Metals Involvement in Alzheimer's Disease Pathogenesis

When Auguste Deter died in 1906, Alois Alzheimer, who had closely followed her mental degradation over the previous 5 years, obtained her brain and performed a post-mortem study. By using a silver-staining method just developed by Bielschowsky, Alzheimer identified aggregations of fibrils and what he called 'miliary foci'. Alterations of that nature had been already observed by others in post-mortem brains, but Alzheimer was the first to relate them to his patient's dementia. He described the case a year later and Auguste Deter remained in medical history as the first clinical case of what has been ever since referred to as Alzheimer's disease. For an English translation of Alzheimer's 1907 paper, see (Alzheimer et al., 1995). 1.1 General description Alzheimer's disease (AD) is an irreversible neurodegenerative disorder, characterized by a gradual loss of the cognitive functions inexorably leading to dementia. From an early stage characterized by a mild loss of recent memory, the disease advances to more devastating symptoms such as faulty judgments and even personality changes, to terminate in a complete loss of reasoning ability and self sufficiency. Death normally ensues 8 to 10 years after diagnosis. AD is often referred to as early- or late-onset depending on whether it appears before or after age 65, and is normally distinguished in familial, i.e., inherited, and sporadic, which is caused by a combination of genetic, lifestyle and environmental factors. About 75% of AD patients have the sporadic form, which has normally a late-onset. The familial form, which affects the remaining 25%, can have instead either an early-onset (about 5% of all familial cases) or a late-onset. The early-onset familial AD is attributed to mutations in one of three genes: amyloid precursor protein (APP), Presenilin1 or Presenilin2. The genetic causes of the late-onset familial AD are not fully assessed, although the inheritance of the ?4 allele of the apolipoprotein E (ApoE4) has been recognized as a risk factor for both familial and sporadic late-onset AD. Carriers of this allele have a 90% statistical risk of contracting AD if they are heterozygote and a virtual certainty if homozygote (Corder et al., 1993).