The current status of Alzheimer’s disease genetics: what do we tell the patients?
Introduction
Over the past two decades, genetic studies have been remarkably successful in the identification of fully penetrant, causal mutations in Mendelian disease genes. However, some of these genes only account for an uncommon subset of generally more widespread disorders such as breast cancer, colon cancer, diabetes and early-onset Alzheimer’s disease. These diseases share several characteristics that classify them as genetically complex and heterogenous. They are complex because there is no single (or simple) mode of inheritance that accounts for their heritability; they are heterogeneous because mutations and polymorphisms in multiple genes interact with one another and with non-genetic factors (Fig. 1). Thus, one plausible explanation for the disappointing achievement of positional cloning strategies in more common and genetically complex diseases is that the underlying and predisposing variants (or “susceptibility genes”) exert only small to modest effects with weak genotype–phenotype correlations [1]. Nonetheless, the magnitude of their attributable risk may be quite large because they are relatively frequent in the population, rendering them a significant public health issue [2].
Alzheimer’s disease (AD), the most common form of age-related dementia, is characterized by progressive and insidious neurodegeneration of the central nervous system leading to a gradual decline of cognitive function and dementia. The key neuropathological features of AD are abundant amounts of neurofibrillary tangles and β-amyloid (Aβ) deposited in the form of senile plaques. While our understanding of the disease pathophysiology still remains fragmentary, it is now widely accepted that genes play an essential role in predisposing to onset and in modifying the progression of the disease. Specifically, disease inheritance shows an age-related dichotomy in which rare but highly penetrant mutations transmitted in an autosomal dominant manner have been thus far responsible for early (≤60 years) onset familial forms of AD, while common polymorphisms with low penetrance appear to have their greatest effect on the more frequent, later onset forms of the disease (LOAD; [3]). Several additional factors aggravate the identification and consistent replication of bona fide AD genes—or other complex disease genes—across studies and populations (such as unknown phenocopy rates, sampling issues, population stratification, etc.). These difficulties are evidenced by the fact that of the almost 100 candidate AD genes analyzed in the literature to date, only four have been proven to either play a direct role in AD pathogenesis (APP, PSEN1, PSEN2) or to significantly increase disease susceptibility in almost every study population analyzed worldwide (i.e. APOE; Table 1).
Despite the complexities of AD genetics, tremendous progress has been made over the past two decades. The knowledge gained from genetic studies of AD was and remains the essential prerequisite for our current understanding of the etiological and pathophysiological mechanisms leading to neurodegeneration in AD as well as for the development of novel strategies for the treatment and prevention of this disease.
Section snippets
Analysis of genetic linkage
Linkage analysis measures the vertical coseggregation of specific marker alleles (e.g. those of microsatellites) and disease phenotype within individual families. This can be done either by formulating specific inheritance models (“parametric analyses”), or model-free (“non-parametric”). If the model is correctly specified, parametric methods are usually more powerful as they permit the use of affected and unaffected individuals alike [4]. However, because one characteristic of complex diseases
Early-onset Alzheimer’s disease
Only small fraction of all AD cases (<5–10%) can be explained by early-onset familial AD [3]. In 1987, initial results showed linkage to the long arm of chromosome 21 encompassing a region that harbored the gene encoding the amyloid precursor protein (APP; gene: APP), a compelling candidate gene for AD [6]. This chromosomal area overlaps with the obligate region for Down’s syndrome, a disease where affected individuals almost invariably develop AD after a certain age. In 1991, the first APP
Late-onset Alzheimer’s disease
As outlined above and in Fig. 1, late-onset Alzheimer’s is characterized by a considerably more multifaceted and interwoven pattern of genetic and non-genetic factors that is only poorly understood. Adding to these complexities are methodological difficulties inherent to common diseases in general and late-onset diseases like AD in particular. These and other characteristics largely reduce the power to detect new loci in reasonably sized samples and make the identification and independent
Clinical implications
How does this continuously increasing knowledge about the genetic make-up of AD translate into clinical practice or, to return to the subtitle of this review: what do we tell the patients? The answer to this question is much less complex than the disease itself and, unfortunately, must read: not much, yet. Predictive genetic testing is a very delicate process in any disease, as it deeply invades the privacy of the individual and his or her family members. If a preventive treatment or cure is
Conclusion
Despite the great progress in the field of AD genetics that has led to the discovery and confirmation of three autosomal-dominant early-onset genes and a late-onset risk-factor, a number of other additional major AD loci are predicted to exist. The hunt for these putative AD genes is aggravated by several factors that generally complicate the identification of complex disease genes: locus and/or allelic heterogeneity; only minor to modest effect size of any given variant; unknown—and difficult
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