scholarly journals Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

2013 ◽  
Vol 19 (6) ◽  
pp. 676-681 ◽  
Author(s):  
B V Hooli ◽  
Z M Kovacs-Vajna ◽  
K Mullin ◽  
M A Blumenthal ◽  
M Mattheisen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Copy Number ◽  
Copy Number Variations ◽  
Familial Alzheimer’S Disease ◽  
Autosomal Copy ◽  
Familial Alzheimer's Disease

Nongenetic Factors as Modifiers of the Age of Onset of Familial Alzheimer's Disease

2003 ◽  
Vol 15 (4) ◽  
pp. 337-349 ◽  
Author(s):  
Silvia Mejía ◽  
Margarita Giraldo ◽  
David Pineda ◽  
Alfredo Ardila ◽  
Francisco Lopera
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Logistic Regression ◽  
Early Onset ◽  
Age Of Onset ◽  
Univariate Analysis ◽  
Personal Factors ◽  
Familial Alzheimer’S Disease ◽  
Familial Alzheimer's Disease ◽  
High Level

Objective: The purpose of this research was to identify environmental and personal factors that could be related to the variability in the age of onset of familial Alzheimer's disease (FAD) (36–62 years). Methods: A sample was taken of 49 subjects with FAD and with the mutation E280A in the presenilin-1 gene on chromosome 14; the sample was divided into two subgroups: 27 individuals with age of onset of the disease between 36 and 46 years (early onset) and 22 individuals whose disease began between 47 and 62 years (late onset). Information on environmental and personal factors was collected by means of a questionnaire answered by the patients if their clinical condition allowed it, or by their relatives; such information was organized in a categorical way. Comparisons between the two groups for each categorical variable were done by means of the chi-square test. Noncollinear variables that showed statistical significance were included as independent variables in a logistic regression analysis to predict their association with early onset of the disease. Results: Only 5 of the 140 studied variables were different between the two groups in univariate analysis: education, surgical history, type of stressful event, depression, and affective losses. The logistic regression model was constituted by education, depression, and affective losses. High-level education had approximately 15 times more probability of association with an early onset of the disease; both the history of affective losses and depressive symptoms had 4 times more probability of a similar association. Conclusions: The association of high-level education and early onset of the disease could be related to an earlier detection of symptoms, in turn determined by greater intellectual and environmental demands. The occurrence of depression and affective losses has been considered a prodromic manifestation of the disease. Our findings are evidence of high clinical heterogeneity even in a genetically homogeneous group.

scholarly journals Brain Expression of Presenilins in Sporadic and Early-onset, Familial Alzheimer’s Disease

2000 ◽  
Vol 6 (10) ◽  
pp. 878-891 ◽  
Author(s):  
Paul M. Mathews ◽  
Anne M. Cataldo ◽  
Benjamin H. Kao ◽  
Anna G. Rudnicki ◽  
Xi Qin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Familial Alzheimer’S Disease ◽  
Brain Expression ◽  
Familial Alzheimer's Disease

P4-099: Early-onset familial Alzheimer's disease and the definition of family: Experience with an indigenous community

2012 ◽  
Vol 8 (4S_Part_18) ◽  
pp. P667-P667
Author(s):  
Jennifer Mackie ◽  
Elana Brief ◽  
Rachel Butler ◽  
Emily Dwosh ◽  
B. Lynn Beattie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Indigenous Community ◽  
Familial Alzheimer’S Disease ◽  
Family Experience ◽  
Familial Alzheimer's Disease ◽  
Definition Of

scholarly journals Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer’s disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Lutgarde Serneels ◽  
Dries T’Syen ◽  
Laura Perez-Benito ◽  
Tom Theys ◽  
Matthew G. Holt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acid ◽  
Early Onset ◽  
Insertion Site ◽  
Computational Modelling ◽  
Rodent Models ◽  
Familial Alzheimer’S Disease ◽  
App Processing ◽  
Familial Alzheimer's Disease

Abstract Background Three amino acid differences between rodent and human APP affect medically important features, including β-secretase cleavage of APP and Aβ peptide aggregation (De Strooper et al., EMBO J 14:4932-38, 1995; Ueno et al., Biochemistry 53:7523-30, 2014; Bush, 2003, Trends Neurosci 26:207–14). Most rodent models for Alzheimer’s disease (AD) are, therefore, based on the human APP sequence, expressed from artificial mini-genes randomly inserted in the rodent genome. While these models mimic rather well various biochemical aspects of the disease, such as Aβ-aggregation, they are also prone to overexpression artifacts and to complex phenotypical alterations, due to genes affected in or close to the insertion site(s) of the mini-genes (Sasaguri et al., EMBO J 36:2473-87, 2017; Goodwin et al., Genome Res 29:494-505, 2019). Knock-in strategies which introduce clinical mutants in a humanized endogenous rodent APP sequence (Saito et al., Nat Neurosci 17:661-3, 2014) represent useful improvements, but need to be compared with appropriate humanized wildtype (WT) mice. Methods Computational modelling of the human β-CTF bound to BACE1 was used to study the differential processing of rodent and human APP. We humanized the three pivotal residues we identified G676R, F681Y and R684H (labeled according to the human APP770 isoform) in the mouse and rat genomes using a CRISPR-Cas9 approach. These new models, termed mouse and rat Apphu/hu, express APP from the endogenous promotor. We also introduced the early-onset familial Alzheimer’s disease (FAD) mutation M139T into the endogenous Rat Psen1 gene. Results We show that introducing these three amino acid substitutions into the rodent sequence lowers the affinity of the APP substrate for BACE1 cleavage. The effect on β-secretase processing was confirmed as both humanized rodent models produce three times more (human) Aβ compared to the original WT strain. These models represent suitable controls, or starting points, for studying the effect of transgenes or knock-in mutations on APP processing (Saito et al., Nat Neurosci 17:661-3, 2014). We introduced the early-onset familial Alzheimer’s disease (FAD) mutation M139T into the endogenous Rat Psen1 gene and provide an initial characterization of Aβ processing in this novel rat AD model. Conclusion The different humanized APP models (rat and mouse) expressing human Aβ and PSEN1 M139T are valuable controls to study APP processing in vivo allowing the use of a human Aβ ELISA which is more sensitive than the equivalent system for rodents. These animals will be made available to the research community.

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