RT Journal Article
SR Electronic
T1 Late-onset vs nonmendelian early-onset Alzheimer disease
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e512
DO 10.1212/NXG.0000000000000512
VO 6
IS 5
A1 Reitz, Christiane
A1 Rogaeva, Ekaterina
A1 Beecham, Gary W.
YR 2020
UL http://ng.neurology.org/content/6/5/e512.abstract
AB There is mounting evidence that only a small fraction of early-onset Alzheimer disease cases (onset <65 years) are explained by known mutations. Even multiplex families with early onset often also have late-onset cases, suggesting that the commonly applied categorization of Alzheimer disease into early- and late-onset forms may not reflect distinct underlying etiology. Nevertheless, this categorization continues to govern today's research and the design of clinical trials. The aim of this review is to evaluate this categorization by providing a comprehensive, critical review of reported clinical, neuropathologic, and genomic characteristics of both onset-based subtypes and explore potential overlap between both categories. The article will lay out the need to comprehensively assess the phenotypic, neuropathologic, and molecular variability in Alzheimer disease and identify factors explaining the observed significant variation in onset age in persons with and without known mutations. The article will critically review ongoing large-scale genomic efforts in Alzheimer disease research (e.g., Alzheimer Disease Sequencing Project, Dominantly Inherited Alzheimer Network, Alzheimer Disease Neuroimaging Initiative) and their shortcomings to disentangle the delineation of unexplained nonmendelian early-onset from late-onset and mendelian forms of Alzheimer disease. In addition, it will outline specific approaches including epigenetic research through which a comprehensive characterization of this delineation can be achieved.αSyn=α-synuclein; AD=Alzheimer disease; ADGC=Alzheimer Disease Genetics Consortium; ADNI=Alzheimer Disease Neuroimaging Initiative; CNV=copy number variation; CpG=cytosine-phosphate-guanine; DIAN-OBS=Dominantly Inherited Alzheimer Network observational study; DNAm=DNA methylation; EOAD=early-onset AD; FTD=frontotemporal dementia; GWAS=genome-wide association study; LOAD=late-onset AD; mEOAD=mendelian EOAD; NFL=neurofilament light chain; NFT=neurofibrillary tangle; nmEOD=nonmendelian EOAD; NPC=Neuropathology Core; PiB=Pittsburgh compound B; READR=Resource for Early-onset Alzheimer Disease Research