Detailed studies of twins can provide support for genetic versus environmental factors in AD. This study is the first to our knowledge to assess the concordance/discordance of NP, NFT and LRP in three sets of MZ twins (six individuals) including one twin pair positive for a PS1 mutation (twin pair B).
This study raises some interesting findings. All of the twins met criteria for definite AD with a history of dementia and neuropathological findings consistent with AD.27
The semiquantitative NP and NFT staging was concordant within all twin pairs despite wide variability in the age of onset, clinical presentation and duration of disease. This variability was most marked in the two twin pairs (A and C) without a PS1 mutation. This lack of correlation between neuropathology and disease duration supports the concept of early deposition of tau and amyloid and confirms an important role for genetic factors in the development of NP and NFT in AD.
In contrast, LRP was not concordant within the MZ twin pairs and there was a suggestion of a relationship between LRP and age of disease onset and/or duration of disease. The twin within each pair with the earlier age of onset and longer duration of disease had the greater LRP burden. This difference was most marked in the two twin pairs without the PS1 mutation. A similar relationship between duration of disease and severity of LRP has been reported in PS1 mutation associated familial AD.22
Recent studies have looked at the concordance of LRP in AD kindreds with PS1 and PS2 mutations22
and in kindreds with familial LOAD.28
The genetic influences for the development of LRP seem highest in families with the PS1 mutation compared with the PS2 mutations,22
while families with LOAD demonstrate more variability in the development of LRP, suggesting the influence of other factors.28
This pattern was reflected in our three twin pairs.
The discordance within the twin pairs for LRP suggests factors such as duration of disease, age of onset and environment have a greater impact than genetic factors on the development of LRP in AD. Of course, this may not be the case for LRP without coexistent AD.
Four of the six individuals had varying combinations of LRP and AD pathology. The presence of neocortical or limbic LRP tended to correlate with the presence of behavioural disturbances, fluctuating disorientation and gait disturbances, and the twin with the highest LRP burden fulfilled clinical criteria for dementia with Lewy bodies (C2).
The PS1 A79V mutation, observed in MZ twin pair B, has been reported by other investigators.29,30
Previously reported subjects with this mutation tended to have a later age of onset of disease (mid to late 50s) and a slower course than subjects with other PS1 mutations.29,30
This trend was true in our family B. To our knowledge, family member B IV‐10 represents the oldest age of onset (79 years) of a person with a PS1 mutation.
It is interesting that the twins reviewed in this study had such a wide range of age of onset (differences within pairs ranging from 4 to 18 years), most marked in the twins with LOAD rather than the PS1 twins. Other large studies have found the difference in age of onset to be smaller in MZ twins, between 0 and 7 years,9
although MZ twins can remain discordant in the development of AD for up to ~21–22 years.10
The broad range of disease onset in MZ twins strongly implies the importance of environmental factors influencing this phenomenon. That these environmental factors remain largely unknown is underlined by the remarkably common environments experienced by the twins in this study.
Following submission of this paper, Kauwe and colleagues have reported a family with late onset AD and the A79V mutation in PS1 (Ann Neurol 2007;61:446–53).