AUTHOR=Liang Zhihou , Wu Yan , Li Chuanzhou , Liu Zhijun 

TITLE=Clinical and genetic characteristics in a central-southern Chinese cohort of early-onset Alzheimer's disease

JOURNAL=Frontiers in Neurology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1119326

DOI=10.3389/fneur.2023.1119326

ISSN=1664-2295

ABSTRACT=<sec><title>Background</title><p>Mutations in the presenilin-1 (<italic>PSEN1</italic>), presenilin-2 (<italic>PSEN2</italic>), and amyloid precursor protein (<italic>APP</italic>) genes have been commonly identified in early-onset Alzheimer's disease (EOAD). Some of the mutations in the three causative genes, especially the <italic>PSEN1</italic> gene, result in variable phenotypes and exhibit clinical heterogeneity among EOAD families.</p></sec><sec><title>Methods</title><p>Using next-generation sequencing (NGS), we performed genetic screening in a Chinese cohort of 18 patients with EOAD, consisting of five familial EOAD and 13 sporadic cases.</p></sec><sec><title>Results</title><p>We identified two likely pathogenic <italic>PSEN1</italic> mutations (one novel) and a novel <italic>APP</italic> mutation in three cases of EOAD, where two are familial and one is sporadic, respectively. In addition, we detected a few variants of uncertain significance (VUS) in several genes, including not only the two known variants in <italic>PSEN2</italic> (p.H169N and p.V214L) but also genes causal of other types of dementia or previously identified as risk factors for AD, suggesting the possible involvement of multiple genes in the etiopathology of AD. The patients carrying <italic>PSEN1</italic> mutations had an earlier mean age at the onset than those with <italic>PSEN2</italic> or <italic>APP</italic> variants. The initial symptoms varied greatly among patients in the EOAD cohort, from progressive memory impairment and epilepsy to uncommon motor symptoms such as involuntary tremors in the upper extremities.</p></sec><sec><title>Conclusions</title><p>In conclusion, our study provides further evidence of the genetic profile of patients with EOAD from China and expands the mutation spectrum of both <italic>PSEN1</italic> and <italic>APP</italic>. In addition, our results highlight the clinical heterogeneity in patients with EOAD and mutations in <italic>PSEN1, PSEN2</italic>, and <italic>APP</italic> and suggest strong effects of genetic variants on clinical phenotypes. Future functional studies are needed to clarify the interaction between AD-causative gene mutations and phenotypic heterogeneity.</p></sec>