Title:Molecular Genetics of Early- and Late-Onset Alzheimer’s Disease
VOLUME: 21 ISSUE: 1
Author(s):Md. Sahab Uddin*, Sharifa Hasana, Md. Farhad Hossain, Md. Siddiqul Islam, Tapan Behl, Asma Perveen, Abdul Hafeez and Ghulam Md Ashraf*
Affiliation:Department of Pharmacy, Southeast University, Dhaka, Department of Pharmacy, Southeast University, Dhaka, Pharmakon Neuroscience Research Network, Dhaka, Department of Pharmacy, Southeast University, Dhaka, Chitkara College of Pharmacy, Chitkara University, Chandigarh, Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Glocal School of Life Sciences, Glocal University, Saharanpur, Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah
Keywords:Alzheimer's disease, APP, PSEN1, PSEN2, APOE4, TYROBP.
Abstract: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 factors. 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 gene variants such as APP, PSEN1, and PSEN2
leading to the disease. 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
5-10% 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 the 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 by using the technology of next-generation sequencing in EOAD families,
including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants are identified
through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis
of EOAD. The existence of the ε4 allele is responsible for increasing the severity of
EOAD. However, several ε4 allele carriers 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 genetic facets which will assist in understanding
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 that might elucidate the genetic etiology of AD and highlight
the role of massively parallel sequencing technologies for novel gene discoveries.
