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Alzheimer’s disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic components. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood with three genes variants such as
APP, PSEN1, and PSEN2 leading to disease. On the other hand, some common alleles including APOE are effectively associated with LOAD identified but the genetics of LOAD is not clear to date. It has been accounted that about 5% to 10% of
EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented
the severity of EOAD risk in carriers, and APOE ε4 allele was considered as a hallmark of EOAD. A great number of
EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease- triggering genes yet.
Although several genes have been identified through using the technology of next-generation sequencing in EOAD families
including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants were identified through exome sequencing in
EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers live into their 90s that propose the presence of
other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics
of EOAD and LOAD etiology to discover new potential genetics facets which will assist to understand the pathological
mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article based on current knowledge represents the overview of the susceptible genes of EOAD,
and LOAD. Next, we represent the probable molecular mechanism which might elucidate the genetic etiology of AD and
highlight the role of massively parallel sequencing technologies for novel gene discoveries.
Molecular Aspects of Cellular Dysfunction in Alzheimer’s Disease: The Need for a Holistic View of the Early Pathogenesis
