Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

Background: Variants in and (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the variant who also had two copies of the apolipoprotein E3 Christchurch variant ( ). Heterozygosity for the variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the variant is prevalent.

Methods: We analyzed data from 27 participants with one copy of the variant among 1077 carriers of the variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the variant. Two participants underwent brain imaging, and autopsy was performed in four participants.

Results: Among carriers of who were heterozygous for the variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of carriers without the variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the and variants who underwent brain imaging, F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent F-flortaucipir PET imaging, tau findings were limited as compared with persons with in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the and variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the variant but not the variant.

Conclusions: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).