Most AD is late-onset, and results from a combination of numerous genetic factors (many different mutant gene variants) as well as environmental factors such as aging. One of the strongest common genetic risk factors is the ε4 mutant allele of the APOE gene, which shows dose-dependent effects with two copies of the mutant allele conferring greater risk than one copy, whereas the APOE ε2 allele can be protective (ε3 is the wild-type allele). The APOE protein is involved in the transport of cholesterol to the membranes of neurons.
Beyond APOE, dozens of common and rare variants have been identified that associate with AD risk; they are identified through genome wide association studies (GWAS) that analyze the association of genetic variants with a disease phenotype such as AD in large populations. Collectively these investigations underscore that late-onset AD risk emerges from many small-effect alleles interacting with age and environment.
As mentioned above, dominant (only one of two genes needs to be mutant to give rise to AD) PSEN2 mutations can cause early-onset familial Alzheimer’s by altering the activity of γ-secretase, the intramembrane protease that generates amyloid-β (Aβ) peptides from APP. Excess and mislocalized Aβ produce amyloid plaques that are characteristic of AD. These deposits can kill neurons directly, and in addition drive the hyperphosphorylation of the microtubule-associated tau protein, which aggregate inside of neurons giving rise to neurofibrillary tangles (NFTs) that are toxic and correlate closely with cognitive decline (QH). Clinically, PSEN2 families show high but not 100% penetrance with onset typically in mid-life, though variability in age of onset suggests the influence of modifier genes and environments that can modulate disease severity including some members with the PSEN2 who manage to avoid early-onset AD.
Recently, The New York Times profiled one such person, Doug Whitney (aged 76, Figure 1) who carries a rare Presenilin-2 (PSEN2) mutation that has caused early-onset Alzheimer’s in many of his relatives (often by age 44–53). His family is the largest known in the U.S. with an Alzheimer’s-causing mutation. While he has escaped symptoms for ~25+ years beyond expectation, Whitney’s mother, nine of her 13 siblings, and his oldest brother died young from Alzheimer’s.
MRI scans reveal that Mr. Whitney's brain is laden with amyloid plaques as expected, but surprisingly, they also show only a small amount of tau tangles (NFTs) that are limited mainly to the left occipital lobe (visual–spatial area), not in areas involved in cognition and memory (e.g. hippocampus). Symptomatic AD patients typically exhibit large amounts of both, and as mentioned above, tau NFTs are diagnostic for cognitive decline. High amyloid deposits but low tau tangles is referred to as amyloid-tau decoupling, which tends to protect the subject against AD.
One possible explanation is that Mr. Whitney possesses genetic suppressors, i.e. mutations/variants in other genes that neutralize the impact of his PSEN2 mutation. In the literature, there are a limited number of such genetic suppressors that have been characterized, and in particular there are very few single gene suppressors. Two of the most prominent are:
- APOE3-Christchurch (R136S): found in a PSEN1-E280A carrier who stayed cognitively intact for decades and displayed high amyloid but low tau (i.e. decoupling).
- APOE3-Jacksonville (V236E): reduces ApoE self-aggregation and is associated with lower dementia risk and healthier brain aging.
Both are rare single mutations in the APOE gene, and they further implicate this important gene as central in Alzheimer's Disease pathophysiology.
Polygenic suppressors are more likely than a single gene suppressor because the action of multiple variants can combine to suppress the action of the AD-inducing (e.g. PSEN2) mutation. Sequencing of Mr. Whitney's genome did not reveal any of the known single gene suppressors, and so researchers speculated that he may possess uncharacterized polygenic suppressors (link). Bioinformatic analysis suggested candidate suppressor variants but further confirmatory work is needed.
Mr. Whitney's 53-year-old son Brian inherited his PSEN2 mutation but is still asymptomatic. One possibility is that he also inherited his Father's putative polygenic suppressors. A complicating circumstance is that Brian is participating in long-term anti-amyloid clinical trials and continues infusions, raising the question that he is also benefiting from the treatment, which may be preventing or delaying symptom onset.
In a previous post, I described one (somewhat controversial) anti-Alzheimer's Disease treatment. The drug aducanumab (brand name Aduhelm) developed by the biotech company Biogen is a monoclonal antibody that binds Aβ peptides, which helps to clear the extracellular amyloid deposits from synapses and other areas around neurons. MRI imaging shows that the antibody is indeed very effective at reducing the amount of amyloid in the brain, but unfortunately the clinical efficacy on dementia symptoms is much more modest with some studies showing a statistically significant small effect, while others show no improvement. Along with aducanumab, several other anti-amyloid monoclonal antibodies have been approved by the FDA for treatment against AD, but they all remain controversial because of their modest efficacy, high price tag, and sometimes dangerous side effects.
One hypothesis explaining the disappointing efficacy of these therapeutic antibodies despite their ability to clear Aβ amyloid from the brain is that Alzheimer's Disease is a two-step process. First, amyloid builds up from APP cleavage into pathogenic Aβ peptides, then in the second step, the deposits somehow trigger the hyperphosphorylation of tau leading to its aggregation and the formation of tau tangles. These NFTs are downstream mechanistically of amyloid, and hence are the more proximal cause of AD-related dementia. It is possible that in treatment patients the drug is given too late: the amyloid has already generated excess NFTs, which are irreversible, and so removing the amyloid has little effect on decreasing the amount of NFTs.
In the context of this two-step hypothesis, the genetic suppressors are acting on the second step, i.e. the amyloid giving rise to tau hyperphosphorylation and tangles. By preventing or slowing this process, the suppressor variants can decouple amyloid accumulation from tau pathologies. One can envision developing a drug that somehow mimics this decoupling by inhibiting amyloid stimulation of NFTs. APOE is a natural target given the single gene APOE suppressors (Christchurch and Jacksonville) described above.
In summary, the genetics provides hints about the pathophysiology of Alzheimer's Disease. Mr. Whitney is living proof of how putative genetic suppressors may attenuate the impact of a dominant AD-inducing mutant allele by decoupling amyloid build-up from tau tangles. His son Brian inherited the PSEN2 AD variant, but also likely inherited some of the polygenic suppressors that have helped his Father. In addition, Brian is receiving AD treatment, probably monoclonal antibodies against Aβ that help to clear amyloid from the brain. This combination may point the way to possible combination therapies that block both steps in the two-step AD pathogenic process: amyloid accumulation and tau aggregation into tangles.
Figure 1. Doug Whitney with his wife at the Dominantly Inherited Alzheimer Disease Conference this summer (Ian Willms for The New York Times).
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