ApoE genotype: No influence on galantamine treatment efficacy nor on rate of decline in Alzheimer's disease

early-onset familial AD (FAD). Other FAD mutations have been identified in the amyloid precursor protem (APP) gene on chromosome 21 and in the presenilin-2 gene on chromosome I. In order to screen for PS- I mutations, genomic DNA of 20 FAD cases was obtained from blood cells. Appropriate mtronic primers were used to amplify the entire open reading frame of the PSI gene (according to the nucleotide and exon numbering of GeneBank No. L76518-76528) and PCR products were analyzed with single strand conformational polymorphism (SSCP). When an aberrant band pattern was been in the SSCP, direct DNA sequencing was performed to identify the cause of the changed mobility. We identified three PS-I mutations in 5 out of 20 families (25%): the previously repotted mutations Ml46L (three families) and E318G (one family), and a new L219 mutation (one family) leading to a Leu to Phe substitution at amino-acid 219 (L219F) and different from the previously repotted L219P (Leu to Pro) mutation. Clinical history of the patient canying this novel mutation was not different from those with other PSI mutations or with clinically defined FAD without known mutations. In order to exclude the presence of other mutattons in the APP gene in the same subject? a screening on the APP gene was performed with negative results. In conclusion we report a novel mutation in the PS-1 gene as the cause of AD in one Italian family. The high number of clinically defined FAD patients in our series lacking of already described mutations suggests the need fc>rmore extensive genetic research in this field.

ASSOCIATION STUDY BETWEEN A PROMOTER POLYMORPHISM IN THE PRESENILIN 1 GENE AND LATE-ONSET ALZHEIMER’S DISEASE Barr Dermaut.

ofAnttyerp

&iv

Jolirn

Tel, Erasmus

Cruts,

Univ

of Antwerp

Duistermuut, eckhovm, Duijn,

(UIA),

Erasmus Univ

Eru.mus

(U/A),

VIE, BBS, Antwrrpm

Univ Med Sch. Rotterdam Univ

of Antwerp Univ

Mrd

VIE, Med

(UIA),

BBS, Antwerpen

Sch, Rotterdam VIE,

Sch, Rotterdam

Belgium;

Netherlands:

Raw

Belgium;

Jeaninr

Netherlands;

BBS, Antwerpen

Gerwin

Roks,

Radrmakcrv. Christine

Brlgium;

Murc

J HouwingVan Bro-

Corn&z

M wn

Belgium

Several authors have recently mvestigated the poaaibility of a genetic assoclatlon between a polymorphism in intron 8 of the presenilin 1 gene (PSENI) and Alzheimer’s disease (AD) with conflicting results. We hypothesized that this inconsistent association might be explained by variation? in regulatory sequences of PSEN I. Accordingly, we recently demonstrated a nearly three times increased risk for developmg early-onset AD m individual, homorygous at a polymorphism upstream of PSENI (CC genotype of -48CiT). These result5 suggested that genetic variations in the PSENI promoter region might be associated with an increased risk of developmg AD. In the present study we analyzed the asaociatlon of the mtron 8 polymorphism as well -48Cm in 356 AD patients and 230 controls in a late-onset population-based case-control study. For none of the two polymorphisms, association with late-onset AD (LOAD) was found. Further, we re-analyzed the published literature on PSENI intron 8 in a meta-analysis but failed to detect a significant relation with AD. Together, these results suggest that genetic variations at the PSENI locus do not influence the risk of developmg LOAD.

fold increased compared to controls from the same area. Our study shows that AD in this isolated population is not fully explained by the known AD genes. The impact of APOE was high, yet comparable with that found in the general population. At present, a genome hearch I\ conducted to identify new AD genes.

APOE GENOTYPE: NO INFLUENCE ON GALANTAMINE TREATMENT EFFICACY NOR ON RATE OF DECLINE IN ALZHEIMER’S DISEASE Jeroen

Aer.wn.s.

Wim Parve,

Gtvwin

Roks. Lodewijk

Snijden,

Erasmus

Univ

ofAntwerp,

Mrd

Ctr,

A Sandkuijl,

Mrd Antwerp

Rotterdam

Ctr,

Pew

Rotterdam

Eel&m;

Heutink, Netherlunds;

Ben A Oostra,

John

ISOLATED

C Van Swirten,

Christine Cornrlia

Pieter

POP-

Jlm

Van Broeckhown,

M Van Duijn,

Erasmus

Nrthrrlunds

Genetic factors play an important role m the etiology of AlLheimer’s disease (AD). Mutations in the amyloid precursor protein gene (APP) and the preaenilm genes (PSENIIPSEN2) cause autosomal dominant early-onset AD. The most important genetic determinant for AD in the general population is the apolipoproteinE gene (APOE) However, APOE does not explain more than 17% of the occurrence of AD in the general population. In recent years there ia increasing interest in identifying genes in genetically isolated populations such as the Finnish and Icelandic populations. In this study we evaluated the feasibility of studying the genetics of AD in a Dutch recently isolated population of 20,ooO inhabitants. This population was founded 300 years ago by I50 subjects and is characterized by minimal immigration. We ascertained 80 dementia patients originating from this population with a mean onset age of 73 years. The patient population comprised 65% female,. The diagnosis possible/probable AD could be made in 74 patients. Family history in first or wcond degree relatives was positive m 58%. Genealogy was studied up to I5 generations, and revealed that at least 63 patients (79%) were related within I4 generations. Within the pedigree which included 650 ancestors, 4 clusters of patients were identified who were more closely related. One cluster of 8 patients was related wthin 9 generationa, two groups of 8 and 31 patients were related within IO generations, and a group of 7 patients was related wthin I I generations. We screened APP, PSENI, and PSEN2 but found no causal mutations. The APOE ~4 allele frequency wa\ 38% which is comparable with Caucasian AD patient, (37%‘). APOE* wa\ 2.2.5 [95%, Cl I .6-3.1 I

Research

Peter Fdn,

Raeymaekem.

