Alzheimer's disease and Down syndrome: From meiosis to dementia

Several molecular and clinical similarities have been detected in Alzheimer's disease (AD) and Down syndrome (DS). The most remarkable feature is abnormal accumulation of beta-amyloid in the brains of both individuals affected with AD and aging DS patients followed by dementia. In addition, AD patients exhibit dermatoglyphic patterns similar to those in DS, and late maternal age is a risk factor in both diseases. AD and DS could be related genetically because AD families exhibit a higher rate of DS cases and vice versa. Although numerous discoveries have been made in the elucidation of the etiopathogenic factors in AD and DS, little progress has been achieved in understanding the origin of the common features of the two diseases. This article reviews clinical and molecular similarities in DS and AD and also chromosome 21 studies in both diseases. A new hypothesis explaining the association between AD and DS is suggested, and this hypothesis is based on the poorly understood molecular phenomenon of aberrant meiotic recombination. Aberration in meiotic recombination has been consistently detected in chromosomal diseases including trisomy 21 and sex chromosomes. There are no studies dedicated to meiotic recombination in genetic diseases; however, evidence for disturbed recombination has been documented in several neurological diseases such as Huntington's disease, myotonic dystrophy, and fragile X syndrome. Interestingly, the rate of trisomic XXY children born to mothers transmitting fragile X mutation is higher than expected. This finding suggests that AD could be associated with DS in a similar way to which fragile X syndrome is related to trisomy of sex chromosomes. Based on analogy with fragile X syndrome, it can be predicted that AD should demonstrate aberrant meiotic recombination in chromosome 21., most likely in the region D21S1/S11-D21S16 which is linked to early onset familial AD. Based on the same rationale, different patterns of meiotic recombination in the nondisjunct chromosome 21 within DS patients grouped according to the concomitant disease are predicted. (C) 1999 Academic Press.