Genetics of Alzheimer disease

Abstract

Alzheimer disease (AD) is the most common causes of neurodegenerative disorder in the elderly individuals. Clinically, patients initially present with short-term memory loss, subsequently followed by executive dysfunction, confusion, agitation, and behavioral disturbances. Three causative genes have been associated with autosomal dominant familial AD (APP, PSEN1, and PSEN2) and 1 genetic risk factor (APOEε4 allele). Identification of these genes has led to a number of animal models that have been useful to study the pathogenesis underlying AD. In this article, we provide an overview of the clinical and genetic features of AD.

Figure 1

Amyloidogenic processing of the amyloid precursor protein (APP) and generation of the β-amyloid peptides. The APP protein can be cleaved by 3 different secretases: α, β, or γ. Subsequent to “normal” α-secretase cleavage, sAPPα is produced and released into the extracellular space and the C83 peptide remains in the cell membrane (panel B). Subsequent to β-secretase cleavage, sAPPβ is produced and released into the extracellular space and the C99 peptide remains in the cell membrane Subsequent to β-secretase cleavage, the C99 peptide is “abnormally” cleaved by γ-secretase to yield an Aβ peptide and the AICD peptide. Scale is approximate. Aβ indicates amyloid-β peptide; AICD, amyloid precursor protein intracellular domain; sAPPβ, soluble fragment amyloid-β peptide; TMD, transmembrane domain. Large arrow represents accumulation of plaques or amyloid plaque deposition.

Figure 2

Amyloid precursor protein (APP) structure and mutations. Thus far, over 32 different APP missense mutations have been identified, of which a few are shown. SP indicates signal peptide; KPI, Kunitz protease inhibitor domain; Aβ, amyloid-β; TM, transmembrane domain. Scale is approximate.

Figure 3

Presenilin 1 (PSEN1) structure and mutations. Thus far, there have been at least 123 mutations in the PSEN1 gene described, of which a few are shown. For a more complete list of PSEN1 mutations, see http://www.molgen.ua.ac.be/ADMutations. TM indicates transmembrane domains. Scale is approximate.

Figure 4

Presenilin 2 (PSEN2) structure and mutations. Thus far, there have been at least 16 mutations in the PSEN2 gene described, of which a few are shown. For a more complete list of PSEN2 mutations, see http://www.molgen.ua.ac.be/ADMutations. TM indicates transmembrane domains. The V393M novel mutation was most recently found in 1 case (Lindquist et al). Scale is approximate.

Figure 5

Apolipoprotein E (APOE) structure and single nucleotide polymorphisms (SNPs). The general protein structure of APOE is shown. The 2 SNPs in exon 4 and corresponding protein locations are shown (rs429358 and C112R; and rs7412 and R158C). The 3 APOE ε4 alleles (ε2, ε3, and ε4) are defined by 2 SNPs, rs429358 and rs7412, with ε2 defined by nucleotides T-T; ε3 defined by T-C, and ε4 defined by C-C, respectively.