Abstract
Biomarker definitions for preclinical Alzheimer’s disease (AD) have identified individuals with neurodegeneration (ND+) without β-amyloidosis (Aβ-) and labeled them with suspected non-AD pathophysiology (SNAP). We evaluated Apolipoprotein E (APOE) ε2 and ε4 allele frequencies across biomarker definitions—Aβ-/ND- (n = 268), Aβ+/ND- (n = 236), Aβ-/ND+ or SNAP (n = 78), Aβ+/ND+ (n = 204)—hypothesizing that SNAP would have an APOE profile comparable to Aβ-/ND-. Using AD Neuroimaging Initiative data (n = 786, 72±7 years, 48% female), amyloid status (Aβ+ or Aβ-) was defined by cerebrospinal fluid (CSF) Aβ-42 levels, and neurodegeneration status (ND+ or ND-) was defined by hippocampal volume from MRI. Binary logistic regression related biomarker status to APOE ε2 and ε4 allele carrier status, adjusting for age, sex, education, and cognitive diagnosis. Compared to the biomarker negative (Aβ-/ND-) participants, higher proportions of ε4 and lower proportions of ε2 carriers were observed among Aβ+/ND- (ε4: OR = 6.23, p<0.001; ε2: OR = 0.53, p = 0.03) and Aβ+/ND+ participants (ε4: OR = 12.07, p<0.001; ε2: OR = 0.29, p = 0.004). SNAP participants were statistically comparable to biomarker negative participants (p-values>0.30). In supplemental analyses, comparable results were observed when coding SNAP using amyloid imaging and when using CSF tau levels. In contrast to APOE, a polygenic risk score for AD that excluded APOE did not show an association with amyloidosis or neurodegeneration (p-values>0.15), but did show an association with SNAP defined using CSF tau (β = 0.004, p = 0.02). Thus, in a population with low levels of cerebrovascular disease and a lower prevalence of SNAP than the general population, APOE and known genetic drivers of AD do not appear to contribute to the neurodegeneration observed in SNAP. Additional work in population based samples is needed to better elucidate the genetic contributors to various etiological drivers of SNAP.
Highlights
There was an unadjusted difference in the distribution of Apolipoprotein E (APOE) genotypes across biomarker groups (χ2(15) = 179, p
The sample size is reduced due to the fact that FLAIR images were only acquired as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI)-2 protocol, the pattern of results remain largely consistent with the unadjusted reports above, suggesting differences in white-matter hyperintensity burden are not contributing to the observed associations between APOE and biomarker groups
The polygenic risk score (PGRS) for Alzheimer’s disease (AD) was unrelated to amyloidosis or neurodegeneration, but did show an association with suspected non-AD pathophysiology (SNAP) defined using cerebrospinal fluid (CSF) tau (F(3,518) = 2.76, p = 0.04) whereby the Aβ-42-/Tau+ group (p = 0.02) and the combined Aβ-42+/Tau+ group (p = 0.04) had higher PGRS than the biomarker negative group
Summary
Participants were selected from the AD Neuroimaging Initiative (ADNI). ADNI launched in 2003 as a public-private partnership. The original ADNI study enrolled approximately 800 participants, aged 55–90 years, excluding serious neurological disease (other than AD), history of brain lesion or head trauma, and history of psychoactive medication use (for full inclusion/ exclusion criteria see http://www.adni-info.org). These funders had no role in the data analysis, interpretation, or publication. All participants at each site, and analysis of ADNI’s publically available database was approved by our local Institutional Review Board prior to data analysis
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