It is now more than 15 years since the discovery of the first genes involved in AD, and while we are still on a quest for additional genes, we have learned a lot about the disease. The processing of APP through cleavage by γ-secretase, an enzymatic complex whose catalytic subunit is formed by the presenilins [38
], is considered by many as a key in the disease process. It leads to generation of the amyloidogenic peptide Aβ (Figure ) and its aggregation into fibrils and toxic oligomeric forms, the earliest effectors of synaptic compromise [39
], followed by neurodegeneration. The direct involvement of the products of at least three out of the four known genes in this hypothesis is no coincidence and significantly strengthens the confidence that this is a promising target for treatment. These genes have greatly enhanced our knowledge of the pathway leading to the production of amyloid (Figure ), which has in turn provided targets for intervention.
Figure 1 The amyloidogenic and non-amyloidogenic cleavage pathway of APP. Mutations in APP, PSEN1 or PSEN2 cause early-onset AD. PSEN1 and 2 are components of γ-secretase. The amyloidogenic peptide Aβ is shown in orange. reliable associations from (more ...)
Treatments targeting APP processing include those diverting cleavage toward the non-amyloidogenic α-secretase pathway (α-secretase enhancers) and those inhibiting the amyloido-genic pathway of beta and gamma secretase (β- or γ-secretase inhibitors). Pharmacological agents that enhance α-secretase activity include, among others, non-steroidal anti-inflammatory drugs (NSAIDs), statins and estrogens through activation of protein kinase C [40
]. These agents have been tested with varying results. The effectiveness of estrogens has been suggested by many in vitro
and in vivo
studies; however, data from the Women's Health Initiative Memory Study [41
], a large randomized controlled trial, did not show a consistent positive effect. The possibility that there is a critical period for neuroprotection [42
] and that genetic variation or other predisposing factors might modify the effects of estrogens requires further examination [43
]. The use of NSAIDs has seen support from epidemiological studies as likely to reduce the risk for the disease; however, the results of clinical investigations so far have not been encouraging [44
]. The use of statins for AD prevention has shown conflicting results. Initial cross-sectional studies showed risk reductions that were better than 50% (for a review see Rockwood et al
]). Clinical trials and cohort studies, however, failed to show the protective effect that has been consistently observed in cross-sectional studies [46
The possibility of indication bias in cross-sectional studies (that is, people with AD are less likely to receive statin treatment) cannot be ruled out, although it has been accounted for by some studies [46
]. The debate and interest in statins remains open, as support from prospective clinical trials is clearly necessary before they can be considered a preventive measure for AD [47
]. The recognition that ADAM10
from the ADAM family of metalloproteases exhibits α-secretase activity [48
] and is regulated by retinoic acid [49
] has led to the inclusion of retinoic acid in the list of potential therapeutic agents [50
]. Retinoic acid has shown promising results in an AD mouse model [51
] but its potential as a therapeutic agent for AD in humans has not yet been examined.
Agents that inhibit the amyloidogenic pathway include β-and γ-secretase inhibitors. Beta-secretase inhibitors have only recently been developed [52
], and initial tests on transgenic mice are positive, showing decreased Aβ production [53
]. Gamma-secretase inhibitors have also shown positive results in laboratory animal models and, administered in low doses, they are safe in humans and reduce plasma Aβ [54
]. A major limitation in the use of these inhibitors is that APP is not the only substrate of γ-secretase. Other substrates include NOTCH, ERBB4 and many other type I membrane protein stubs [54
]; therefore, significant inhibition of the enzyme could lead to serious side-effects. This limitation might be bypassed to some extent as more selective agents are developed.
The role of APOE
in AD appears to be more complex than that of APP
and the presenilins. Studies of its functional involvement have implicated the homeostasis of cholesterol and phospholipids, synaptic integrity, amyloid metabolism, phosphorylation of tau, accumulation of neurofibrillary tangles and neuronal survival [55
]. Nevertheless, APOE
is an important player in pharmacological intervention research. Many studies have suggested that the APOE
genotype can influence the outcome of existing treatments [56
], making it interesting from a pharmacogenetics perspective, while others have suggested that targeting the regulation of APOE
expression is a potential treatment approach [55
]. Interestingly, drugs that modify the expression of APOE
include statins which, as discussed above, have already shown promise.
Many of the genes that have been implicated in AD - albeit not consistently - by association studies are involved in multiple aspects of the disease [58
], including the generation of neurofibrillary tangles, amyloid aggregation, amyloid clearance, oxidative stress and hypoxia, inflammation and apoptotic cell death. Most of these processes are already targeted by therapeutic agents either directly or through effects of drugs chosen to target other disease mechanisms. When the validity and exact nature of the genetic associations is elucidated in the near future, together with new reliable associations from GWAS, the best targets and strategies to intervene will become clearer.
At the level of molecular genetic diagnosis and risk assessment, there is a sharp divide between early- and late-onset disease. In FAD, mutations in one of three genes (APP
) can be found in more than 80% of patients [59
]. Although there is currently no effective cure or prevention strategy, knowledge of the risk, and prenatal diagnosis, might be desired and is possible. For late-onset AD, however, our current knowledge does not allow useful genetic testing. The increase in risk by APOE
ε4 is of questionable use as most carriers will not become affected and half of the patients do not carry this allele. This is even more questionable for less established genetic associations. As we begin to discover more and more genes and genetic variants involved in AD and learn the details of their functions and interactions with each other and the environment, it is most likely that one day in the not so distant future accurate risk and age of onset prediction will become a reality. Such capability, combined with strategies for prevention and effective treatments, perhaps tailored to each patient through pharmacogenetics, could lead to solving this major public health problem.