AD, Autosomal dominant; FAD, familial Alzheimer disease; NA, not applicable.

Data derived from St. George-Hyslop PH, Farrer LA: Alzheimer’s disease and the fronto-temporal dementias: diseases with cerebral deposition of fibrillar proteins. In Scriver CR, Beaudet AL, Sly WS, Valle D, editors: The molecular and metabolic bases of inherited disease, ed 8, New York, 2000, McGraw-Hill; and Martin JB: Molecular basis of the neurodegenerative disorders. N Engl J Med 340:1970–1980, 1999.

The identification of the four genes associated with AD has provided great insight not only into the pathogenesis of monogenic AD but also, as is commonly the case in medical genetics, into the mechanisms that underlie the more common form, nonfamilial or sporadic AD. Indeed, overproduction of one proteolytic product of βAPP, called the Aβ peptide, appears to be at the center of AD pathogenesis, and the currently available experimental evidence suggests that the βAPP, presenilin 1, and presenilin 2 proteins all play a direct role in the pathogenesis of AD.

The Pathogenesis of Alzheimer Disease: β-Amyloid Peptide and Tau Protein Deposits

The Amyloid Precursor Protein Gives Rise to the β-Amyloid Peptide


Figure 12-24 The normal processing of β-amyloid precursor protein (βAPP)and the effect on processing of missense mutations in the βAPP gene associated with familial Alzheimer disease. The ovals show the locations of the missense mutations. See Sources & Acknowledgments.

In monogenic AD due to missense substitutions in the gene encoding βAPP (APP), however, several mutations lead to the relative overproduction of the Aβ42 peptide. This increase leads to accumulation of the neurotoxic Aβ42, an occurrence that appears to be the central pathogenic event of all forms of AD, monogenic or sporadic. Consistent with this model is the fact that patients with Down syndrome, who possess three copies of the APP gene (which is on chromosome 21), typically develop the neuropathological changes of AD by 40 years of age. Moreover, mutations in the AD genes presenilin 1 and presenilin 2 (see Table 12-5) also lead to increased production of Aβ42. Notably, the amount of the neurotoxic Aβ42 peptide is increased in the serum of individuals with mutations in the βAPP, presenilin 1, and presenilin 2 genes; furthermore, in cultured cell systems, the expression of mutant βAPP, presenilin 1, and presenilin 2 increases the relative production of Aβ42 peptide by twofold to tenfold.

The central role of the Aβ42 peptide in AD is highlighted by the discovery of a coding mutation (Ala673Thr) in the APP gene (Fig. 12-25) that protects against both AD and cognitive decline in older adults. The protective effect is likely due to reduced formation of the Aβ42 peptide, reflecting the proximity of Thr673 to the β-secretase cleavage site (see Fig. 12-25).


Figure 12-25 The topology of the amyloid precursor protein (βAPP), its nonamyloidogenic cleavage by α-secretase, and its alternative cleavage by putative β-secretase and γ-secretase to generate the amyloidogenic β amyloid peptide (Aβ). Letters are the single-letter code for amino acids in β-amyloid precursor protein, and numbers show the position of the affected amino acid. Normal residues involved in missense mutations are shown in highlighted circles, whereas the amino acid residues representing various missense mutations are shown in boxes. The mutated amino acid residues are near the sites of β-, α-, and γ-secretase cleavage (black arrowheads). The mutations lead to the accumulation of toxic peptide Aβ42 rather than the wild-type Aβ40 peptide. The location of the protective allele Ala673Thr is indicated by the dashed arrow. See Sources & Acknowledgments.

The Presenilin 1 and 2 Genes

The APOE Gene is an Alzheimer Disease Susceptibility Locus

TABLE 12-6

Amino Acid Substitutions Underlying the Three Common Apolipoprotein E Polymorphisms


These figures are estimates, with differences in allele frequencies that vary with ethnicity in control populations, and with age, gender, and ethnicity in Alzheimer disease subjects.

Data derived from St. George Hyslop PH, Farrer LA, Goedert M: Alzheimer disease and the frontotemporal dementias: diseases with cerebral deposition of fibrillar proteins. In Valle D, Beaudet AL, Vogelstein B, et al, editors: The online metabolic & molecular bases of inherited disease (OMMBID). Available at: www.ommbid.com/.

The mechanisms underlying these effects are not known, but apoE polymorphisms may influence the processing of βAPP and the density of amyloid plaques in AD brains. It is also important to note that the APOE ε4 allele is not only associated with an increased risk for AD; carriers of ε4 alleles can also have poorer neurological outcomes after head injury, stroke, and other neuronal insults. Although carriers of the APOE ε4 allele have a clearly increased risk for development of AD, there is currently no role for screening for the presence of this allele in healthy individuals; such testing has poor positive and negative predictive values and would therefore generate highly uncertain estimates of future risk for AD (see Chapter 18).

Other Genes Associated with AD

Although case-control association studies (see Chapter 10) of candidate genes with hypothetical functional links to the known biology of AD have suggested more than 100 genes in AD, only one such candidate gene, SORL1 (sortilin-related receptor 1), has been robustly implicated. Single nucleotide polymorphisms (SNPs) in the SORL1 gene confer a moderately increased relative risk for AD of less than 1.5. The SORL1-encoded protein affects the processing of APP and favors the production of the neurotoxic Aβ42 peptide from βAPP.

Genome-wide association studies analyses (see Chapter 10), on the other hand, have greatly expanded the number of genes believed to be associated with AD, identifying at least nine novel SNPs associated with a predisposition to nonfamilial late-onset forms of AD. The genes implicated by these SNPs and their causal role(s) in AD are presently uncertain.

Overall, it is becoming clear that genetic variants alter the risk for AD in at least two general ways: first, by modulating the production of Aβ, and second, through their impact on other processes, including the regulation of innate immunity, inflammation, and the resecretion of protein aggregates. These latter variants likely modulate AD risk by altering the flux through downstream pathways in response to a given load of Aβ.

Diseases of Mitochondrial DNA (mtDNA)

The mtDNA Genome and the Genetics of mtDNA Diseases


Figure 12-26 Representative disease-causing mutations and deletions in the human mtDNA genome, shown in relation to the location of the genes encoding the 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 proteins of the oxidative phosphorylation complex. Specific alleles are indicated when they are the predominant or only alleles associated with the phenotype or particular features of it. OH and OL are the origins of replication of the two DNA strands, respectively; 12S, 12S ribosomal RNA; 16S, 16S ribosomal RNA. The locations of each of the tRNAs are indicated by the single-letter code for their corresponding amino acids. The 13 oxidative phosphorylation polypeptides encoded by mitochondrial DNA (mtDNA) include components of complex I: NADH dehydrogenase (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6); complex III: cytochrome b (cyt b); complex IV: cytochrome c oxidase I or cytochrome c (COI, COII, COIII); and complex V: ATPase 6 and 8 (A6, A8). The disease abbreviations used in this figure (e.g., MELAS, MERRF, LHON) are explained in Table 12-7. CPEO, Chronic progressive external ophthalmoplegia; NARP, neuropathy, ataxia, and retinitis pigmentosa. See Sources & Acknowledgments.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Disorders

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