public-health imperative once effective therapeutics have been identified. However, an evaen more sophisticated knowledge of the biology of Alzheimer’s disease would be needed to identify functional imaging techniques and biochemical events, or both, which can be monitored in cerebrospinal fluid or plasma. The two proteolytic processing pathways of APP holoprotein