Beersr

Hugo

Gerrts.

Frmk

Kmings,

Belgium

Objective: Apolipoprotein E (APOE) has been shown to be a genetic risk factor for Alzheimer’s disease (AD). Associations of APOE genotype have been repotted with a number of clinical characteristics, including age of ornet, rate of decline, and responsiveness to therapy. This study aimed to test wme of these hypotheses in a large study population of AD patients. Methods: APOE genotype was determined for 1528 Caucasian subjects, diagnosed by NINCDS/ADRDA criteria a$ probable AD patients, enrolled in four international placebo-controlled clinical trials of 3-12 months‘ duratton, designed to evaluate efficacy ot treatment with galantamine or sabelurole. In addition to patient demographics and baseline scores for Mini-Mental State Examination, scores on the Disability Assessment for Dementia (DAD) and the cognitwe subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) were recorded at the statt, during, and at the end of the study. Results: APOE t4 homorygotea had a significantly lower age of disease onset compared with patients with other APOE genotypes. The ~4 allele was significantly over-represented in females compared with males, and in the group of subjects with an AD family history. Based on longitudinal data of 504 placebo-treated AD patients, the linear annual rate of change in score was 5 points on the ADAS-cog scale and 1 I on the DAD scale. The t4 allele copy number did not influence these rates of decline. Sabeluzole treatment was not effective in the overall group compared with the placebo-treated group, nor in any subgroup stratified by t4 allele count. Galantamine produced cognitive and functtonal improvements that were not affected by ~4 allele count. Conclusions: Our data confirm a strong association between ~4 homozygotes and age of onset of AD. They do not, however, support an effect of t4 allele copy number on rate of cognitive and functional decline nor on the efficacy of galantamine in patients with AD.

Poster Presentation:

Imaging

III

PROGRESSION OF HIPPOCAMPUS AND CORPUS CALLOSUM ATROPHY AS INDEPENDENT MARKERS OF STRUCTURAL DISEASE PROGRESSION IN ALZHEIMER’S DISEASE

.&fan

Hum/d

Humprl,

Munich

Gernumy;

rity,

Munich

H Schapiro,

ALZHEIMER’S DISEASE IN A GENETICALLY ULATION: THE GRIP STUDY.

Sean Lilienfrld,

Janssen

Germuny; Lob

of

Hun-Jurr~en

Moeller,

Unnc

Gmnnny

Munich

J Tripel,

Wolfrum Gear

Bayer,

Dept

of P,sychiatry.

Dept

Psychiatry,

E Alrxundrr,

Neurmcirncrs. Stanley

Arizona

N~ztinnul

I Rupoport,

State Univ.

Institute

Dept

Ludwig-Marimrlian

Univ.

Ludwig~Muximillians-UnivrrBethrsdu,

on Aging,

ofPsychiatry,

MD;

Mark

Brthesda,

MD;

Ludwig-Mrrximilian

Background:Postmortem atudiea suggest that the earliest morphological changes in Alzheimer’s disease (AD) are found in hippocampus and adjacent cortex. Further observations indicate a temporal sequence of primary altocortical and secondary neocortical degeneration during disease progression. Hippocampus atrophy correlates with allocortical neuronal degeneration in clinicopathological studies. Atrophy of the corpus callowm, independently of primary white matter degeneration, reflects loss of mtracottical projectmg pyramidal neurons in neocottex. Objectives: First, to determine the temporal sequence and rate of degeneration of hippocampus and corpus callosum in AD. Second, to answer the questIon, whether rates of atrophy were correlated with rates of cognitive decline and third, whether both markers could be proposed as independent morphological parameters for in-v& mapping of structural disease progression in AD. Methods: MRI-derived tneasures of corpus callosum and hippocampus were compared between 27 clinically diagnosed AD patients (MMSE 13.5 [k 8.71) and 28 age- and gender-matched healthy control subjects. Rates of corpus callosum and hippocampus atrophy were determined in 21 AD patients and IO control subjects studied longitudinally for a follow-up period of 15.9 months [t 8.21 and 24.1 months [t 6.81, respectively. Results: Hippocampus and corpus callosum \i~e was significantly reduced in AD (37 lo, 16 %, respectively). Hippocampus atrophy preceded corpus calloaum atrophy in mild AD. We found mean relative rates of atrophy per year for corpus callosum (6.9 %) and hippocampus (12.2 %) in AD which were significantly larger than rate< of atrophy of 0.2 % 0.9 % per year in healthy controls. Rates of corpus callowm, but not of hippocampus atrophy, were correlated with the progression of cognitive impairment in AD patrents. Conclusions: We suggest that hlppocampw and corpus callosum are independent markers of allocortical and neocortical degeneration and may be apphed in studies mapping discare pmgres\ion and effects of disease modifying drugs on brain structure in AD over a wide range of clmical disease severity.