The A431E mutation in PSEN1 causing Familial Alzheimer’s Disease originating in Jalisco State, Mexico: an additional fifteen families

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Background/Aims: Biological markers of utility in tracking Alzheimer’s disease (AD) during the presymptomatic prodromal phase are important for prevention studies. Changes in cerebrospinal fluid (CSF) levels of 42-amino-acid β-amyloid (Aβ₄₂), total tau protein (t-tau) and phosphorylated tau at residue 181 (p-tau₁₈₁) during this state are incompletely characterized. Methods: We measured CSF markers in 13 carriers of familial AD (FAD) mutations that are fully penetrant for causing AD (PSEN1 and APP) and in 5 non-mutation-carrying family members. Results: Even among the entirely presymptomatic mutation carriers (n = 9), Aβ₄₂ was diminished (388.7 vs. 618.4 pg/ml, p = 0.004), and t-tau (138.5 vs. 50.5 pg/ml, p = 0.002) and p-tau₁₈₁ (71.7 vs. 24.6 pg/ml, p = 0.003) were elevated. There was a negative correlation between Aβ₄₂ levels and age relative to the family-specific age of dementia diagnosis. Conclusions: Our data are consistent with a decline in CSF Aβ₄₂ levels occurring at least 20 years prior to clinical dementia in FAD.

Section: Methodsmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers and Proximity to Diagnosis in Preclinical Familial Alzheimer’s Disease

Ringman

Coppola

Elashoff

et al. 2012

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“…There were 33 nondemented and 3 demented subjects from 10 families with PSEN1 mutations and 2 families with V717I APP mutation. The 10 PSEN1 families included 1 with L235V [12], 1 with G206A [13], and 7 with A431E substitution (founder effect originating in Jalisco State in Mexico [14,15]). Subjects who tested positive for the mutation will be referred to as carriers and subjects who tested negative for the mutation will be referred to as controls.…”

Section: Methodsmentioning

confidence: 99%

“…As the age of onset is relatively consistent within any given family [15], relative age was defined as the difference between the median age of dementia diagnosis for the family and each subject’s age. Relative age ranged from –35 to +2 years (i.e., from 35 years prior to 2 years after the median age of dementia diagnosis for the respective family).…”

Section: Methodsmentioning

confidence: 99%

Cortical and Hippocampal Atrophy in Patients with Autosomal Dominant Familial Alzheimer’s Disease

Apostolova

Hwang

Medina

et al. 2011

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Background: Both familial and sporadic Alzheimer’s disease (AD) result in progressive cortical and subcortical atrophy. Familial autosomal dominant AD (FAD) allows us to study AD brain changes presymptomatically. Methods: 33 subjects at risk for FAD (25 for PSEN1 and 8 for APP mutations; 22 mutation carriers and 11 controls) and 3 demented PSEN1 mutation carriers underwent T₁-weighted MPRAGE 1.5T MRI. Using the hippocampal radial distance and cortical pattern matching techniques, we investigated the effects of carrier status and dementia diagnosis on cortical and hippocampal atrophy. All analyses were corrected for age and relative age (years to median age of disease onset in the family). Results: The dementia cases had pronounced cortical atrophy in the lateral and medial parietal, posterior cingulate and frontal cortices and hippocampal atrophy bilaterally relative to both nondemented carriers and controls. Nondemented carriers did not show significant cortical thinning or hippocampal atrophy relative to controls. Conclusions: FAD is associated with thinning of the posterior association and frontal cortices and hippocampal atrophy. Larger sample sizes may be necessary to reliably identify cortical atrophy in presymptomatic carriers.

“…Seven families were known to harbor the A431E substitution [14] , and one each the L235V [15] and G206A [16] substitutions in the PSEN1 gene. Two families had the V717I substitution in the APP gene [17] .…”

Section: Study Subjectsmentioning

confidence: 99%

Increased Prevalence of Significant Recurrent Headache in Preclinical Familial Alzheimer’s Disease Mutation Carriers

Ringman

Romano

Medina

et al. 2008

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Background/Aims: A previous study found a high prevalence of headaches in persons with familial Alzheimer’s disease (FAD) due to a PSEN1 mutation. In our study we compared the prevalence of headaches between nondemented FAD mutation carriers (MCs) and non-mutation-carrying controls (NCs). Methods: A headache questionnaire that assessed the prevalence of significant headaches and diagnosis of migraine and aura by ICHD-2 criteria was administered to 27 individuals at risk for FAD. Frequency of significant headaches, migraine, and aura were compared between MCs and NCs by χ² or Fisher’s exact tests. Results: Twenty-three subjects were at risk for PSEN1 mutations and 4 for an APP substitution. The majority of subjects were female (23/27). MCs were more likely to report significant recurrent headache than NCs (67 vs. 25%, p = 0.031). Forty percent of MCs had headaches that met criteria for migraine whereas 17% of NCs met such criteria. The tendency for a higher prevalence of headaches in MCs held for different PSEN1 and APP mutations but was not significant unless all families were combined. Conclusions: In this population, headache was more common in nondemented FAD MCs than NCs. Possible mechanisms for this include cerebral inflammation, aberrant processing of Notch3, or disrupted intracellular calcium regulation.