Abstract
ApoE4, the strongest genetic risk factor for Alzheimer’s disease (AD), has been shown to be associated with both beta-amyloid (Aβ) and tau pathology, with the strongest evidence for effects on Aβ, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aβ42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aβ42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aβ42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aβ 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aβ42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-β burden and tau aggregation at specific time points in AD pathogenesis.
Highlights
Alzheimer’s disease (AD), the most frequent neurodegenerative disease, is characterized by an accumulation of extracellular beta-amyloid (Aβ) plaques and intracellular tau tangles in the brain
We analyzed in detail the impact of apolipoprotein E4 (ApoE4) allele frequency on Cerebrospinal fluid (CSF) concentrations of AD core biomarkers (Aβ 42, t-tau and p-tau) cross-sectionally and on progression of decline in a cohort of mild cognitive impairment (MCI) subjects from the Dementia Competence Network, stratified into 3 groups: MCI-stable individuals, MCI-AD progressors and MCI subjects progressing to other forms of dementia
Our results confirm a clear impact of ApoE4 on all CSF AD core biomarkers: (1) In our total sample, ApoE4 carriers had lower concentration of CSF Aβ42, and increased concentration of t-tau and p-tau than non-carriers in a gene-dose-dependent manner
Summary
Alzheimer’s disease (AD), the most frequent neurodegenerative disease, is characterized by an accumulation of extracellular beta-amyloid (Aβ) plaques and intracellular tau tangles in the brain. Extended author information available on the last page of the article with both genetic and environmental risk factors (Scheltens et al 2021). According to epidemiological and genomewide association studies, apolipoprotein E4 (ApoE4) is the greatest single genetic risk factor for late-onset AD sporadic (Corder et al 1993; de Rojas et al 2021). Three common polymorphisms in the ApoE gene, ɛ2, ɛ3, and ɛ4, result in a single amino acid change in the ApoE protein. ApoE ɛ2, ɛ3, and ɛ4 alleles strongly alter, in a dose-dependent manner, the likelihood of manifesting Alzheimer's disease and cerebral amyloid angiopathy (Verghese et al 2011). Heterozygous ApoE4 carriers have an approximately fourfold increase of risk compared with the most prevalent homozygous carriers of the ε3 allele, whereas in homozygous ApoE4 carriers, the increase of risk is approximately 12-fold (Holtzman et al 2012)
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