Etiology of Alzheimer’s Disease: Possible Genetic and Environmental Factors in the Onset of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia in the elderly and denotes about 70% of all dementia cases 1. It causes more than 100,000 deaths each year and is the fourth leading cause of death after heart disease, cancer and stroke 3. Two major characteristics of Alzheimer’s Disease have been identified: 1) neurofibrillary tangles and, 2) extracellular plaques containing amyloid disposition 1. The latter characteristic will be the most important characteristic to keep in mind w

Although genetic researchers have made great contributions to the understanding of Alzheimer’s disease in finding the APP, PS1, and PS2 genes and postulating their possible involvement in the etiology of Alzheimer’s disease, perhaps the most important breakthrough has been the finding of e4 allele of Apolipoprotein E (APOE) gene. Corder and colleagues found that when studying 42 late onset families with AD, APOE e4 allele shows a dose dependant increase in risk for AD 5. This means that individuals with two copies of the e4 allele on the average had an earlier age of onset than those with one e4 allele, who had an earlier onset than individuals with no e4 allele 5. So, for example, at age 75, 86% of individuals with two e4 alleles were diagnosed with AD, while it dropped significantly to 61% and 24% in individuals with one e4 allele and no e4 allele, respectively 5. This taken together with their finding that two e4 alleles were sufficient to cause AD by the age of 80 shows the major role e4 allele of APOE plays in the late onset of AD 5.

In conclusion, APP, PS1, PS2, b-amyloid of APOE gene, and environmental factors such as head injuries, HSV1 virus, and aluminum are causing b-amyloid accumulation and neurofibrillary tangles in the hippocampus, neocortex, and also olfactory regions of the brain. These b-amyloid accumulation and neurofibrillary tangles are somehow causing neural death in those regions of the brain.

We all know that, Muhammad Ali, the most famous boxer of all times, now suffers from AD most likely due to (or triggered by) the severe head injuries he experienced during his boxing career. Roberts and colleagues noticed that there seemed to be a correlation between boxers with severe head injuries and dementia. Roberts and colleagues also knew that most cases (80%) of Alzheimer’s disease is caused by environmental factors (such as head injuries) that may or may not interact with the patients genotype. So, they compared 150 patients with severe head injuries who had died as a result with 44 (age-matched) controls with no head injuries to see if head injury triggers bAP disposition 6. The temporal lobe and parietal cortex were examined from each case by labeling bAP by its specific antibody and examining them under a light microscope 6. They found that 30% of the head injury cases exhibited bAP disposition in the temporal and parietal regions, thus causing neural death in those regions 6. Also, although the frequency and extent of bAP disposition seemed to increase dramatically over 60 years of age in both controls and individuals with head injuries, there was more bAP disposition in patients with head injuries than controls 6. Roberts et al. also found bAPP activity near the vicinity of bAP deposits, which led them to conclude that increased expression of bAPP is a response to head injury 6. Their conclusion seems to point to the idea that head injuries seem to precipitate the onset of Alzheimer’s Disease in patients with bAPP mutation. The reason this finding is so interesting is because it links an environmental factor, head injuries, to a generic factor (bAPP gene mutation) and suggests that their interaction might work together to result in AD.

So far we have seen the importance of genetic factors such as APP, PS1, PS2 and specially the e4 allele of the APOE gene in the etiology of AD. But we have also seen the importance of environmental factors such as head injuries and viruses in interacting with genetic factors (e4 allele of APOE gene) in the etiology of AD. This interaction can get very complicated. For example, head injury might cause an inflammation that might reactivate HSV1, which might in return interact with e4 allele of APOE gene and play a role in the onset of AD. We have focused our attention to genetic and environmental factors involved in amyloid disposition, one of the two characteristics of AD. Now, I want to focus on another environmental factor, aluminum, that has been a

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