Lucia Madrigal

Presenilin-1–associated abnormalities in regional cerebral perfusion

Objective: To investigate the influence of the presenilin-1 gene (PS-1) mutation on regional cerebral perfusion, SPECT was evaluated in 57 individuals. The subjects were members of a large pedigree from Colombia, South America, many of whom carry a PS-1 mutation for early-onset AD. Methods: Members of this large kindred who were cognitively normal and did not carry the PS-1 mutation (n = 23) were compared with subjects who were carriers of the mutation but were asymptomatic (n = 18) and with individuals with the mutation and a clinical diagnosis of AD (n = 16). Cerebral perfusion was measured in each subject using hexamethylpropyleneamine oxime SPECT. The data were analyzed in two ways: 1) Mean cerebral perfusion in each of 4320 voxels in the brain was compared among the groups using t-tests (t-maps); and 2) each individual received a weighted score on 20 vectors (factors), based on a large normative sample (n = 200), using a method known as singular value decomposition (SVD). Results: Based on t-maps, subjects with the PS-1 mutation who were asymptomatic demonstrated reduced perfusion in comparison with the normal control subjects in the hippocampal complex, anterior and posterior cingulate, posterior parietal lobe, and anterior frontal lobe. The AD patients demonstrated decreased perfusion in the posterior parietal and superior frontal cortex in comparison with the normal control subjects. Discriminant function analysis of the vector scores derived from SVD (adjusted for age and gender) accurately discriminated 86% of the subjects in the three groups (p < 0.0005). Conclusion: Regional cerebral perfusion abnormalities based on SPECT are detectable before development of the clinical symptoms of AD in carriers of the PS-1 mutation.

E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles

A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin‐1 (PS‐1) gene on chromosome 14 in affected individuals in each of seven Colombian early‐onset Alzheimers disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two‐point lod score between the mutation and AD was Z = 8.14 at θ = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS‐1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the ϵ4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations. Hum Mutat 10:186–195, 1997.

The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.

OBJECTIVE To identify a cognitive composite that is sensitive to tracking preclinical Alzheimers disease decline to be used as a primary end point in treatment trials. METHOD We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the worlds largest known early-onset autosomal dominant Alzheimers disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimers disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimers Prevention Initiatives (API) preclinical Alzheimers disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains. RESULTS The optimal test combination included Consortium to Establish a Registry for Alzheimers Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Ravens Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05). CONCLUSIONS We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimers disease decline in autosomal dominant Alzheimers disease mutation carriers and to evaluate preclinical Alzheimers disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimers disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimers disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches.

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimers disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer’s disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimers AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimers disease AAO and open potential avenues for therapy.

Origin of the PSEN1 E280A mutation causing early–onset Alzheimer’s disease

A mutation in presenilin 1 (E280A) causes early‐onset Alzheimers disease. Understanding the origin of this mutation will inform medical genetics.

Exploratory Data from Complete Genomes of Familial Alzheimer Disease Age-at-Onset Outliers

Identifying genes that modify the age at onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its AAO are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease. Hum Mutat 33:1630–1634, 2012.

Homozygosity of the autosomal dominant Alzheimer disease presenilin 1 E280A mutation

We identified several families in Antioquia, Colombia, with early-onset Alzheimer disease (AD) due to the mendelian autosomal dominant inheritance of a PSEN1 E280A gene mutation. Extended family members were interviewed and parish baptism certificates in Antioquian municipalities examined.1 The size of these extended families (including carriers and noncarriers) approaches 5,000 individuals. Full genomes in carriers proved a single founder.2 To support an AD prevention clinical trial, we established a registry in 2010 of all family members over age 8 years.3 Since then we genotyped 3,407 family members and identified 823 (24%) carriers of the PSEN1 E280A mutation. The Comite de Bioetica de la Sede de Investigacion Universitaria, SIU Universidad de Antioquia, approved this study. All participants provided written informed consent. Despite the size of this exceptionally large family and frequent consanguinity, homozygosity at this gene locus had not been reported. The apparent absence of homozygous PSEN1 mutations led to the speculation that E280A homozygosity could be lethal. Generally, homozygous dominant mutations are more severely affected than heterozygotes in both humans and model systems.4 However, human cases in which dominant point mutations are homozygous are rare.

The Colombian Alzheimer's Prevention Initiative (API) Registry

The Colombian Alzheimers Prevention Initiative (API) Registry is a collaborative project among the Neurosciences Group of Antioquia, the Banner Alzheimers Institute, and Genentech. The main goal is to provide a source of interested research participants and data to support the API‐Colombia Autosomal Dominant Alzheimers Disease Trial and help find treatments to delay or prevent the clinical onset of Alzheimers disease.

Factorial and discriminant analyses of neuropsychological variables in familial and sporadic late onset Alzheimer disease

INTRODUCTION Prevalence of late onset Alzheimers disease (LOAD) both familial and sporadic is increasing with the raising proportion of third-age population. There are evidences either supporting or rejecting the existence of differences in the behavior of neuropsychological variables between familial and sporadic cases of LOAD. OBJECTIVE To identify neuropsychological variables discriminating between familial and sporadic cases of LOAD, in order to detect clinical manifestations that may provide information on the pathological process of the neurodegenerative process. PATIENTS AND METHODS Using sequential sampling, we selected individuals affected by LOAD according to the criteria of the DSM-IV and NINCS-ADRDA. The following neuropsychological protocol was used: CERAD, Wisconsin, Phonological Fluency, Reys Figure, Raven, A Cancellation Test, WAIS (Arithmetic); also used were: Global Deterioration Scale, Functional Assessment Staging of Reisberg (FAST), Barthel and Yesavage. Parametrical and non-parametrical univariate, factorial (principal components) and discriminant analyses were performed. In total, 52 patients were analyzed (average age: 74.8 years; mean age at onset of the disease: 69 years; time of diseases evolution: 5.7 years; average of educational level: 6.4 years). RESULTS No significant statistical differences were found in clinical or neuropsychological variables between familial and sporadic cases of LOAD. Additionally, neither variables nor models were detected discriminating significantly between them. CONCLUSION Familial and sporadic cases of LOAD present the same clinical and neuropsychological phenotype which makes very probable that sporadic cases are low penetrance familial ones.