Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer’s Disease

Abstract

Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer’s disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes.

Alzheimer's Disease Investigated via Gene-Environment Interactions, Biochemical Pathways, Cellular Processes, and Disease Phenotype Variability

“…Diets high in saturated fats and cholesterol exacerbate amyloid-beta (Aβ) peptide production and accumulation, worsening Alzheimer's disease development and progression, particularly in individuals with PSEN1 mutations. The typical Western diet, characterized by high intake of red meat, processed foods, and sugary snacks, is associated with increased Alzheimer's disease risk, promoting in ammation and oxidative stress, which can exacerbate neurodegeneration in those with PSEN1 mutations [41,55,56].…”

“…Variability in brain structure and function, as well as differences in the distribution and severity of Alzheimer's pathology, may contribute to differences in age of onset, symptom severity, and disease progression among individuals carrying similar mutations in the PSEN1 gene. Differences in the extent of Aβ deposition, tau pathology, neuroin ammation, synaptic dysfunction, and neurodegeneration may in uence disease phenotype [41,56].…”

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

“…In addition, the involvement of PSEN1 in multiple pathways regulating calcium homeostasis, Notch signaling, or beta-catenin stability, among others, causes PSEN1 mutations to impact other neurodegenerative but also non-neurodegenerative diseases [142,146], a fact that severely interfere with the design and development of new therapeutic avenues for AD based on PSEN1 level changes. As an example, in recent clinical trials for autosomal dominant AD, human carriers of PSEN1 mutations have been longitudinally assessed for Aβ42 and p-tau in CSF but not for APP or PSEN1/2 levels, together with clinical symptoms and imaging analysis as endpoints for drug efficacy evaluation [147].…”

Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets

“…Late-onset AD (LOAD) is a multifactorial syndrome that typically begins after age 65. PSEN1 mutations have also been discovered in some atypical AD variants as well as in FTD, DLB, and PD [35]. While a number of risk genes are linked to LOAD (i.e., APOE4e4), age and a long list of other risk factors (e.g., gender, socioeconomic and educational status, diabetes) are associated with it [33].…”