Alzheimer\'s disease (AD) is a progressive neurodegenerative disorder and the predominant form of dementia globally. No reliable diagnostic, predictive techniques, or curative interventions are available. MicroRNAs (miRNAs) are vital to controlling gene expression, making them valuable biomarkers for diagnosis and prognosis. This study examines the transcriptome of olfactory ecto-mesenchymal stem cells (MSCs) derived from individuals with the PSEN1(A431E) mutation (Jalisco mutation). The aim is to determine whether this mutation affects the transcriptome and expression profile of miRNAs and their target genes at different stages of asymptomatic, presymptomatic, and symptomatic conditions. Expression microarrays compare the MSCs from mutation carriers with those from healthy donors. The results indicate a distinct variation in the expression of miRNAs and mRNAs among different symptomatologic groups and between individuals with the mutation. Using bioinformatics tools allows us to identify target genes for miRNAs, which in turn affect various biological processes and pathways. These include the cell cycle, senescence, transcription, and pathways involved in regulating the pluripotency of stem cells. These processes are closely linked to inter- and intracellular communication, vital for cellular functioning. These findings can enhance our comprehension and monitoring of the disease\'s physiological processes, identify new disorder indicators, and develop innovative treatments and diagnostic tools for preventing or treating AD.

Alzheimer\'s disease (AD), the most common neurodegenerative disease and the first cause of dementia worldwide, has no effective treatment, and its pathological mechanisms are not yet fully understood. We conducted this study to explore the proteomic differences associated with Familial Alzheimer\'s Disease (FAD) in olfactory ecto-mesenchymal stem cells (MSCs) derived from PSEN1 (A431E) mutation carriers compared with healthy donors paired by age and gender through two label-free liquid chromatography-mass spectrometry approaches. The first analysis compared carrier 1 (patient with symptoms, P1) and its control (healthy donor, C1), and the second compared carrier 2 (patient with pre-symptoms, P2) with its respective control cells (C2) to evaluate whether the protein alterations presented in the symptomatic carrier were also present in the pre-symptom stages. Finally, we analyzed the differentially expressed proteins (DEPs) for biological and functional enrichment. These proteins showed impaired expression in a stage-dependent manner and are involved in energy metabolism, vesicle transport, actin cytoskeleton, cell proliferation, and proteostasis pathways, in line with previous AD reports. Our study is the first to conduct a proteomic analysis of MSCs from the Jalisco FAD patients in two stages of the disease (symptomatic and presymptomatic), showing these cells as a new and excellent in vitro model for future AD studies.

Alzheimer\'s disease (AD) is the most common cause of dementia, characterized by progressive loss of cognitive function, with β-amyloid plaques and neurofibrillary tangles being its major pathological findings. Although the disease mainly affects the elderly, c. 5-10% of the cases are due to PSEN1, PSEN2, and APP mutations, principally associated with an early onset of the disease. The A413E (rs63750083) PSEN1 variant, identified in 2001, is associated with early-onset Alzheimer\'s disease (EOAD). Although there is scant knowledge about the disease\'s clinical manifestations and particular features, significant clinical heterogeneity was reported, with a high incidence of spastic paraparesis (SP), language impairments, and psychiatric and motor manifestations. This scoping review aims to synthesize findings related to the A431E variant of PSEN1. In the search, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the guidelines proposed by Arksey and O\'Malley. We searched and identified 247 studies including the A431E variant of PSEN1 from 2001 to 2021 in five databases and one search engine. After the removal of duplicates, and apply inclusion criteria, 42 studies were finally included. We considered a narrative synthesis with a qualitative approach for the analysis of the data. Given the study sample conformation, we divided the results into those carried out only with participants carrying A431E (seven studies), subjects with PSEN variants (11 studies), and variants associated with EOAD in PSEN1, PSEN2, and APP (24 studies). The resulting synthesis indicates most studies involve Mexican and Mexican-American participants in preclinical stages. The articles analyzed included carrier characteristics in categories such as genetics, clinical, imaging techniques, neuropsychology, neuropathology, and biomarkers. Some studies also considered family members\' beliefs and caregivers\' experiences. Heterogeneity in both the studies found and carrier samples of EOAD-related gene variants does not allow for the generalization of the findings. Future research should focus on reporting data on the progression of carrier characteristics through time and reporting results independently or comparing them across variants.

