Nine families with autosomal dominant Alzheimer's disease (AD), all of whom had the Ala431Glu substitution in the PSEN1 gene and came from Jalisco State in Mexico, have been previously reported. As they shared highly polymorphic flanking dinucleotide marker alleles, this strongly suggests that this mutation arose from a common founder. In the current letter, we expand this observation by describing an additional 15 independent families with the Ala431Glu substitution in the PSEN1 gene and conclude that this mutation is not an uncommon cause of early-onset autosomal dominant AD in persons of Mexican origin.

Rare autosomal dominant mutations result in familial Alzheimer's disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late-onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation-carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD-relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes.

Background

Spanish-language screening tests that are sensitive to the early cognitive changes of Alzheimer's disease (AD) are needed. Persons known to be at 50% risk for young-onset AD due to presenilin-1 (PSEN1) mutations provide the opportunity to assess which measures on the Mini-mental State Examination (MMSE) are most sensitive to these early changes.

Methods

We performed genetic and Spanish-language cognitive testing on 50 Mexican persons without dementia at risk for inheriting PSEN1 mutations. We then compared the performance on sub-items of the MMSE between PSEN1 mutation carriers (MCs) and non-carriers (NCs) using t-tests and Fisher's exact tests. Exploratory multiple logistic regression analyses were also performed.

Results

Twenty-nine persons were MCs and 21 NCs. NCs tended to achieve higher levels of education (p = 0.039) than did MCs. MCs tended to perform more poorly when spelling "MUNDO" backwards and on Orientation, particularly regarding the date. In multiple regression analyses the ability of backwards spelling to predict PSEN1 mutation status was reduced when education was included as an independent variable.

Conclusion

Subjects in the earliest stage of PSEN1-related AD showed deficits on orientation to date and in divided attention when spelling backwards. It is unclear if educational level should be considered an associated feature or a con-founding variable in this population although it should be taken into account when considering performance on the MMSE task of divided attention. The relative lack of deficits on delayed recall of three words probably represents the insensitivity of this measure in early AD. This study supports the utility of autosomal dominant AD as a model of the more common sporadic form of the disorder.