It is still unclear whether these deposits are the cause or effect of AD, but studies have linked both the number of tangles and the amount of free plaque-forming protein in the brain to the degree of dementia in the patient. This protein is a necessary component of the brain and is normally cut by an enzyme to form the final amyloid protein. A secondary pathway for amyloid protein formation exists, however, in which APP is clipped by two enzymes, resulting in the formation of the -amyloid peptide. It is this fragment that clumps together to form plaques in the brain. Tangles, by comparison, are largely composed of a phosphorylated form of the tau protein.
Unphosphorylated tau is nonpathogenic and is involved in cell structure.
Upon phosphorylation, however, it is thought to wrap around neurons and interfere with their structure. Several factors have been associated with increased incidence of the disease, including age, genetics, and gender. However, the association between the APOE gene and AD is variable and dependent upon ethnicity. Studies indicate that more women than men are diagnosed with AD, but whether this is simply the result of a difference in life span between the genders is unknown. Other studies have found a higher incidence of dementia in those with no education versus those with at least a high school diploma and that an increase in intellectual activity from early to mid-adulthood was associated with a significant reduction in the likelihood of AD onset.