APOECh Heterozygosity Delays Cognitive Impairment in Alzheimer’s Disease

Apolipoprotein E Christchurch (APOE^Ch) heterozygosity shows evidence of delayed onset of cognitive impairment among members of a Colombian kindred with a high incidence of autosomal dominant Alzheimer disease (AD), according to the findings of a study published in the New England Journal of Medicine.

Some variants of the APOE and presenilin 1 (PSEN1) genes are shown to impact AD risk. A previous case study on a patient with the PSEN^1E280A variant who had 2 copies of the rare Christchurch variant (R136S) of APOE3 demonstrated delayed cognitive impairment. Researchers conducted a retrospective cohort study to determine if heterozygosity for APOE^3Ch variant (APOE^3Ch/e3, APOE^3Ch/e2, or APOE^3Ch/e4) delays the onset of cognitive impairment or dementia. 

A family of approximately 6000 members in Antioquia, Colombia is known to have more than 1000 carriers of the E280A variant of the PSEN1 gene. The researchers screened 1077 descendants of this family aged 18 and older with at least 1 parent with the PSEN^1E280A variant; this variant leads to mild cognitive impairment and is followed by autosomal dominant AD. 

Participants completed neuropsychological tests and neuropsychologists classified their cognitive status. The Functional Assessment Staging (FAST) system and Mini-Mental State Examination (MMSE) were used to determine the level of functional impairment.

Of the 1077 patients who were carriers of PSEN^1E280A, 121 patients had the APOE^3Ch variant, with 1 patient homozygous for APOE^3Ch and 27 patients who were carriers of PSEN^1E280A. 

Among the 27 patients with PSEN^1E280A and APOE^3Ch heterozygosity, there was 1 death without cognitive impairment at age 57, 13 patients with mild cognitive impairment or dementia, and 13 patients who did not meet the criteria for cognitive impairment. There were 4 patients who underwent an autopsy and 2 who had brain imaging data. 

The median age at cognitive impairment onset was 52 (95% CI, 51-58 years) in patients who were carriers of PSEN^1E280A who were heterozygous for the APOE^3Ch variant compared to age 47 (95% CI, 47-49 years) among a matched cohort of PSEN^1E280A carriers without the APOE^3Ch variant.

Additionally, the median age at dementia onset among patients with the APOE^3Ch variant was 54 (95% CI, 49-57 years) compared to age 50 (95% CI, 48-51 years) among noncarriers of APOE^3Ch. 

Of the 2 participants with the APOE^3Ch and PSEN^1E280A variants with brain imaging data, readings showed some maintained metabolic activity in brain areas that are usually involved in AD. One of the patients who received 18F-flortaucipir positron emission tomography (PET) imaging showed limited tau findings compared to patients with PSEN^1E280A with cognitive impairment.

The autopsy data showed that patients with APOE^3Ch and PSEN^1E280A variants had less vascular amyloid pathology compared to patients with PSEN^1E280A variant without the APOE^3Ch variant.

Study limitations included the small population size and that the biological insight observed in this family may not translate to other groups of people. 

“Further studies involving larger and more ethnically diverse samples of persons with Alzheimer’s disease may shed light on any apparent protective effect of the APOE^3Ch variant,” the researchers concluded. 

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.