CRISPR–Cas9–Mediated Genetic Correction for Alzheimer's Disease A Hypothetical Therapeutic Framework

Abstract Introduction:Alzheimer's Disease (AD) is an irreversible, progressive illness of neurodegeneration and the primary cause of dementia, responsible for an estimated 60–80% of cases of neurologic dementia. The pathologic hallmarks—extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs)—were first described by Alois Alzheimer in 1906, but a mysterious disease-modifying therapy has yet to be created. Existing neuropharmacological strategies, effectively acetylcholinesterase inhibitors and the NMDA receptor antagonist memantine, offer only symptomatic and temporary relief. The repeated inability of Aβ therapies to pass clinical tests in sporadic AD points to the complexity of the disease and indicates that earlier or more interventions could be necessary. CRISPR/Cas9 technology is revolutionary and permits the prospect of correction of the AD's genetic and molecular underpinnings rather than only symptom management. This gene-targeting approach offers a promise for disease-modifying, targeted treatment unmatched until now. Method:The CRISPR/Cas9 system is a precise and programmable gene-editing system modeled after the bacterial immune response system. It consists of a combination of one guide RNA (sgRNA) that locates the target gene sequence and the Cas9 endonuclease that actually cleaves the DNA. When the sgRNA binds to its complementary DNA sequence in genes such as APP, PSEN1, or PSEN2, Cas9 makes a double-strand cut at the target site. The cell's natural DNA repair machinery then goes to work to repair the break—either by non-homologous end joining (NHEJ), which kills the gene and silences it, or homology-directed repair (HDR), which uses a donor DNA template to precisely repair or replace the mutated sequence. In AD research, this mechanism makes it possible to selectively silence β-amyloid–producing genes like BACE1 or correct deleterious alleles like APOE4 to the healthy APOE3 allele. Introduction of the Cas9-sgRNA complex to neuronal cells is possible through viral vectors like adeno-associated virus (AAV) or non-viral systems like lipid nanoparticles or ribonucleoprotein complexes. This method provides a specific and efficient molecular basis for designing gene-targeting therapeutics for AD. Results:CRISPR/Cas9 gene editing in genes associated with AD, APP, PSEN1, BACE1, and APOE4 was very effective in mitigating β-amyloid deposition, decreasing tau hyperphosphorylation, and improving neuronal function in vivo and in vitro. Efficient delivery through viral and non-viral vectors demonstrated precise gene modification with low off-targeting, with high specificity reported in neuronal cells. Studies on functional outcomes in animal models of AD showed improved learning and memory performance, which was associated with reduced amyloid plaque burden and neuroinflammation. These findings demonstrate not only that CRISPR/Cas9 affects core pathogenic pathways but also that it is translatable to measurable cognitive enhancement, an indication of potential as a disease-modifying therapy. Conclusion:CRISPR/Cas9 presents a specific and potent approach to correcting the genetic and molecular etiology of AD. CRISPR/Cas9 holds potential as a disease-modifying therapy due to its ability to reduce amyloid, recover neuronal function, and improve cognitive outcomes. It represents a leap over symptomatic treatment towards targeted, gene-directed therapy, holding promise for personalized therapy in AD patients and potential for clinical translation with appropriate safety assessment.