Early-onset familial AD

PS-2, are found as the most frequent causes of early onset familial AD cases [5]. The prese-nilins are involved in APP processing by enzymes called secretases [6]. 

While variants in these three genes (APP, PSl, and PS2) account for between 30% and 50% of early-onset familial AD, overall they account for less than 2% of all cases of AD (Klaver et al., 1998 Finckh et al., 2000 Liddell et al., 1995 Rosenberg et al., 2000). 

Miss-sense mutations in PSl and PS2 are associated with early-onset familial AD. Analyses of brains from AD patients with PSl mutations have demonstrated a significant increase in the amount of Ap42-immunoreactive deposits in hippocampus, cerebral cortex, and other brain regions (Lemere et al., 1996). The majority of miss-sense mutations occur in highly conserved sites (Fraser et al., 2000). They are predominantly located in highly conserved TM domains, at/near putative membrane interfaces, or in the large hydrophiUc loop. Dimerization models suggest that PSl and PS2 mutations influence the assembly or stabiUty of the functional preseniUn complex (Cervantes et al., 2(X)1). 

A strong genetic association exists between early onset familial forms of AD (FAD) and the 42 amino acid species of the Ap peptide (Hutton et al., 1998 Younkin,... 

I, Pollen DA, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HAR, Haines JL, Peiicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer s disease. Nature 375 754—760. 

AD, Fraser PE, Rommens JM, George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer s disease. Nature 375 754-760. 

Epidemiological studies have shown that mutations in APP and presenilin genes are linked to rare familial and early-onset forms of AD (2). This observation led to the amyloid cascade hypothesis suggesting that excessive AB production is the primary cause of the disease. 

In addition to age, other factor s are associated with an inareased risk of AD. In developed countries, AD appears to be more common in v omen. Lack of education is a risk factor for senile dementia in China and Europe (Zhang et al., 1990 Schmand et al., 1997). Head daunra is also a risk factor for both sporadic (Mortimer et al., 1991) and familial AD (Guo et al., 2000). Silent myocardial infarcts and coronary stenosis triple the risk for AD (Aronson etal., 1990 Sparks etal., 1990), suggesting the importance of vascular risk factors. Other potential risk factors being studied include diabetes and hypertension (Ott et al., 1999 Peila et al., 2002 Qiu etal., 2005). As discussed below, a large number of genetic mutations are now associated with either early-onset AD or with increased risk of late-onset AD. 

Like APP mutations, the PS 1 and PS2 mutations can lead to increased levels of Ap h brain. Whether the presenilins interact directly with APP through their putative y-secretase activity, or act as co-factor for another y-secretase, remains unclear. Furthermore, the relationship betw een identified causal mutations and AD phenotype is not necessarily simple. For example, PS 1 mutations associated with familial early-onset AD have been identified in individuals with frontotemporal dementia who have no evidence of the Ap accumulation characteristic of AD. 

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