Genetic association between Alzheimer's disease and the low density lipoprotein receptor-related protein gene in the French population

S64

Orui Prqerm&wt:

(286(

OXIDATIVE STRESS, ENZYMATIC ACTIVITIES TIVE DECLINE IN THE EVA STUDY

Claudine

Berr,

Grenoble

1, Grenoble

Alain

Fm’irr,

INSERM

LBSO,

U360. Frunce;

Pam

France;

Veronque

Unix, Grrnohle

Marie-Jeunne

Gourlet,

I. Grenoble

INSERM

AND COGNI-

Richard, U360,

LBSO,

(288)

I

GENETIC ASSOCIATION BETWEEN ALZHEIMER’S DISEASE AND THE LOW DENSITY LIPOPROTEIN RECEF’TOR-RELATED PROTEIN GENE IN THE FRENCH POPULATION

UniL

Par;.> Frunce;

Patrice

Verpillat,

INSERM

France

Toulouse 0289,

Paris

Le Kremlin

Didier

de Pontchaillou.

Dominique INSERM

Rrnnes

Campion, U53S.

Bicerre

Hannequin,

France:

INSERM

Kremlin

C France;

INSERM

Sandrinr

Bouley,

ELI 9906, Rourn

France;

Michrle

Puel, Hasp

Epi 9906, Rouen France;

Bicetrr

France;

Alexis

Purpan,

Fruncoisr

Brim.

INSERM

Frmce

The low density lipoprotein receptor-related protein gene (LRP) is a candidate gene in AD. On one hand, its protein is involved in the physiopathology of AD and has been localized to sende plaques: on the other hand, LRP is located on 12q, a region where genetic linkage with AD was described. Two common polymorphisms, a tetranucleotide repeat in the 5’ region and a dinucleotide polymorphism in exon 3, were found to be associated with AD. But subsequent association studies have shown conflicting results. In this study, we explored the association between these two polymorphisms and AD in 274 French Caucasian AD patients and 290 matched controls. As a strong linkage disequilibrium was found between alleles of the two polymorphisms, we performed the analyses combinmg the two polymorphisms a$ an haplotype. This allowed to increase the power of the study. Haplotype frequencies differed significantly between AD cases and controls (p=O.O4). Stratification of the data by APOE status indicated that this difference was, however, confined to APOE 4 carriers. The association reported here suggests that LRP may explain part of the genetic susceptibility to AD. However, given the fact that the exon 3 polymorphism represents a silent nucleotide substitution, a biologically active variant may exist elsewhere in the LRP gene itself.

HIGH AP0E-f IN KENYA Nilesh

B PATEL. Kariuki, Hendrir.

United

Nymri Univ

Westw-n Reserve

ALLELE FREQUENCIES

Univ of Nairobi,

upon Tyne. Newcastle Hugh

Context: Dementia ia a very common disease occurrmg in old age, %ith many methodological problems to solve for its epidemiological approach. The penal&d hkelihood approach allowa us to model the age-specific incidence of dementia taking into account explanatory variables using data from a large cohort study, Paquid. Objective: To study the age-specific risk of dementia according to three potential risk factors : gender, educational level and wine consumption Methods: During the eight-year follow up of the Paquid cohort study, a random sample of 3777 subject\ living in Gironde and Dordogne (France), 280 incident cases of dementia were Identified. At baseline and at each follow up, demented subjects have been actively screened, using DSMIII R criteria for dementia. The age-specific risk wah estimated with the penalized likelihood method which take age as the basic time scale of the analysis. Results: The evolution with age of the risk of dementia wah different according to each of the three risk factors. The estimated incidences computed xparately for men and women croaaed after 75 years showing an interaction between age and gender: the risk was higher in men than in women before 75 years, and lower after this age. The incidence of dementia for wbjects with low education parallel\ those with a high education but five to six years earlier, suggesting an additive risk model. Finally, the incidence of dementia in moderate drinkers diverge progressively from those of non or mild drinkers, suggesting a proportional hazards model. Conclusion: The study of age-specific risks of dementia according to a given risk factor allows to better understand the cumulative effects of these factors and by this way. the physiopathology of. the disease.

U535,

France:

Hasp

Frmce;

Clerger-Darpour.

