APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease

Variants in APOE and PSEN1 (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 PSEN1 ^E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 ^Ch). Heterozygosity for the APOE3 ^Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 ^E280A variant is prevalent.

We analyzed data from 27 participants with one copy of the APOE3 ^Ch variant among 1077 carriers of the PSEN1 ^E280A 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 APOE3 ^Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants.

Among carriers of PSEN1 ^E280A who were heterozygous for the APOE3 ^Ch 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 PSEN1 ^E280A carriers without the APOE3 ^Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 ^Ch and PSEN1 ^E280A variants who underwent brain imaging, ¹⁸F-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 ¹⁸F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 ^E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 ^Ch and PSEN1 ^E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 ^E280A variant but not the APOE3 ^Ch variant.

Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 ^Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).