Risk Factors

Early onset AD is not very common and occurs below the age of 60. The majority of early onset AD is caused by rare genetic variations found in a small number of families worldwide recognized as familial AD and can develop sometimes in individuals as young as 30. However, the most common form is the sporadic form, which represents approximately 90 % of AD cases.

Unfortunately, the causes of the sporadic form of AD are not yet known. The risk factors which seem to play a major role in both types are discussed below.

1.1.4.1 Sporadic AD

For the widespread late onset sporadic AD, age is by far the most common risk factor (Gao et al. 1998). During aging, cells in the human brain, like cells in other organ systems, experience cellular changes such as oxidative stress, mitochondrial dysfunction, metabolic impairment, DNA damage and apoptosis (Mattson 2006).

Changes in neurotransmitter and neurotrophic factor signaling pathways which are amplified in neurodegenerative diseases are also a consequence of aging. Although the abovementioned mechanisms seem to connect aging to AD, the exact means and the order of events are still obscure.

Other non-genetic risk factors besides aging are environmental factors, including aspects of diet and lifestyle. For instance patients with more varied activities, including intellectual, physical, recreational and social activities, are less likely to develop AD (Friedland et al. 2001). Also low calorie diets and increased consumption of omega 3 fatty acids have been linked to a decreased risk of developing AD. The role of other diseases such as hypertension, hyperlipidemia, type 2 diabetes mellitus and hyperhomocysteinemia in increasing the risk for developing AD is still debatable. Other medical risk factors include head trauma, clinical depression,

and some medications such as vitamin E or NSAIDs may reduce the risk of acquiring dementia. (Ownby et al. 2006; Patterson et al. 2008; Mattson 2006).

The only well established genetic factor that can increase a person's susceptibility for sporadic AD is Apolipoprotein E [APOE]. APOE belongs to the low density lipoprotein receptor gene family, and it is suggested that it could provide a system for lipid transport and cholesterol homeostasis in the brain (Pitas et al. 1987). There are three different isoforms of APOE gene [APOE-ε2, APOE-ε3 and APOE-ε4]. Increased risk is linked with inheritance of the APOE-ε4 allele has helped explain some of the variations in age of onset of Alzheimer's disease based on whether people have inherited zero, one, or two copies of the ε 4 allele from their parents. The more APOE-ε4 alleles inherited, the lower the age of disease onset (Corder et al.

1993;Saunders et al. 1993). The exact mechanism is unidentified, but Aß deposits are more abundant in ε 4-positive than in ε 4-negative cases (Schmechel et al. 1993). In addition, APOE4 is associated with a number of other factors that may contribute to AD pathology, including low glucose usage, mitochondrial abnormalities, and cytoskeletal dysfunction (Mahley et al. 2006).

1.1.4.2 Familial AD

Although familial AD [FAD] is very rare its importance should not be underestimated. Fact is without the familial cases we would have been far behind in our knowledge about AD. FAD is associated with an autosomal dominant pattern of inheritance, with three major genes whose mutations are known to contribute to the disease. In the mid 80’s, as Mann et al observed that individuals with Down’s syndrome develop the clinical and neuropathological features of AD, studies on the amyloid precursor protein [APP] as a genetic determinant of AD began (Mann et al. 1985). Since Down’s syndrome is characterized by the presence of an extra copy of genetic

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then considered. A few years later the gene encoding for APP was identified and its mutations as a leading cause of hereditary AD (Kang et al. 1987). The different APP mutations were given their names according to the families where they were discovered, for example the Swedish mutation was first discovered in 2 Swedish families by Lannfelt and his coworkers (Mullan et al.

1992). The APP mutations are clustered near the α-, β-, or γ-secretase cleavage sites, having a direct effect on APP processing [see figure 1-7]. The discovery of these mutations led to the development of transgenic cell and animal models that were essential for many thriving findings in the field of AD.

Figure 1-7

Amyloid precursor protein

Amyloid precursor protein showing the sites where FAD mutations occur [illustrated in red]. The Swedish and London mutations are clustered near the ß-secretase and γ-secretase respectively.

In the current study a cell model over expressing the Swedish double mutation and a transgenic animal model expressing both the Swedish double and the London mutations were utilized. The Swedish APP double mutation [KM670/671NL] promotes the processing of APP by the ß-secretase causing a massive increase in total Aß levels (Citron et al. 1992). In the London mutation the total amount of Aß doesn’t change , however the proportion of

Aß 42 increases by 50–90 % (Suzuki et al. 1994). Thus the London mutation shifts the balance of γ-secretase cleavage slightly toward the 42 over the 40 cleavage site.

Although the APP mutations were the first identified in FAD, it is believed that they are responsible for only 5-20 % of all FAD cases. On the other hand mutations in presenilin 1 [PS1] gene found on chromosome 14 are assumed to be accountable for approximately 85 % FAD. Homologue to PS1 are mutations in presenilin 2 [PS2] localized on chromosome 1, and they are very rare. Research conducted on PS mutations revealed that they specifically promote Aß 42 generation from APP (Turner 2006).