Monica

TO GENDER,

INSERM

UZRY. Paris

Serge Belliard,

Oxidative strew Enzymatic activities and Cognitive decline in the EVA study A large body of evidence indicates that free radicals are crucial in aging processes and age-associated pathological changes. As individuals age, accumulation of oxidativr damage related to a systemic antioxidant/pro-oxidant imbalance may reduce functional capacity and increase the risk of disease. We present results on the longitudinal relation between primary enzymatic antioxidant protection and cognitive decline. We studied vascular and cerebral aging in high cognitive functioning subjects aged 62-72 years at time of biological evaluation, volunteers in the EVA (Etude du Vieillissement ArtCriel ) cohort. In 1993-1995, we measured red blood cells activities of two enzymes: cytoplasmic form of wperoxide dismutaw (CuZn-SOD) which convert superoxide radicals into H202 and s&no dependent glutathione peroxldase (GSHPx) which breaks down peroxides. Subjects completed regularly a global cognitive test (MMSE), the cognitive function change was evaluated by the difference in MMSE scores during the 4.year follow-up in 981 individuals with enzymatic activities determinations (follow-up rate of 81%). Mean loss in MMSE score was low ( 0.17 points), a loss of at least 3 points in MMSE score was observed in 71 subjects (7.2%) defining individuals with cognitive decline (CD). At baseline, there was no association between MMSE score and enzymatic activities. After 4.year follow-up, initial GSH-Px activity appeared to be significantly lower in individual CD+ (41.2t 10.3 U/g Hb vs. 44.429.4 in CD-, p<26>.008). Conversely, there was an increase of CuZn-SOD activity in CD+ subjects (1.13+0.10 Ulmg Hb vs. 1.10 f 0. IO, p<26>.05). Same trends were observed when controlling for age, sex, education, depressive symptomatology, alcohol and tobacco consumption (p<26>.01 for GSH-Px and p126>.04 for C&n-SOD). CuZn-SOD and GSH-Px are known to act in tandem prowding the primary enzymatic antioxidant protection. These rewlts will be discussed in regard to the direct implication of oxidative stress in vascular and neurodepenerative mechanisms which could lead to cognitive impairment.

AGE SPECIFIC RISK OF DEMENTIA ACCORDING EDUCATION AND WINE CONSUMPTION

Epidemiology

Nairobi

Kingdom;

Provincial,

Nyeri

of Indianapolis,

Univ,

Clewlund,

Kenya; Paul

Kioy,

Kenya;

Indianapolis,

IN ELDERLY

Raj N Kularia,

Univ of Newcastle

Univ of Nairobi, Kathleen IN:

KIKUYU

Hall,

Robert

Nairobi Fred

Kenya;

Umerzugt.

P Friedland,

Case

OH

Ageing Kenyans acquire cerebral pathological lesions diagnostic of Alzheimer’\ disease (AD) but it is unclear whether apolipoprotein E (APOE) genotype modifies risk of disease in African populations. To assess population-based estimates of prevalence and incidence of AD and other common demenuas, we recently completed a pilot study involving a sample of 105 Kikuyu (Bantu) elderly living in one of the highland locations m Nyeri district near Mt Kenya. This study ha5 enabled us to vahdate established cross-cultural clinical and cognitive screening criteria, APOE genotyping and other methods used to assess AD in Nigerian, African-American (Indianapolis) and other (Newcastle, UK) communities. In an effort to evaluate the relationship between APOE allele frequenceis and dementia in elderly Kenyans, we assessed allele frequencies in 87 healthy age matched controls and 18 demented elderly Kikuyu living in the Thunguma location of Nyeri. The frequency of APO/%4 allele was 25.4% in non-demented controls compared to an overall 30.0% in the demented group of whom half were diagnosed with Alzheimer type of dementia. We found that the ~2 allele frequencies in the sample were 2.6% and 0% in controls and demented subjects. This in contrast to the increased risk of AD associated with ~2 allele in African Americans in Manhattan and supports our observations from the Indianapolis and Nigerian samples. We conclude that similar to our findings in Ibadan, there appears no relationship between ~4 and dementia in these propsectively a\xssed Bantu Kenyans. It is plausible that yet unknown genetic factors may contribute to AD risk in certain ethnic groups or protect them against APOE-~4 by Interaction wth other factors. Supported by grants for the Alzheimer’s Association and the NIH

)290)

LIPOPROTEIN(A) IS A RISK FACTOR FOR ALZHEIMER’S DISEASE INDEPENDENTLY OF APOLIPOPROTEIN E GENOTYPE

Vincen;o

Solfrizti,

Geriatrics

L’nio

of Bari,

Bnri

Amonio

Cqxmo.

Italy;

Fran~rsco

Panza.

of Buri, Ban‘ Italy: Anna

M Basile,

Francrsw

Torres,

Frunco

Mastmiami,

Anna

M Colacicro,

Cristiano

Dept

of Geriatrics

.

Univ

Dep~

A Capurso. of Ban’, Bari

of

Unia Italy;

Univ
The ~4 allele of apolipoprotein E (apoE) has been associated with both increased risk of Alrheimer’s disease (AD) and high serum total cholesterol (TC), while increased serum lipoprotein(a) [Lp(a)] has been associated with cerebrovascular disease (CVD). We explored the role of serum Lp(a), TC, and apoE polymorphism in AD, evaluating a sample of 124 subject?, 61 AD pattents and 63 healthy, unrelated subjects. Assuming that sex. apoE carriers. and TC are considered important risk or protective