Is APOE4 Homozygosity Indicative of a Genetic Form of Alzheimer Disease?

APOE4 homozygotes may have a distinct, genetic type of Alzheimer disease (AD), according to study findings published in Nature Medicine.  

While it is known that an APOE4 gene increases the risk of developing AD, there is a lack of studies estimating the symptom onset among APOE4 homozygotes. Researchers conducted a study to evaluate the changes in clinical status, pathology, and biomarkers among patients who are APOE4 homozygotes to determine if this gene variant can be characterized as a form of genetically driven dementia. 

Pathological data was collected from the National Alzheimer’s Coordinating Center (NACC) and 5 multicenter cohorts of patients with AD biomarkers. The researchers evaluated the biological extent of AD in the postmortem NACC cohort and among in vivo biomarkers from the clinical cohorts. A total of 3297 brain donors were identified from the NACC database and 10,039 from the clinical cohorts. 

The NACC cohort had AD neuropathological change (ADNC) scores, which indicates the clinical genetic risk of AD. The researchers found that nearly all patients who were APOE4 homozygotes had high or intermediate ADNC (95%) and that neuropathology reports remained consistent across all age groups at the time of death.

Across 5-year age intervals, the frequency of abnormal biomarkers was higher among patients who were APOE4 homozygotes compared to APOE3 homozygotes starting from age 55. Almost all patients who were APOE4 homozygotes had abnormal levels of cerebrospinal fluid amyloid-β (CSF Aβ), with 75% reporting positive amyloid scans. At age 80, there was an 88% biological penetrance for all amyloid and tau biomarkers and this result remained consistent when analyzing females and males separately. 

Patients who were APOE4 homozygotes began experiencing symptoms of AD at an average age of 65.6. APOE4 homozygotes also began to experience mild cognitive impairment (MCI) at an average age of 71.8, dementia at 73.6, and death at 77.2. All these symptoms were experienced 7 to 10 years sooner than patients who were APOE3 homozygotes (P <.05).

The main difference between patients who were APOE4 homozygotes and patients with autosomal-dominant AD was the differences in hippocampal atrophy, with the APOE4 homozygotes having decreased volumes across all age categories. 

Symptom onset and biomarker changes among patients who were APOE4 homozygotes were similar to those of patients with dominant AD and Down syndrome. Participants in the dementia stage did not show significant differences in amyloid or tau positron emission tomography (PET) across different haplotypes, although they displayed earlier clinical and biomarker changes. 

Study limitations included the use of convenience samples, that ADNC is not a specific measure of neuropathological lesions, and the lack of consistent biomarker tests across study sites.

“[W]e propose a reappraisal of the conceptual framework and statistical approaches to favor the use of those commonly utilized in genetically determined dementias rather than the conceptual and analytical approach used in sporadic AD studies,” 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.