Profiles of β-Amyloid Peptides and Key Secretases in Brain Autopsy Samples Differ with Sex and APOE ε4 Status: Impact for Risk and Progression of Alzheimer Disease

Abstract

The APOE ε4 allele was originally reported to contribute to risk of Alzheimer's disease (AD) in women, yet male and female AD patient-derived data are routinely pooled. Histopathological hallmarks of AD include neurofibrillary tangles centered on hyperphosphorylated Tau and plaques composed of the β-amyloid (Aβ) peptide that is derived by sequential secretase-mediated cleavage of the Amyloid Protein Precursor (APP). We chose to examine profiles of Aβ(1-40), Aβ(1-42), and N-truncated (i.e., p3-related) fragments in the plaque-associated fraction of autopsied cortical and corresponding hippocampal samples from donors with a diagnosis of early-onset (EOAD) and late-onset (LOAD) AD. Levels of Aβ(1-40), Aβ(1-42), and the p3 fragment-enriched pool were increased in EOAD and LOAD samples, and correlated well within -but not between- regions. Counterintuitively, these increases were similar regardless of the AD donor's APOE ε4 status. Focusing on the donor's sex and APOE ε4 status as nominal variables (i.e., omitting diagnosis from the stratification) revealed that increases in Aβ peptides were specific to female carriers of the ε4 allele and correlated with the proportional expression of BACE1/β-secretase and ADAM10/α-secretase in the cortex and with nicastrin (γ-secretase) expression in the hippocampus. These data preliminarily support the possibility that AD follows distinct amyloidogenic processes in males and females, and that the APOE ε4 allele exerts a major influence on the disease process, particularly in women. This knowledge could significantly impact the (re)interpretation of unsuccessful outcomes of clinical interventions targeting either Aβ peptides directly or the secretases implicated in APP processing.

Alzheimer Disease and Selected Risk Factors Disrupt a Co-regulation of Monoamine Oxidase-A/B in the Hippocampus, but Not in the Cortex

“…We recently reported on the frequency of ε4 carriers across cases in our sample set, which includes ε3/ε3 and ε4/ε4 homozygotes as well as ε2/ε3, ε2/ε4, and ε3/ε4 heterozygotes ( Nyarko et al, 2018 ). A limitation of our sample set is that it does not allow for stratification based on individual APOE allele heterozygosity and homozygosity.…”

“…Our recent report suggested that APOE ε4 might be exerting effects independently of any diagnosis of AD ( Nyarko et al, 2018 ). Based on that observation, we re-evaluated our data based strictly on the donor’s APOE ε4 status (i.e., excluding ‘diagnosis’ as a variable in our analyses).…”

“…The outcomes discussed in the previous section, based on comparing sample means, generally confirmed what has been reported in the literature. We have recently reported that variability in regional Aβ levels in carriers of the APOE ε4 allele correlated with the variability in the expression of catalytic enzymes implicated in the generation of the Aβ peptide ( Nyarko et al, 2018 ). We re-examined our data so as to determine whether any of the parallel increases observed in MAO-A and MAO-B parameters quantified up to this point might be indicating a more subtle relation and, if so, whether any potential correlation was influenced by risk factors or AD itself.…”

“…The APOE2, APOE3, and APOE4 variants differ by arginine (Arg) and/or cysteine (Cys) substitutions, i.e., Cys/Cys (E2), Cys/Arg (E3), and Arg/Arg (E4), at positions 112 and 158, respectively. APOE restriction isotyping for the two single nucleotide polymorphisms encoding for these substitutions was done as described fully elsewhere ( Nyarko et al, 2018 ). Briefly, PCR amplification was performed on 500 ng of genomic DNA and the resulting 226 bp amplicon was restricted with Afl III and Hae II.…”

APOE ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia

“…Given the strong biological rationale, limited sample size, and a significant interaction observed for the language domain, this was a valid approach, which has also been used by other groups. 34,35 However, studies in larger sample sizes are warranted.…”