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Age at onset: important marker of genetic heterogeneity in Alzheimer's disease

The Pharmacogenomics Journal volume 4, pages 138–140 (2004)Cite this article

The increase in prevalence of Alzheimer's disease (AD), the most common form of dementia, with age is one of the best-documented facts in psychiatric epidemiology. Less than 2% of people are affected with AD below the age of 45 years. However, this figure increases markedly to 10% in the over 65s reaching a staggering 47% in the 85 plus age group. Not surprisingly, age at onset has been used to subgroup patients with AD: Early-onset (‘presenile’) AD starts before the age of 65 years and late-onset (‘senile’) is reserved for AD in persons over 65 years of age. That the two forms are etiologically different, at least in a subset of patients, is evident from genetic studies.

Mutations in three genes have been shown to cause early-onset familial AD (FAD). These genes are the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) with the PS1 mutations being associated with the earliest ages of onset and the PS2 mutations exhibiting much later ages of onset. In some families, these PS2 mutations cause disease even after 65 years of age with the age of onset within a family varying markedly. This effect contrasts with that observed for PS1 mutations where relatively small differences in ages of onset occur within a family. The mode of inheritance is autosomal dominant with near complete (100%) penetrance. The genetics of late-onset AD is strikingly different. Many cases are nonfamilial and penetrance is incomplete. In contrast to Mendelian disorders there have been few success stories in finding causal mutations for genetically complex diseases. Despite several complete genome scans and hundreds of attempts to associate specific genes with senile dementia, only one gene, Apolipoprotein E (APOE) is widely recognized as being an important player in its pathogenesis. The ɛ4 allele of APOE has been shown to increase risk of AD across most populations in a dose-dependent manner, which inversely correlates with the age of onset. In addition to and independent of the genotype-associated risk, APOE also exerts risk as a result of specific promoter polymorphisms leading to increased apoE expression.1 However, taken together this explains less than 30% of the genetic variance of AD and we know from twin studies that other genes must be involved. Therefore, the challenge ahead of us is to devise alternate approaches which will help locate the remaining AD-associated genes.

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Acknowledgements

We thank Ana Gnjec for helpful discussions. RNM is supported by the McCusker Foundation for Alzheimer's Disease Research.

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Authors and Affiliations

  1. Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Centre for Human Genetics, Edith Cowan University, Perth, Australia

    R N Martins

  2. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Nedlands, Western Australia

    R N Martins

  3. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA

    J Hallmayer

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Correspondence to R N Martins.

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Martins, R., Hallmayer, J. Age at onset: important marker of genetic heterogeneity in Alzheimer's disease. Pharmacogenomics J 4, 138–140 (2004). https://doi.org/10.1038/sj.tpj.6500239

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