APOE4 gene linked to early onset of Alzheimer's disease

In a recent study published in Nature Medicine, researchers examined the impact of APOE4 (short for apolipoprotein E4) homozygosity on Alzheimer's disease (AD) using pathological, clinical, and biomarker analysis. They found that APOE4 homozygotes exhibit AD pathology and elevated levels of AD biomarkers beginning at age 55, representing a distinct variant of AD and a new target for therapy.

Alzheimer's disease (AD) is associated with both rare and common genetic variants that contribute to its pathogenesis. Mutations in genes such as APP, PSEN1, and PSEN2 cause early-onset autosomal dominant AD (ADAD), while multiple other genes increase the risk of sporadic AD. APOE is a significant genetic risk factor, with APOE4 homozygotes having a significantly higher lifetime risk of AD dementia compared with heterozygotes or noncarriers. However, the predictability of symptom onset in APOE4 homozygotes has not been thoroughly studied. The predictable sequence of pathological, biomarker, and clinical changes in genetically determined AD provides information about the pathophysiology of AD. Although previous studies have assessed the effect of APOE on biomarker changes, few have analyzed the gene dosage effect on AD biomarker categories in APOE4 homozygotes. Understanding these genetic influences may aid in the development of individualized prevention strategies and treatment approaches for asthma.

Therefore, the aim of this study was to evaluate pathological, clinical and biomarker changes in individuals with APOE4 homozygosity to determine whether they could be classified as a distinct type of genetically determined dementia, potentially representing one of the most common monogenic diseases.

This study used two separate sources of human data:

1. a neuropathological study that used data from brain donors from the National Alzheimer's Disease Coordinating Center (NACC) (n = 3,297), and
2. in vivo analysis of five clinical cohorts with different biomarkers (n = 10,039).

The study included individuals from NACC with neuropathological assessment, APOE haplotype data, clinical assessment, and age at onset information. In addition, five clinical cohorts included data from the Alzheimer's Disease Neuroimaging Initiative, the A4 study, the ALFA study, the Wisconsin Alzheimer's Disease Prevention Registry, and the OASIS3 project. These cohorts covered a variety of biomarkers, with a focus on preclinical AD. All available clinical diagnosis and APOE haplotype data were used in participants.

For biochemical analysis, biofluid measurements were collected in 1,665 participants across three sites. Elecsys technology was used to analyze cerebrospinal fluid (CSF) Aβ1–42 and pTau181 and SIMOA (short for single-molecule array) for plasma pTau and NfL. Aβ1–40 measurements were not available at three sites, and Aβ1–42 or Aβ1–40 ratios were not included.

For brain imaging, hippocampal volume was assessed using T1-weighted MRI (magnetic resonance imaging) in 5,108 participants. In addition, amyloid PET (positron emission tomography) imaging was performed using various tracers in 7,490 participants, and 1,267 participants underwent tau PET imaging with flortaucipir.

In addition, the study used various statistical methods including chi-square tests, Kruskal-Wallis tests, pairwise comparisons, Kaplan-Meier survival analysis, Cox regression model, and Welch t-test.

In postmortem data, APOE4 homozygotes consistently showed high or intermediate scores for changes in AD neuropathology across all age groups. In vivo biomarker analysis showed that APOE4 homozygotes had significantly higher levels of abnormal biomarkers compared with APOE3 homozygotes beginning at age 55 and with almost complete penetrance of abnormal biomarker levels by age 65.

APOE4 homozygotes show earlier onset of symptoms of Alzheimer's disease (AD), mild cognitive impairment, dementia, and death compared to APOE3 homozygotes. The predictability of symptom onset time in APOE4 homozygotes is comparable to that in individuals with PSEN1 mutations and Down syndrome.

AD biomarkers in APOE4 homozygotes showed early abnormalities, with changes in cerebrospinal fluid (CSF) Aβ1–42 protein levels and Centiloid scores before age 50. Increases in CSF and plasma phosphorylated tau (pTau) levels were observed in the early 50s, approximately 10–15 years before symptom onset. Neurofilament light chain protein levels increased sharply, indicating neurodegeneration, while hippocampal atrophy began earlier, suggesting a distinct trajectory of APOE4-related biomarkers. Integrated modeling highlighted similarities in biomarker changes between APOE4 homozygotes, ADAD, and Down syndrome, with notable differences in hippocampal atrophy. Biomarker changes in the AD dementia stage showed no significant differences between APOE haplotypes, suggesting consistency of pathology regardless of genotype and age. In addition, clear gene dosage effects were found in APOE3 and APOE4 heterozygotes in terms of neuropathology, cognitive changes, age at death, and biomarker profiles.

Despite the large-scale analysis of APOE4 homozygotes, the study is limited by convenience sampling bias, as well as variability between datasets, missing Aβ1–40 data, cross-sectional design, and predominantly white participant demographics. Future studies will prioritize inclusion of diverse populations to fully understand the impact of APOE4 on AD risk.

In conclusion, the study provides compelling evidence that APOE4 homozygotes represent a distinct genetic manifestation of Alzheimer's disease. This finding has significant implications for public health, genetic counseling practices for carriers, and the direction of future research initiatives.