That’s a result of Xu et al 2022, “Accelerated epigenetic aging in newborns with Down syndrome”.
This study furthers our understanding of a syndrome of accelerated aging. The authors show a significant acceleration of an epigenetic aging marker in the blood of people with Down syndrome. Furthermore, they show that this effect is present at birth and is significantly stronger in newborns who have Down syndrome plus GATA1 mutations. This association with GATA1 mutations is intriguing as GATA1 mutations are associated with transient abnormal myelopoiesis. One thing that this study does not do is investigate the mechanism by which this age acceleration occurs.
One hypothesis based on this finding is that it might help explain why people with Down syndrome have an increased susceptibility to Alzheimer’s disease. Lore has long been that this is due to the triplication of amyloid precursor protein, however, this study suggests that age acceleration may also play at least a part in the increased susceptibility of people with Down syndrome to aging-associated cognitive impairment and Alzheimer-type neuropathology.
A new-to-me concept is the idea of an Everest regression — “controlling for altitude, Everest is room temperature” — wherein you use a regression model to remove a critical property of an entity, and then go on to make inappropriate/confusing/misleading inferences about that entity.
My immediate thought is that this is an excellent analogy for one of my concerns regarding regressing out the effect of age in studies of Alzheimer’s disease (AD). It’s such a tricky topic.
On the one hand, not everyone who reaches advanced age develops the amyloid beta plaques and other features that defines the cluster of AD pathology. Whereas there are potentially other changes in brain biology that you will see in advanced aging but not AD, such loss of dendritic spines, epigenetic changes, and accumulation of senescent cells.
On the other hand, advanced age is the most important risk factor for AD and explains most of the variance in disease status on a population basis. Arguably, a key part of why some “oldest old” folks do not have AD are protective factors. There have also been suggestions that accelerating aging is part of AD pathophysiology; although, as far as I can tell, the evidence for this remains preliminary. From this perspective, advanced age in AD is like the high altitude of Everest — it’s one of the key associated features.
So if you are trying to find the effects of AD pathophysiology, for example in a study of postmortem human brain samples, should you adjust for the effect of age or not? This is a practical and tricky question without a clear answer. It probably depends on your underlying model of how AD develops in the first place.
So I think it’s worthwhile to be cognizant of the potential hazards of adjusting for age — namely, that you risk inadvertently performing an Everest regression and removing an important chunk of the pathophysiology that you actually want to understand.
In the past 20 years, deep brain stimulation (DBS) has been used for over 100,000 patients with Parkinson’s disease. The success of this procedure has led investigators to try DBS for other neurologic conditions, such as Alzheimer’s disease (AD).
In 2016, Lozano et al reported on one of the largest trials for DBS in AD, the “ADvance” trial, in which they targeted the fornix, a bundle of nerve fibers in the center of the brain that is the major output tract of the hippocampus.
This was a well-run, double-blind, randomized study. One of the nice aspects about brain stimulation trials is the ease of performing a sham stimulation arm. That is, treatment can be randomly turned either “on” and “off” for a period of time, allowing a subset of participants to serve as controls (stimulation turned “off”) for a period of time before they actually do get the stimulation (stimulation turned “on”) in case it is actually helpful.
In terms of the trial results, one of the patients (out of 42) had an implant infection. Overall, the trial did not show a significant benefit mitigating the decline in ADAS-13 or CDR-SB scores (measures of cognitive function):
While this trial did not show efficacy at their sample sizes, personally I expect that DBS for early AD could work to at least alleviate symptoms, if the right circuits were targeted at the right time.
My reasoning here is that we know that a few other cognitive strategies can help slow the course of AD, including processing speed training and acetylcholinesterase inhibitors.
There are at least 4 active DBS trials for AD on clinicaltrials.gov:
An important paper from Füger et al last month, in which they labelled individual microglia in mouse brains and tracked their locations over 1.5 years. Here were some of their major findings:
The median lifespan of microglia was estimated to be approximately 2.5 years, which is close to the mean lifespan of the mice that they were studying. So, it is fair to think of microglia as long-lived tissue macrophages. It is also clear how changes in microglia epigenetics in earlier life could affect late-life cognitive outcomes.
Microglia died at a higher rate in older mice, suggesting that aging may lead to alterations in microglia function that could affect neurodegenerative disease.
In APPPS1 mice, microglia proliferate 3x more than usual in areas of the cortex without amyloid plaque, but only proliferate a normal amount in areas of the cortex with amyloid plaque. This suggests that any increase in microglia near plaque is likely due to migration, not local proliferation.
An interesting study from Risacher et al splits ADNI participants into three subtypes of Alzheimer’s, based on whether their baseline atrophy was more severe in the hippocampus and/or cortex. These groups were previously defined based on where in the brain pathologic tau deposits are predominant on postmortem exam, but the authors adapted them to the MRI level. Here were their definitions:
We know that many traumatic brain injuries (TBIs) can be devastating. An important research topic is predicting what the effect a TBI of a particular type and severity will have on neuropathology and behavior.
Neuropathology is relatively easier to measure, but it is still hard to tell causality because a lot of the “markers” of TBI seen on neuropathologic exam are also sometimes seen in individuals who never had a TBI. Although their degree or distribution might be different.
