Genesfamilial And Lateonset Ad

AD is broadly divided into two types. The first and relatively better understood category is early-onset familial AD, which I will abbreviate as FAD. FAD is relatively rare, accounting in aggregate for a few percent of total AD cases (see reference 48 for a review). FAD is inherited in an autosomal dominant fashion and is highly penetrant, meaning that if you inherit a single copy of the gene you are highly likely to develop AD before age 60. So far, FAD-causing mutations have been identified in the human genes for APP, PS1, and PS2.

The second category of AD is late-onset AD, commonly abbreviated LOAD. LOAD is associated with several risk factors, the most common of which are age and the inheritance of specific genes. The LOAD-related genetic factor that has been unambiguously demonstrated to date is the inheritance of the epsilon4 (e4) allele type of Apolipoprotein E (ApoE4; see references 49-51). ApoE alleles vary normally among individuals. If you inherit the e4 allele, you have an increased likelihood of developing LOAD. Interestingly, if you inherit the less common e2 allele, there is a small protective effect against AD.

The existence of inherited factors in AD, of course, indicates that subtypes of the disease do in fact have a genetic component. This is not as obvious as it might at first sound, given that even FAD patients do not develop AD until age 40 or so at the earliest. Thus, even the inherited forms of AD are time-dependent and multifactorial.

One mystery for FAD is how an inherited disorder, present from conception, can take so long to develop clinical manifestations. FAD may require a second (albeit common) environmental insult, perhaps even one that can accumulate over time. An alternative model is that the kinetics of the underlying biochemistry are extremely slow. Finally, it may be that the underlying process is one for which appreciable compensatory capacity exists relative to the rate of insult accumulation (see Box 4). At present, these temporal aspects of AD development remain inexplicable.

One commonality across all forms of AD is the involvement of the metabolism of APP and its products. All the FAD autosomal dominant mutations, and the inheritance of the ApoE-e4 allele, result in altered metabolism of the amyloid precursor protein (APP). These inherited factors moreover have in common that their major consequence is elevated production of Ap42 in the CNS. In the following sections, I will briefly review how this is thought to happen.

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