APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.).

Figure 1.. Limited Tau Pathological Findings and Relatively Preserved Regional Cerebral Metabolic Activity in Persons Heterozygous for the PSEN1^E280A and APOE3^Ch Variants.

Shown are baseline amyloid-β positron-emission tomographic (PET) images (Panel A; ¹¹C-Pittsburgh compound B [PiB]) and tau PET images (Panel B; ¹⁸F-flortaucipir). Sample coronal views (upper images) and sagittal views (lower images) are shown for each. For visual comparison, samples that were obtained from two participants are shown: from a typical person with the E280A variant of presenilin 1 (PSEN1^E280A) who had mild cognitive impairment (Panels A and B, left images), and from a person with the PSEN1^E280A variant who was also heterozygous for the APOE3^Ch variant (right images). The color-coded scale bar indicates the PiB distribution volume ratio (DVR) or flortaucipir standardized uptake value ratio (SUVR) values; blue represents the lowest binding and red represents the highest binding, with values ranging from 1.0 to 2.0. The person who was heterozygous for the APOE3^Ch variant had greater amyloid-β plaque burden and a relatively limited tau burden as compared with persons with the PSEN1^E280A variant in whom the onset of mild cognitive impairment occurred at the typical age in this kindred, as exemplified by the person whose images are shown here. Panel C shows ¹⁸F-fludeoxyglucose (FDG) PET images indicating the precuneus cerebral metabolic rate for glucose. In all three panels, the sample was obtained from a person with the PSEN1^E280A variant. The leftmost image in Panel C shows the sample of a person in whom the onset of mild cognitive impairment occurred at a typical age in this kindred, the middle image a sample from a person heterozygous for the APOE3^Ch variant, and the rightmost image a sample from a second person heterozygous for the APOE3^Ch variant. The color-coded scale bar indicates FDG SUVR values; blue represents lowest values and red represents highest values, with values ranging from 0.5 to 1.8. SUVR values represent the regional cerebral metabolic rate for glucose.

Figure 2.. Cumulative Incidence of Mild Cognitive Impairment and Dementia among Persons with the PSEN1^E280A Variant.

Shown are the cumulative incidence functions of mild cognitive impairment and dementia among persons with the PSEN1^E280A variant, 27 of whom had the APOE3^Ch variant and 1050 of whom did not. The analyses of mild cognitive impairment shown in Panel A and of dementia shown in Panel B included all the participants. The analyses of mild cognitive impairment shown in Panel C and of dementia shown in Panel D included matched samples from 27 persons with the APOE3^Ch variant and 326 persons without this variant. Participants were matched for sex, APOE genotype, and years of formal education. Death without a diagnosis of mild cognitive impairment or dementia was a competing risk. Shading indicates the 95% confidence interval.