Mohammed T. Abou-Saleh

220 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYdepression and medical illness, may be involved 23 , but dementiais the main cause; in the absence of dementia and physicalillness no decline was found 24 . However, the incidence ofcognitive decline and dementia seems to be very sensitive to thecriteria used. Adults aged 22–56 who were dementia-free atbaseline showed little change over a period of 3–4 years in mostcases 25 and even over 6 years, persons aged 50 and overshowed, on average, only very slight decreases in cognitiveperformance, attributed to precocious ageing; only 4% satisfiedthe criteria for dementia 26 . However, on a sophisticatedneuropsychological test battery, 28% of testable persons aged30+ were deemed to show cognitive deterioration after 4 years,and of those aged over 50 only 30% showed no cognitivedecline; as in AD, memory and learning were affected early 27 .Whether persons with DS age prematurely or whether they agenormally but are at increased risk of AD remains controversial.Further national and cross-national studies of the prevalence,incidence and natural history of dementia in both DS and inother LD are required 28 .NEUROPATHOLOGY AND GENETICSThe gene coding for familial Alzheimer’s disease is nowknown to be distinct from the amyloid precursor protein(APP) gene, which is also situated on the long arm ofchromosome 21. Overexpression of the triplicated APP generesults in higher concentration of APP in DS brains than inbrains of elderly controls or of patients with AD 29 . Theincreased amyloid deposition in AD could be due to somecases of AD being trisomy-21 mosaics, resulting from nondysjunctionduring mitosis; such cases might possess otherfeatures of DS 30 . A shared susceptibility to non-dysjunctionand AD could account for an increased risk of dementiareported among the mothers of persons with DS 31 . Metaanalysisof seven studies of the ApoE polymorphism in DSfound a similar distribution between DS adults and nonretardedcontrols, and no significant difference between DSpersons with and without dementia 32 . There were, however,trends for the E2 allele to be associated with later onset ofdementia and later age at death in non-dementing persons,and for the E4 allele to be associated with earlier onset.Cognitive decline in DS may be influenced by an unidentifiedgene situated at D21S11 33 .Clinico-pathological CorrelationsThe first change is the deposition of b-amyloid peptide (b/A4) inthe cerebral cortex and elsewhere, in the form of diffuse,amorphous plaques, and may be seen as early as the second orthird decade; soon afterwards microglial cells and ubiquitinprotein can be detected, and by the age of 35 years ‘‘cored’’amyloid deposits are seen at post mortem in most subjects 34 .Atthis stage neurofibrillary tangles (NFT) are numerous in parts ofthe hippocampus and amygdala but are seen only in isolatedcortical neurons. Eventually, and usually after the age of 50, thedistribution and density of senile plaques and NFT and loss ofneurons conform to the pattern seen in AD 34 . This is the age whenclinical dementia usually appears 13 . This gradual evolution ofpathological change partly explains the puzzling temporaldiscrepancy between the onset of pathological and clinicalmanifestations of dementia in DS. Whether or not a similarevolution of neuropathological change occurs in AD is stillunknown.REFERENCES1. Van Schrojenstein Lantman-de Valk HMJ, Haveman MJ, MaaskantMA et al. The need for assessment of sensory functioning in ageingpeople with mental handicap. J Intellect Disabil Res 1994; 38: 289–98.2. Strauss D, Eyman RK. Mortality of people with mental retardationin California with and without Down’s syndrome. Am J Ment Retard1996; 100: 643–53.3. Evenhuis HM. Further evaluation of the Dementia Questionnaire forpersons with mental retardation (DMR). J Intellect Disabil Res 1996;40: 369–73.4. Gedye A. Dementia Scale for Down Syndrome. Manual. GedyeResearch and Consulting: Vancouver, 1995.5. Deb S, Braganza J. 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