LETTER TO THE EDITOR

Re: Unstable Trinucleotide Repeats in Alzheimer’s Disease?

To the Editor:Many hereditary neurological or neuromuscular dis-

orders, with evidence of slow progress and frequentlygenetic anticipation, have now been shown to be due toan expansion in the number of tandem repeated tri-nucleotides (4). Such tandem repeats occur inside ornear the genes involved in the disease and theirnumber is often highly variable.

Alzheimer’s Disease (AD) is a hereditary autosomal-dominant slowly progressive disorder. Recently manystudies have indicated that AD is a complex neurologi-cal disorder exhibiting several genetic forms character-ized by either early or late onset of disease (1). Muta-tions in three genes are involved in many cases of earlyonset familial AD. Two of these genes encode presenilinI and presenilin II, proteins respectively known asS182 (chromosome 14) and STM2 (chromosome 1).Both are seven-transmembrane integral proteins andare 67% homologous to each other in amino acidsequence. The third gene encodes b-amyloid precursorprotein (bAPP) and is located on chromosome 21. bAPPis a cell surface protein and has several isoformsgenerated by alternative splicing of a gene containing19 exons.

In the bAPP gene (GenBank Sequence AccessionY00264 (2)) there is a trinucleotide which is tandemlyrepeated seven times. The repeated triplet (acc) occursin exon 6, is expressed in all isoforms, and produces atranslation of 7 threonines beginning from the 256thamino acid.

Onset of neurological diseases, caused by variationsin the number of tandem repeats, is closely related tothe number of repeats; this number is different frompatient to patient. Examples of such disorders are (4):Dentato-Rubro-Pallido-Luysian Atrophy, Huntington’sDisease, Myotonic Dystrophy, Spinobulbar MuscularAtrophy, some types of Spinocerebellar Ataxia, andmany fragile site syndromes. What happens geneticallyin the above diseases could also occur in AD: that is, theabove-mentioned triplet in bAPP might be unstable

and could therefore be related to some forms of AD. Wehave not found any reference to research into this.Usually, the number of repeats in the above disorders is10 or greater in the absence of disease, and in disease ismuch higher. The number of repeats in bAPP gene mayseem to be too low when compared to the above diseasesbut it is notable that in Spinocerebellar Ataxia type 6 acomparable, and even lower, number of repeats (4–16 innonataxia individuals) has been recently reported (5).Hence, we consider that it could be important toinvestigate the number of such repeats in patients withAD, affected at different times of life, especially since agenetic involvement remains to be assigned to manycases of late onset AD and some of early onset disease.

REFERENCES

1. Dewji, N. N., and S. J. Singer. 1996. Genetic clues to Alzheimer’sdisease. Science 271: 159–160.

2. Kang, J., H. G. Lemaire, A. Unterbeck, J. M. Salbaum, C. L.Masters, K. H. Grzeschik, G. Multhaup, K. Beyreuther, and B.Muller-Hill. 1987. The precursor of Alzheimer’s disease amyloidA4 protein resembles a cell-surface receptor. Nature 325: 733–736.

3. La Spada, A. R., H. L. Paulson, and K. H. Fischbeck. 1994.Trinucleotide repeat expansion in neurological disease. Ann.Neurol. 36: 814–822.

4. Warren, S. T. 1996. The expanding world of trinucleotide repeats.Science 271: 1374–1375.

5. Zhuchenko, O., J. Bailey, P. Bonnen, T. Ashizawa, D. W. Stockton,C. Amos, W. B. Dobyns, S. H. Subramony, H. Y. Zoghbi, and C. C.Lee. 1997. Autosomal dominant cerebellar ataxia (SCA6) associ-ated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nature Genet. 15: 62–69.

Valerio Parisi*Valeria De Fonzo†Enrico Bersani‡

Dipartimento di Fisica*EuroBioPark†Centro Interfacolta ‘‘Vito Volterra’’‡Universita di Roma ‘‘Tor Vergata’’Via della Ricerca Scientifica 100133 Rome, Italy

EXPERIMENTAL NEUROLOGY 148, 393 (1997)ARTICLE NO. EN976609

393 0014-4886/97 $25.00Copyright r 1997 by Academic Press

All rights of reproduction in any form reserved.