Jayadev S, Steinbart EJ, Chi YY, Kukull WA, Schellenberg GD, Bird TD.
Conjugal Alzheimer disease: risk in children when both parents have Alzheimer disease.
Arch Neurol. 2008 Mar;65(3):373-8.
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The findings in this study are consistent with an increasing number of studies indicating that family history is an important, but poorly understood risk factor for the development of Alzheimer disease. This study suggests that there are unknown genetic risk factors for Alzheimer disease which may be as important, if not more important, than the known genetic risk factor, apolipoprotein (ApoE) 4. The high prevalence of ApoE4 in the family history group also raises the possibility that the unknown family history factor may have confounded prior studies, which did not take family history into account. In other words, prior research that made comparisons between research groups defined by ApoE genotype may have been biased by the high prevalence of the unknown family history genetic factor in the ApoE4 group.
Very interesting study, though not quite conclusive. Research designs and analyses could potentially have been made even better by, for instance, including relevant controls. Hopefully, the potential presence of recessive FAD cases or gene-gene interactions might be established. It would be interesting to examine whether Hiroshi Mori's new APP mutation can be identified in any of the patients (Tomiyama et al., 2008).
Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, Takuma H, Kuwano R, Imagawa M, Ataka S, Wada Y, Yoshioka E, Nishizaki T, Watanabe Y, Mori H.
A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia.
Ann Neurol. 2008 Mar;63(3):377-87.
Important as is the paper by Jadaev et al., and going a long way to confirm the genetic etiology of "ordinary" AD as distinct from obviously familial EOAD, one is surprised to find to it, with all those percentages, a "biometrician" flavor (the Galton-Pearson side of the famous early twentieth-century quarrel with the "Mendelians" or "geneticists" led by Bateson). Using "censored data" corrections to account for the people who, either through premature death or by observation cut-out, were not observed beyond the estimated range of AD manifestation in the parents, it should have been possible to estimate a Mendelian segregation ratio, as did Breitner et al. 20 years ago. It was one half with one first-degree affected relative in the Breitner paper; it would be three quarters in the present case—both parents affected—under the same Mendelian transmission. The very high theoretical segregation ratio would explain the fact that a high proportion of affected parents were observed by Jadaev et al. in spite of the severe limitation of the observation span. Indeed, we showed (Bruni et al.) that monogenic dominant Mendelian transmission on the model of familial EOAD is compatible with the epidemiology of apparently sporadic LOAD under the simple hypothesis of a theoretical mean age of expression ~80 years of the mutated gene(s), if stochastic repartition (standard deviation ~6 years) of the age of expression, and data censorship are accounted for.
Breitner JC, Murphy EA, Silverman JM, Mohs RC, Davis KL.
Age-dependent expression of familial risk in Alzheimer's disease.
Am J Epidemiol. 1988 Sep;128(3):536-48.
Bruni AC, Montesi MP, Salmon D, Gei G, Perre J, el Hachimi KH, Foncin JF.
Alzheimer's disease: a model from the quantitative study of a large kindred.
J Geriatr Psychiatry Neurol. 1992 Jul-Sep;5(3):126-31.