Abnormally phosphorylated tau, an indicator of Alzheimer\'s disease, accumulates in the first decades of life in the locus coeruleus (LC), the brain\'s main noradrenaline supply. However, technical challenges in in-vivo assessments have impeded research into the role of the LC in Alzheimer\'s disease. We studied participants with or known to be at-risk for mutations in genes causing autosomal-dominant Alzheimer\'s disease (ADAD) with early onset, providing a unique window into the pathogenesis of Alzheimer\'s largely disentangled from age-related factors. Using high-resolution MRI and tau PET, we found lower rostral LC integrity in symptomatic participants. LC integrity was associated with individual differences in tau burden and memory decline. Post-mortem analyses in a separate set of carriers of the same mutation confirmed substantial neuronal loss in the LC. Our findings link LC degeneration to tau burden and memory in Alzheimer\'s, and highlight a role of the noradrenergic system in this neurodegenerative disease.

Mutations in three genes (APP, PSEN1, and PSEN2) are the main cause of the autosomal dominant early-onset Alzheimer\'s disease (AD-EOAD). In PSEN1, the A431E (c.1292C>A, rs63750083) mutation is suspected to have exerted a founder effect in the State of Jalisco, Mexico. In Guadalajara, Jalisco, Mexico, this mutation was found in 46 index cases evaluated for AD-EOAD. In our genealogical analysis, 301 affected relatives of the mutation carriers were identified, 195 of whom were already deceased at the time of interview. Moreover, 560 descendants had a 50% risk of carrying the mutation, and 348 were potentially at risk. A systematic phenotyping was performed in 39 patients. The mean onset age was 42.5 ± 3.9 years, and no significant difference in onset age was observed between the male and female patients. Furthermore, a substantial clinical heterogeneity and high frequencies of spastic paraparesis, language disorders, and neuropsychiatric symptoms were observed. To our knowledge, the investigated families represent the second biggest population carrying a PSEN1 mutation in Latin America, offering a unique opportunity to study the genetic basis of Alzheimer\'s disease. Addressing AD-EOAD warrants an integral approach involving a deep understanding of its clinical behavior, as well as counseling protocols and prevention studies.

Presenilin 1 gene (PSEN1) mutations are the most common cause of familial Alzheimer\'s disease (FAD). One of the most abundant FAD mutations, PSEN1 A431E, has been reported to be associated with spastic paraparesis in about half of its carriers, but the determining mechanisms of this phenotype are still unknown. In our study we characterized three A431E mutation carriers, one symptomatic and two asymptomatic, from a Mexican family with a history of spastic paraparesis in all of its affected members. At cognitive assessment and MRI, the symptomatic subject showed an atypical non-amnestic mild cognitive impairment with visuospatial deficits, olfactory dysfunction and significant parieto-occipital brain atrophy. Furthermore, we found several periventricular white matter hyperintensities whose progression pattern and localization correlated with their motor impairment, cognitive profile, and non-motor symptoms. Together, our data suggests that in this family the A431E mutation leads to a divergent neurological disorder in which cognitive deterioration was clinically exceeded by motor impairment and that it involves early glial and vascular pathological changes.

We report a 35 year-old male with childhood learning disability and early onset dementia who is homozygous for the A431E variant in the PSEN1 gene. Presenilin1 mutations are associated with autosomal dominant Alzheimer\'s dementia with young and somewhat stereotyped onset. Such variants may cause Alzheimer\'s dementia through aberrant processing of amyloid precursor protein through effects on γ-secretase activity. γ-secretase is involved in the cleavage of many proteins critical to normal function, including brain development. Therefore, manifestations in persons without normal Presenilin1 function is of interest.
Clinical evaluation including family history, examination, brain MRI, and genetic analysis.
Our patient had mild developmental delay, chronic nighttime behavioral disturbance, and onset of progressive cognitive deficits at age 33. Clinical evaluation demonstrated spastic paraparesis and pseudobulbar affect. Brain MRI revealed cerebral atrophy disproportionate to age. Chronic microhemorrhages within bilateral occipital, temporal, and right frontal lobes were seen. Sanger sequencing confirmed homozygosity for the A431E variant in PSEN1, which is a known pathogenic variant causing autosomal dominant Alzheimer\'s dementia.
Our report demonstrates that homozygosity for pathogenic Presenilin1 variants is compatible with life, though may cause a more aggressive phenotype with younger age of onset and possibly REM behavior disorder.