The linkage of presenilin and tau mutations to the development of Alzheimer's disease is not unexpected based on over two decades of research. Nor is it very surprising that there would be evidence of altered amyloid beta levels in the cerebral spinal fluid (CSF) of people harbouring presenilin mutations even two decades before the disease produces obvious cognitive symptoms. However, in many clinical studies with Alzheimer's patients, there is actually usually a DECREASE in the level of the pathogenic 42 kDa beta-amyloid (A-beta42) protein in their CSF relative to healthy controls and patients with Parkinson's disease and progressive supra nuclear palsy. While initially counter-intituitve, the decrease in CSF A-beta42 appears to reflect increased ability of this abnormally cleaved form of beta-amyloid to aggregate into plaques in the brain.

It is very likely that production of A-beta 42 and another hallmark of Alzheimer's disease, i.e. abnormal hyperphosphorylation of the tau protein evident in paired helical filaments that are found in neurofibrillary tangles, both occur very early in adult life. I recall attending an Alzheimer's disease research conference in Rochester, N.Y. about 15 years ago and hearing a lecture from an elderly German pathologist who had autopsied over 400 human brains during his career. He described how he had observed plaques and tangles in the brains of people even in their early 20's, and the frequency of the plaques and tangles appeared to increase with age in the general population. Alzheimer's patients showed much higher rates of the accumulation of these lesions. He did, however, encounter a few individuals that died in their 90's that were apparently free of any plaques and tangles. In view of this, it is not surprising that one in four people over age 85 have manifestations of Alzheimer's disease. Only a small portion of Alzheimer's patients have recognizable genetic mutations that predispose them to this disease, so genetic screening is likely to be helpful in a limited number of cases.

At Kinexus Bioinformatics Corporation, in collaboration with research colleagues at the University of British Columbia, we found using our antibody microarrays more than 36 proteins that displayed abnormal phosphorylation or expression in peripheral blood lymphocytes from Alzheimer's patients as compared to controls that were only mildly cognitively impaired or had other neurological disorders. Therefore, it seems very feasible that less painful blood tests can be developed to identify people at greatest risk much earlier in the disease process. This would be less expensive and traumatic to patients than lumbar punctures to draw CSF to measure A-beta-42 and phospho-tau levels. Regretfully, despite repeated attempts to obtain grant funding from the Canadian Institutes for Health Research and more local Alzheimer's disease and hospital foundations to further develop an Alzheimer's disease diagnostics test with the biomarkers that we discovered, we have not been able to pursue this further in the last couple of years. Nevertheless, I remain confident that similar screening methods will permit the development of early Alzheimer's disease diagnostic tests that will also be useful for monitoring the effectiveness of therapeutic drugs in the near future.