I would like to underscore a point that is made at the end of the paper: The results of our study suggest that genetic risk factors play a much smaller role in AD with onset at or after age 85. If so, then this very late onset group of patients may be an ideal target population in which to further investigate environmentally mediated risk factors hypothesized to play a role in AD (e.g. many of the cardiovascular risk factors).

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This interesting paper raises a number of technical questions in my mind.

For one, I noticed that in Table 2, variance explained by genetics was significant for the younger series of twins, but apparently not for the older twin series. This would be consistent with family data from my group and others.

For another, it is unclear to me how much of a role low statistical power may have had in the failure to provide significant evidence that heritability is lower in those older than 80 years of age.

A third issue is the more or less comparable concordance rates observed in the monozygotic (MZ) twins in the younger (probandwise: 33.3 percent) and older (31.6 percent) series contrasted with the big increase from 0 percent to 10.8 percent in the younger and older dizygotic (DZ) twins series. Assuming that the role of genetic factors is reduced as age at onset increases, one might hypothesize that concordance rates would be reduced in an older series of MZ twins versus a younger one. That was not the case in this sample. However, because AD is so highly age-related, with...  Read more

This interesting paper raises a number of technical questions in my mind.

For one, I noticed that in Table 2, variance explained by genetics was significant for the younger series of twins, but apparently not for the older twin series. This would be consistent with family data from my group and others.

For another, it is unclear to me how much of a role low statistical power may have had in the failure to provide significant evidence that heritability is lower in those older than 80 years of age.

A third issue is the more or less comparable concordance rates observed in the monozygotic (MZ) twins in the younger (probandwise: 33.3 percent) and older (31.6 percent) series contrasted with the big increase from 0 percent to 10.8 percent in the younger and older dizygotic (DZ) twins series. Assuming that the role of genetic factors is reduced as age at onset increases, one might hypothesize that concordance rates would be reduced in an older series of MZ twins versus a younger one. That was not the case in this sample. However, because AD is so highly age-related, with incidence doubling every five years, many more cases can be expected to emerge at these late ages, and this would tend to make the likelihood of the concordance rate between any two individuals (related or not) increase with age. So what is striking to me, then, is not so much the persistence of the MZ concordance rate in the older versus the younger series (in fact, there was a very slight decline) as the absence of an increase. And, as noted, this is in contrast to the DZ concordance rate, which does increase substantially in the older versus the younger twin series.

Another curious result (related, I think, to the above) is the observed incidence rates in the younger and older MZ and DZ twin series. At 4.5 percent, the incidence rate among the younger MZ twins was more than twice that observed in the younger DZ twins. Given strong genetic factors, one would expect higher rates overall in comparably aged MZ over DZ twins, since the likelihood of concordance is higher in the MZ twins (i.e., when one case arises, there is an increased likelihood over DZ twins that a second one will arise). In the older series, however, the incidence rate for the MZ twins was 8 percent, substantially less than the 12.5 percent rate in the DZ twins. Where there was a greater than sixfold increased incidence in older DZ twins compared with younger DZ twins, there was only a 1.8-fold increased incidence in older MZ twins compared with younger MZ twins.

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