There is a three-generation history of LOAD in the family reported in this study. Only the proband's DNA was sequenced, and as a result there is no evidence of segregation of disease with the mutation. However, this mutation has been reported in an early-onset AD family in the UK. It would be interesting to know whether the family in this paper is related to the original family but exhibiting a later age of onset. If this were the case, it would greatly strengthen the case for pathogenicity with reduced penetrance. The conclusion that screening autosomal-dominant AD cases with late-onset AD for PS1 mutations is worthwhile.

View all comments by Alison Goate

We first described the PSEN1-R269H mutation in a single case of early-onset AD (Gomez-Isla et al., 1997). There, the R269H PS1 mutation was associated with higher amounts of total cerebral Aβ and Aβ x-42, and increased NFT counts. Like the PSEN2 N141I mutation (Levy-Lahad et al., 1995), the PSEN-R269H mutation now appears to be associated with both early- and late-onset AD. For both mutations, the possibility of genetic modifiers influencing age-dependent penetrance may be worth pursuing.

References:
Gomez-Isla T., Wasco W., Pettingell W.P., Gurubhagavatula S, Schmidt S.D., Jondro P.D., McNamara M., Rodes L.A., DiBlasi T., Growdon W.B., Seubert P., Schenk D., Growdon J.H., Hyman B.T., Tanzi R.E. Novel Presenilin 1 Gene Mutation: Increased ?-Amyloid and Neurofibrillary Changes. Annals of Neurology, 1997; 41: 809-813. Abstract

Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima Jm Pettingell WH, Yu C, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science, 1995; 269: 973-977. Abstract

View all comments by Rudy Tanzi