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Advanced Neurology Genomic insights into Alzheimer

in understanding this neurodegenerative disorder, of the γ-secretase enzyme. Mutations in these genes can
numerous aspects of its pathogenesis remain elusive. AD lead to abnormal cleavage of the APP gene, resulting in
is characterized by the aggregation of misfolded proteins, excessive Aβ peptide deposition [8,9] . Understanding the
precipitating the degeneration of specific brain regions and diverse clinical effects of pathogenic mutations on the APP
culminating in dementia . This pathological hallmark gene can also inform our understanding of other genetic
[3]
has been pivotal in advancing our molecular and genetic mutation subtypes, including those on PSEN1 and PSEN2
comprehension of the disease . genes, such as Glu126fs and Lys306fs , which share
[4]
[11]
Genetics play a substantial role in AD, contributing similar mechanisms.
to an estimated 70% of the disease’s risk . This impact of Furthermore, comprehension of these mutations and
[1]
genetics highlights the critical importance of elucidating their effects indirectly contributes to our understanding
the genetic mutations and underlying molecular of sporadic AD, augmenting our insights into the broader
mechanisms that govern the recognition and prognosis of landscape of AD, regardless of subtype . The identification
[8]
AD [1,3] . However, it is worth noting that, when considering of Aβ depositions, amyloid plaques, and neurofibrillary
causality, approximately 90% of AD cases remain tangles in most fAD cases has significantly advanced our
sporadic. Nevertheless, a comprehensive understanding understanding of the amyloid cascade and shed light on
of the genetics and molecular mechanisms across all AD other potential pathogenic mechanisms.
subtypes is essential for the development, testing, and
utilization of novel treatments designed to target these The previous research has indicated that specific
[5]
specific mutations or causal pathways . mutations may influence clinical features, as observed
in comparisons between patients with PSEN1 mutations
AD manifests in two primary forms: late-onset and (often presenting with seizures, spastic paraparesis,
early-onset AD (EOAD). The more common late-onset myoclonus, and cerebellar signs), patients with APP
AD is often sporadic but may have an increased risk mutations (frequently displaying aggression), and patients
associated with the ApoE4 genotype . Conversely, EOAD, with PSEN2 mutations (typically experiencing a longer
[6]
constituting <10% of cases, includes familial AD (fAD) disease duration and more frequent disorientation) .
[12]
cases, of which 5 – 10% are attributed to genetic mutations
in three key genes: Presenilin-1 (PSEN1), amyloid precursor The influence of mutations extends to varying
protein (APP), and rarely Presenilin-2 (PSEN2) [6,7] . While pathogenic mutations within the same gene, a
autosomal dominant mutations in the PSEN1, PSEN2, phenomenon particularly observed when examining
and APP genes account for a relatively small proportion mutations in different regions of the APP, PSEN1, and
of AD cases, gaining insights into the mechanisms PSEN2 genes. Autosomal mutations in the APP gene
behind fAD and its causative mutations is instrumental in associated with fAD have been observed across multiple
[13]
understanding other forms of EOAD and even the more ethnic populations , each manifesting unique clinical
[14]
prevalent sporadic late-onset AD. The accumulation of features and characteristics .
Aβ peptide deposits in the brain is a recognized hallmark For example, mutations occurring at the APP residue
in both sporadic AD (sAD) and fAD . This concept, V717, such as the London mutation (V717I), V717G, and
[8]
known as the amyloid cascade hypothesis, postulates that V717L, present similar phenotypes with clinical symptoms
Aβ deposition leads to neuronal cell death, often through including dyscalculia, myoclonus, and seizures . In
[15]
Tau protein aggregation, though the precise mechanisms contrast, mutations occurring at different residue locations
remain elusive . lead to heterogeneous phenotypes, exemplified by the
[5]
The APP gene encodes the Aβ peptide, a crucial Flemish subtype (A692G) compared to variants at residue
substrate following enzymatic cleavage by β-secretase V717. Unlike the V717 variants, the A692G variant does
and γ-secretase enzymes . While α secretase enzyme not induce seizures and myoclonus but instead results in
[9]
typically facilitates normal Aβ cleavage, the inclusion of cerebrovascular events, a feature less frequently observed
β- and γ-secretase can result in pathological Aβ peptide in patients with other mutation subtypes [15,16] .
deposition in the brain [9,10] . Certain mutations in the Moreover, even variants occurring at the same residue
APP gene can disrupt this cleavage pathway, resulting in can manifest diverse phenotypes, as evidenced by the
pathological outcomes. Notably, not all APP mutations are comparison of the Arctic mutation (E693G) with the
pathogenic, as some appear to confer a protective effect by Dutch mutation (E693Q). While both mutations result in
reducing Aβ42/Aβ40 ratios . amyloid angiopathy, the Dutch mutation is characterized
[10]
Similarly, the PSEN1 and PSEN2 genes exert influence on by recurrent cerebrovascular events, whereas patients with
the amyloid cascade through their impact on the function the Arctic mutation exhibit a purely cognitive phenotype .
[16]

Volume 2 Issue 4 (2023) 2 https://doi.org/10.36922/an.1734