Mohammed T. Abou-Saleh

THE GENETICS OF ALZHEIMER’S DISEASE 219for multiple diseases, and therefore for generalized morbidity, andincreased the risk of mortality from multiple causes. Thistranslates into increased burden on the health care deliverysystem and higher costs.Apolipoprotein E is a major serum lipoprotein involved incholesterol metabolism. Lipoproteins derived from E4 are clearedmore efficiently from the blood than those derived from E3 andE2. Apolipoprotein E does not cross the blood–brain barrier butis synthesized in the brain by astrocytes. In the brain, APOE isthought to be involved in the mobilization and redistribution ofcholesterol and phospholipid during membrane remodelingassociated with the plasticity of synapses 3 .The biological basis for the association between the E4 alleleand AD is unclear, however. APOE is found in senile plaques andfibrillary tangles and binds to Ab in the cerebrospinal fluid. Invitro studies have indicated that APOE isoforms may differentiallyaffect deposition of Ab. Binding studies suggest that APOEisoforms have different affinities for Ab. However, these resultsare controversial because different studies suggest differentisoforms have the highest affinity for Ab. The APOE isoformshave been shown to promote Ab fibral formation in vitro. Otherstudies, however, show that E3 but not E4 binds to tau,preventing aggregation of tau and neurofibrillary tangle formation.Neurite extension and branching is more extensive in E3-treated cells compared with E4-treated cells. APOE E4 has alsobeen shown to have increased antioxidant activity compared withE3 3 .Although there is a consensus that APOE E4 is stronglyassociated with AD, this does not mean that tests for the genotype(which are comercially available) should be used for diagnostictesting. A consensus working group has recommended that, at thepresent time, APOE genotyping should not be used for predictivetestings. APOE genotype alone does not provide sufficientsensitivity or specificity to allow genotyping to be used as adiagnostic test. Because AD develops in the absence of E4 andbecause many patients with APOE E4 seem to escape the disease,genotyping is also not recommended for use as a predictive genetictest 4 .REFERENCES1. Strittmatter WJ, Saunders AM, Schmechel D et al. Apolipoprotein-E:high-avidity binding to B-amyloid and increased frequency of type 4allele in late-onset familial Alzheimer’s disease. Proc Natl Acad SciUSA 1993; 90: 1977–81.2. Plassman DL, Breitner JCS. Recent advances in the genetics ofAlzheimer’s disease and vascular dementia with an emphasis on gene–environment interactions. J Am Geriat Soc 1996; 44: 1242–50.3. Lendon CL, Shall F, Goate AM. Exploring the etiology of Alzheimer’sdisease using molecular genetics. J Am Med Assoc 1997; 277: 835–1.4. American College of Medical Genetics. Statement on the use ofapolipoprotein E testing for Alzheimer’s disease. J Am Med Assoc1995; 274: 1627–9.Down’s Syndrome and Alzheimer’s Disease: UpdateDavid W. K. Kay and Brian MooreUniversity of Newcastle upon Tyne, UKOne of the unresolved questions for the dementia of Down’ssyndrome (DS) as a model for Alzheimer’s disease (AD) is thelong interval, often up to 20 years, that separates the appearanceof the AD pathology in the brains of individuals dying after theage of 35 from the clinical manifestations of dementia.EPIDEMIOLOGY OF DEMENTIAStudy of decline and dementia is important for service as well astheoretical reasons. The life expectancy of a 1 year-old DS childwith mild/moderate handicap is now 55 years 2 . However, the widevariation in premorbid abilities and the presence of physical,particularly sensory impairments 1 often makes the diagnosis ofdementia difficult. With ICD-10 criteria as standard, theDementia Questionnaire for Persons with Mental Retardation 3and the Dementia Scale for Down Syndrome 4 both perform well,but the Mini-Mental State Examination is too difficult 5 . Bothcaregiver information and longitudinal monitoring of cognitiveperformance are desirable 6 . Cortical atrophy may be demonstratedby brain imaging 7,8 . Dementia is frequently associated withlate-onset epilepsy, and late-onset epilepsy is associated withclinical evidence of dementia 9–11 . Serial EEGs may reveal diffuseabnormalities and slowing of the dominant rhythm associatedwith the decline of cortical functions 12 .In a meta-analysis of prevalence studies, the age distribution ofdementia onset in DS was unimodal, with mean age of onset 51.7years (SD 7.1, range 31–68), and earlier onset in women 13 . Agespecificprevalence rates of dementia in population-based sampleswere: age 30–39, 2.0–3.4%; age 40–49, 9.4–10.3%; age 50–59,36.1–40%; and age 60–69, 54.5% 14–16 . DS subjects aged 50 yearsor over were significantly impaired on memory tests comparedwith younger subjects 17 . Dementia rates were increased in elderlypeople with learning disabilities (LDs) as a whole 18 but the ratesin DS were higher 19 . Persons with DS and dementia are alsoreported to show more non-cognitive symptoms than otherpersons with LDs and dementia 20 . Dementia contributed significantlyto decline in adaptive behaviour and skills after age 40,independently of age, while absence of medical illness had afavourable effect 21 .Longitudinal StudiesAdaptive behaviour deteriorates more in DS than in matchedcontrols with other LDs 22 . Treatable conditions, such as