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Dominant Alzheimer's Disease Delayed in Individuals Heterozygous for Protective APOE3 Variant

NEW YORK – New research suggests that carriers of an autosomal dominant Alzheimer's disease gene who also have a single copy of a protective variant of the APOE3 gene tend to develop cognitive impairment and related brain changes later in life than those without the APOE3 variant.

For a study published in the New England Journal of Medicine on Wednesday, researchers at Harvard Medical School, the University of Antioquia, and other centers in the US, Colombia, and Germany looked at the clinical consequences of being heterozygous for the so-called Christchurch variant, APOE3-Ch, of the apolipoprotein E-coding gene.

"Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE-Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease," co-senior and co-corresponding authors Joseph Arboleda-Velasquez, a researcher at Harvard Medical School and the Mass Eye and Ear Schepens Eye Research Institute, and Francisco Lopera, an investigator at the University of Antioquia in Colombia, and their colleagues wrote.

The team's analysis involved 1,088 Colombian individuals from a large family with a variant in PSEN1 that is behind an autosomal dominant form of Alzheimer's disease. Among the participants were 27 individuals who carried both the risky variant in PSEN1, which encodes presenilin 1, and were heterozygous for the protective APOE-Ch variant.

The researchers found that cognitive impairment occurred at the age of 52 years, on average, in individuals carrying one copy of the APOE3 Christchurch variant, compared to cognitive symptoms at an average age of 47 in those without the protective variant. Similarly, dementia symptoms appeared to be delayed by roughly four years in the subset of individuals who were heterozygous for the protective variant.

Though the delay in clinical features was not as dramatic as that reported in a past study of an individual from the Colombian population who was homozygous for the protective variant in combination with the Alzheimer's-associated PSEN1 variant, the current results argued against prior findings that did not see a protective effect for those heterozygous for the Christchurch variant in a small set of participants.

"The analyses that we present here encompassed a larger cohort with APOE3-Ch and PSEN1-E280A variants, with more comprehensive longitudinal clinical characterization," the authors explained, "and indicated that APOE3-Ch heterozygosity is apparently linked to delay in the expected cognitive impairment."

With the help of brain imaging in two of the individuals with the PSEN1 risk variant and APOE3 protective variant, meanwhile, the team saw only subtle metabolic shifts and tau protein changes in parts of the brain that are usually affected by Alzheimer's, contrasting with the more dramatic changes that typically accompany cognitive changes in individuals with the Alzheimer's-related PSEN1 variant alone.

Those findings were further backed up by analyses of amyloid-beta, tau, and vascular features found in brain samples collected during autopsy from four individuals carrying one copy of the Alzheimer's-protective APOE3 variant.

"Our new study is significant because it increases our confidence that this target is not only protective, but druggable," Arboleda-Velasquez said in a statement. "We think that therapeutics inspired by protected humans are much more likely to work and to be safer."

The team cautioned that the current study did not compare disease protection in individuals heterozygous and homozygous for the protective variant and was limited to a specific cohort from Colombia with autosomal dominant Alzheimer's risk.

Consequently, the authors suggested that larger studies involving individuals from other populations with diverse genetic backgrounds can provide further clues to the protective qualities of the APOE3 Christchurch variant in those carrying one or two copies of it.

Even so, they noted that the new results "provide evidence that APOE3-Ch heterozygosity delayed the onset of cognitive impairment in a form of autosomal dominant Alzheimer's disease and may have a protective effect against Alzheimer's disease and neurodegeneration in this population."