In 1987, a genetic linkage study in four large ADAD families 17-AAG buy found a gene locus at 21q11.2 to 21q22.2, but not in the 21q22 region associated with the Down syndrome phenotype [8]. Then, in 1991, a missense point mutation (Val-Ile) at codon position 717 was discovered in the APP gene in a single family with linkage to chromosome 21 [9]. This report identified the specific mutation in this family and provided a possible mechanistic link between the APP mutations and abnormalities in amyloid processing seen in these families. Most of the variants in APP occur between residues 714 and 717 near the putative site for ??-secretase cleavage [10]. At least 38 additional ADAD APP mutations have since been identified. One year after the discovery of mutations in APP as a cause of ADAD, four different laboratories identified another locus for ADAD on 14q24 [11-14].

The gene PSEN1 was cloned 3 years later, encoding the protein presenilin 1 [15]. Presenilin 1 is a highly conserved membrane protein required for ??-secretase to produce amyloid-beta (A??) from APP [16]. Since the initial finding of the PSEN1 mutation, approximately 180 different mutations that cause ADAD have been identified http://www.molgen.ua.ac.be/ADMutations/. Within a year of cloning PSEN1, a gene with substantial nucleotide and amino-acid homology was discovered on the long arm of chromosome 1 in two families [15]. This gene, PSEN2, appears to account for only a small percentage of ADAD cases and may be associated with a later age of onset and slower disease progression than mutations in PSEN1 and APP.

The discovery AV-951 of the genetic causes of ADAD catalyzed research on the relationship of ADAD to SAD. The clinical, imaging, pathologic and biochemical relationships have been individually described by groups around the world, each following a relatively small number of affected families. While the pathogenic cause of ADAD is an inherited mutation, the molecular pathogenic causes of SAD have not yet been identified. Therefore, although the two forms of the disease may have fundamentally different initial pathways, they share a remarkably similar pathophysiology. These descriptions have provided key insights into the causes of both SAD and ADAD. The characteristics of ADAD compared with the more common sporadic late-onset AD are summarized in Table ?Table11.

Table 1 Comparison of autosomal-dominant Alzheimer’s disease with sporadic Alzheimer’s disease Clinical presentation of ADAD In broad terms, the clinical presentation of ADAD is very similar to that of SAD. Like SAD, selleck chemicals Crizotinib most ADAD cases present with an insidious onset of episodic memory difficulties followed by inexorable progression of cortical cognitive deficits. The most obvious difference between familial and sporadic cases of AD is the younger age at onset in individuals with ADAD mutations.