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APOE4/4 Patients With Early Alzheimer’s Have Distinct Biological Profile

January 12, 2021

Patients with early Alzheimer’s disease homozygous for the ε4 allele of apolipoprotein E gene (APOE4/4) had accelerated hippocampal atrophy and cortical thinning that correlated with cognitive decline, according to a study published online in Alzheimer's & Dementia: Translational Research & Clinical Interventions.

“These findings suggest that hippocampal volume and cortical thickness may be of value for trials at the early symptomatic phase of Alzheimer’s disease (mild cognitive impairment or earlier), for selecting subjects who are likely to decline cognitively over 78 weeks,” researchers reported. “This would be especially helpful for prevention studies in presymptomatic subjects, who would otherwise require studies of at least 3 years’ duration to show cognitive decline.”

The study, supported in part by biopharmaceutical company Alzheon Inc., used data from the Alzheimer's Disease Neuroimaging Initiative Cohort 1 and a tramiprosate trial and included APOE4/4 and APOE3/3 participants with mild cognitive impairment or mild Alzheimer’s disease.

APOE4/4 participants with mild cognitive impairment were approximately 5 years younger, and had significantly smaller hippocampal volumes and worse cognitive scores than APOE3/3 participants at baseline, Alzheon reported in a press release announcing the findings.

Blood Test Shows Promise for Diagnosing Alzheimer’s

Over 2 years, APOE4/4 participants with mild cognitive impairment and mild Alzheimer’s disease, collectively considered early Alzheimer’s disease, had significantly faster hippocampus atrophy and cortical thinning, compared with APOE3/3 participants, the study showed.

In APOE4/4 participants with mild cognitive impairment, but not mild Alzheimer's disease, atrophy rates of hippocampal volume and cortical thinning were significantly linked with cognitive decline. Consequently, researchers plan to use the measures as primary imaging outcomes in an upcoming Phase 3 trial of ALZ-801/tramiprosate, which slowed hippocampal atrophy in Alzheimer’s disease in a previous trial, researchers explained. 

“Correlation of volumetric measures to cognitive change in APOE ε4/ε4 subjects with early Alzheimer’s disease supports their role as efficacy biomarkers,” researchers wrote. “If confirmed in a Phase 3 trial with ALZ‐801 (pro‐drug of tramiprosate) in APOE ε4/ε4 early Alzheimer’s disease subjects, it may allow their use as surrogate outcomes in future treatment or prevention trials in Alzheimer’s disease.”

—Jolynn Tumolo


Abushakra S, Porsteinsson AP, Sabbagh M, et al. APOE ε4/ε4 homozygotes with early Alzheimer's disease show accelerated hippocampal atrophy and cortical thinning that correlates with cognitive decline. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2020;6(1):e12117. 

Alzheon announces new research showing accelerated hippocampus atrophy in APOE4/4 patients with early Alzheimer’s disease [press release]. Framingham, Massachusetts: Alzheon; December 9, 2020.

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