APOE e4 Allele Presents With Varying Faces in Different Neurodegenerative Diseases

Among patients with neurodegenerative disease, the effect of the apolipoprotein ɛ4 allele (APOE ɛ4) on initial symptoms varies according to the underlying neuropathology. That’s the conclusion of a retrospective analysis of a well-characterized U.S. cohort published by Cleveland Clinic researchers in Alzheimer’s Research & Therapy (Epub 2021 Jan 23).

“Alzheimer’s disease (AD) and Lewy body disease are among the most common causes of dementia, with the former recognized as frequently presenting with progressive symptoms of memory loss and the latter with features of parkinsonism, visual hallucinations and sleep changes,” says lead author Jagan Pillai, MD, PhD, a neurologist with Cleveland Clinic Lou Ruvo Center for Brain Health. “APOE ε4 is a common risk gene for both AD and Lewy body disease, but how and why this risk gene affects the clinical onset of symptoms in these neurodegenerative diseases, both alone and in combination, remains an area of intense research.”

Hypotheses and study design

Dr. Pillai and Cleveland Clinic colleagues undertook their analysis to assess initial cognitive symptoms in various neuropathologies as a “potential window in to the primary cognitive domain likely to be affected,” he explains. They set out with two hypotheses:

• That APOE ε4 carriers are more likely than noncarriers to have initial amnestic symptoms (i.e., episodic memory deficits), regardless of underlying neuropathology
• That APOE ε4 carrier status would not affect the likelihood of having initial nonamnestic symptoms (i.e., visuospatial, language, executive/attention)

To explore these hypotheses, they conducted a cross-sectional study using the National Alzheimer’s Coordinating Center (NACC) dataset. “This includes a highly ascertained cohort across 37 U.S. sites, with neuropathology information available for a large share of participants,” Dr. Pillai explains.

A total of 2,228 patients with neuropathology-confirmed AD pathology (ADP) or Lewy-related pathology (LRP), along with documentation of initial cognitive symptoms, were identified and included in the analysis. All had a Clinical Dementia Rating-Global score of 1 or less, indicating either normal cognitive status, mild cognitive impairment or early dementia.

The researchers used logistic regression analysis adjusting for age at evaluation, sex and education to assess for associations between APOE ε4 genotype and initial symptoms (memory, executive, language or visuospatial) among patients with either ADP, LRP or mixed ADP-LRP.

Key findings

The cohort broke down by neuropathology as follows:

• 1,303 patients with ADP alone
• 90 with LRP alone
• 895 with mixed ADP-LRP

In unadjusted analysis, APOE ε4 carrier status did not significantly affect the likelihood of any initial symptoms in either the ADP group or the LRP group, whereas APOE ε4 carriers were more likely than noncarriers to have initial amnestic symptoms among the mixed ADP-LRP group (odds ratio [OR] = 1.56; 95% CI, 1.11-2.19; P = 0.01).

The adjusted logistic regression model showed that APOE ε4 increased the likelihood of initial amnestic symptoms among the ADP group (OR = 1.58; 95% CI, 1.17-2.14; P = 0.003) and the mixed ADP-LRP group (OR = 2.28; 95% CI, 1.05-4.97; P = 0.036) but not among the LRP group.

The most notable finding in the LRP group was that APOE ε4 significantly raised the likelihood of initial visuospatial symptoms in unadjusted analysis (OR = 21.96; 95% CI, 4.02-110.62; P < 0.0001), but the small number of LRP subjects (n = 90) and LRP subjects with visuospatial symptoms (n = 9) limited the utility of adjusted analysis.

Findings in context, and implications for the future

“This study demonstrated that, rather than the APOE ε4 gene increasing the likelihood of initial memory symptoms in both of these neurodegenerative diseases, it did so in Alzheimer’s but not in Lewy body disease,” observes Dr. Pillai. “The APOE ε4 gene did, however, increase the likelihood of visuospatial symptoms in Lewy body disease.”

Another notable finding, he adds, is that initial language symptoms in subjects with AD were more likely among those with a younger age at disease onset, women and those with higher education.

The researchers write that their overall findings point to a need for future studies to search for any underlying biologic interactions between the APOE ε4 gene and neuropathology that may impact specific neural subnetworks.

“The APOE ε4 risk gene has distinctive effects on specific brain regions relating to each of the cognitive symptoms studied, and these findings help us better understand how these effects vary depending on the underlying neuropathology,” Dr. Pillai notes. “This indicates that patients with different initial clinical presentations — in terms of symptoms involving memory, visuospatial effects, language and judgment — likely have different underlying genetic predispositions. This knowledge will be helpful in developing future targeted therapies against these specific symptoms.”