Smaller-effect genes reveal the complexity of Alzheimer’s
Genes affecting the generation of βAP from APP are rare, but they increase one’s chances of getting early-onset AD to near certainty.
Over the years, other genes and gene families impacting the risk of AD have emerged. These gene variants tend to have a much broader distribution in the general population, but their impact on increasing one’s lifetime risk of developing AD is lower than for the so-called familial genes.
Consequently, it has often been necessary to study large populations – as opposed to individual families – to identify these genetic risk factors.
The oldest and best known of these “smaller-effect” genes is a specific variant of apolipoprotein E, known as ApoE4. Possessing a single ApoE4 gene increases one’s lifetime risk of developing AD by three-fold in Caucasians.
While apoE studies by AD researchers have focused on its potential role as a βAP transport protein, this emphasis likely reflects the “βAPtist bias.”
ApoE has been studied more broadly for its causal role in vascular/metabolic disease. Viewed from this perspective, one needs to look no further than the APP gene that sparked the βAPtist movement to find AD’s vascular connections: Mutations within βAP lead to vascular diseases of the brain, and the best established function for one variant of APP is as a regulator of the blood coagulation cascade.
These and other findings in recent years have led AD to be viewed as a vascular/metabolic disease, even prompting AD to be referred to as “type 3 diabetes.”
The role of innate immune system genes in AD
Genome-wide association studies approach the genetics of AD from the opposite end of the spectrum as single family studies. These studies explore the full genome of very large numbers of individuals to look for genes contributing to risk of disease.
Such studies have identified novel genes and gene families that underlie the pathophysiology of AD. Among the more prominent of these players are genes of the innate immune system.
Studies that explore changes in transcriptional activity across the entire genome also implicate the innate immune system in AD.
One interesting example of note is TREM2, an innate immune gene that – similar to ApoE4 – increases lifetime risk of developing AD by three-fold in certain populations. TREM2 genetics extend the curious vascular connection of AD in a way similar to APP: While certain mutations increase risk of AD, other mutations lead to Nasu-Hakola disease – a vascular dementia.
Circling back to tau, there is still no identified tau genetic mutation leading to AD. While this fact has given tau a decided disadvantage in the βAPtist/Tauist war, other properties of tau pathology clearly implicate tau in dementia.
First, there are genetic mutations in tau known to lead to non-AD dementia. As we’ve seen with the TREM2 and APP examples, such mutations offer important clues about AD biology even if they do not specifically lead to AD.
Second, pathologic changes in tau are associated with a wide variety of central nervous system(CNS) disorders, collectively called tauopathies.
Third, the appearance of tau-related pathology in AD correlates much better with the onset of dementia than does the appearance of amyloid plaques (which can precede clinical AD by decades). Thus, the absence of a direct genetic link between tau and AD is a poor argument for de-emphasizing the potential role of tau in the pathogenesis of AD.
An integrated approach to AD is emerging
The recent string of clinical trial failures in AD will teach us little if they are used only to resurrect old βAPtist/Tauist rivalries. Rather, the emerging science reminds us that AD is a complicated disease with multiple stages of development.
Researchers are likely to learn much more about the biology of AD by investigating the common links among pathologies implicated in AD rather than studying those pathologies in isolation.
Four biologies ripe for investigating these common links in AD are βAP/amyloid pathology, tau/neurofibrillary tangle pathology, vascular/metabolic dysregulation, and innate immune dysregulation/neuroinflammation. Just a few of the many known intersection points for these biologies are mentioned here.
Putting all the biological puzzle pieces together will take time. Unfortunately, the AD epidemic facing the aging baby boomer generation is fast approaching with no time to spare.
In the absence of an integrated understanding of how AD develops and what treatments may work best at different disease stages, it is important, like in other complex diseases, to consider strategies such as combination therapy sooner than we might traditionally pursue these.
Apart from the many βAP-focused treatments in later stage clinical development for AD, TRx-0237 is a tau-focused compound in development.
A large number of tau-directed monoclonal antibodies are also in preclinical development. Agents having a vascular/metabolic disease focus include intranasal insulin, the PPARγ agonist pioglitazone, and the calcium channel blocker nilvadipine.
Treatments targeting the immune system include intravenous immunoglobulin and the RAGE antagonist TTP-488.
These agents and others that are more comprehensively reviewed elsewhere, together with symptomatic approaches such as the 5HT6 antagonist idalopirdine – an investigational compound designed to improve neurocognitive function – are possible contenders for combinations.
To make combination therapy in AD a reality, it will – to borrow a phrase – “take a village” to make it happen.
Leaders from industry, the Food and Drug Administration (FDA), the National Institutes of Health (NIH), academia, and patient groups will need to come together to enable funding, trial design, and solve a host of complex issues associated with delivering combination therapy.
But there is hope. Such public-private partnerships like the Global Alzheimer’s Platform and others have already begun to take up this important challenge.