Behavioral effects of TBI are especially hard to measure because you need standardized measures across time in both TBI-affected and TBI-unaffected individuals, controlling for all of the other factors that are known to affect behavior. A tough nut to crack.
They compared the postmortem brains from donors with schizophrenia treated with prefrontal leucotomy (n = 5; more than 40 years prior to death) to age-matched donors with schizophrenia who hadn’t undergone leuctomy (n = 5).
Leucotomy, an obsolete treatment for schizophrenia, involved traumatic interruptions of white matter axons in the prefrontal cortex via burr holes. Here is what the lesions look like on MRI:
These authors looked at cortical tissue slices cut in the coronal plane at the leucotomy site, as well as slices rostral and caudal to the site.
Here were some of their findings:
They found phosphorylated tau in neurons and astrocytes in cortex adjacent to the leucotomy site in 5/5 of the donors treated with leucotomy, but not in the rostral/caudal sites or in the donors who did not have leucotomy.
The p-tau tended to be at sulcal depths or surrounding small blood vessels. This is similar to what is seen in CTE.
They also found amyloid beta depositions in the cortex near the leucotomy sites, but only in the 3/5 donors who had at least one APOE ε4 allele.
Overall, this is really nice study that allows us to see the effect of TBI-associated axon injury in humans in a precisely controlled manner. What we see is that it causes phosphorylated tau accumulations in a similar distribution to that of CTE.
BIIB076 = a monoclonal antibody against both monomeric and fibrillar tau
Both of these drugs are also being tested in PSP, which is a relatively rare, classical familial tauopathy in a way that AD isn’t — because in PSP, the 1-5% of familial cases are known to be caused by certain MAPT mutations. Whereas I don’t know of well-validated genetic mutations in MAPT that are associated with increased risk of Alzheimer’s, except for some preliminary reports of small statistical associations, such as this one.
To try to force myself to be accountable and quantitative, what is my prediction for the probability that each of these two drugs will be approved by the FDA by the end of 2025? Same rules and disclosures as my previous post about this, but two years extended because these drugs are in earlier stages of development.
I’m going with 2.5% for BIIB092 (in phase II) and 1.5% for BIIB076 (still in phase I). Clearly abnormalities in tau proteins are highly associated with pathogenesis in AD, indeed more strongly associated than Aβ, and there have been a number of suggestions that the tau abnormalities are causal.
But in my opinion, we don’t know for sure yet that these tau abnormalities are truly causal, and that stopping tau aggregation will be helpful.
On one hand, if an anti-tau antibody works, why shouldn’t an anti-NFL antibody, or any of the other proteins that are markers of axonal damage in AD and are inversely associated with cognitive status? Maybe they all would, but this thought experiment is a bit troubling to me.
On the other hand, anti-tau antibodies have already been shown to be helpful in an APP-overexpressing AD mouse model, improving both cognitive function and the proportion of mushroom dendritic spines.
It is asking a lot, but I would be more confident about the clinical relevance of this type of mouse study if it were shown that immunotherapies against other protein markers of axon damage, such as anti-NFL antibodies, were not successful in ameliorating cognitive decline, as a negative control.
Certainly I will be rooting for these anti-tau drugs to be successful in clinical trials and I think they make a lot of sense, but like most AD drugs in development, my prediction is that they are a long shot.
Idiopathic normal pressure hydrocephaus (NPH) is a diagnosis of occult hydrocephalus with normal CSF pressure on LP that was first described in 1965 and is often considered one of the treatable causes of dementia.
The original paper used the now uncommon brain imaging technique of pneumoencephalography, which involved draining the CSF, injecting air as a contrast medium, and performing a brain xray:
At my med school we learned NPH by the triad of “wet, wobbly, and wacky”, referring to its classic triad of symptoms: urinary incontinence, gait disturbance, and cognitive impairment.
Like many symptom triads, these symptoms are non-sensitive, with the full triad seen in <60% of patients. It is also non-specific, as urinary incontinence is seen in ~20-40% of those over 60, gait impairment is seen in ~20% over those over 75, and mild cognitive impairment is seen in ~35% of those over 70.
Espay et al explain all of this in the introduction of their critical literature review of idiopathic NPH. One of their major points is that ventricle enlargement is also non-specific, as it is common in other neurodegenerative diseases such as AD, DLB, and PSP.
Here are some of their other points:
There are no specific clinical, imaging, or neuropathologic findings in NPH.
The determination of ventricle enlargement on MRI is subjective and not standardized.
A “true” diagnosis is dependent upon a treatment response to CSF diversion via a ventriculoperitoneal shunt (VPS), which is circular and problematic.
There has never been a well-defined RCT to evaluate the use of VPS in NPH.
Because many patients diagnosed with NPH may in fact have NPH that is secondary rather than a precursor to other neurodegenerative diseases, the fact that VPS may lead to short-term cognitive amelioration even in these patients suggests that VPS should still be considered as a way to improve cognition even in patients that are diagnosed with these neurodegenerative diseases.
Overall, this paper is well worth a read for people interested in treatments for dementia.
Cells can die for a variety of reasons. Some of them are intentional (“programmed”) in response to exposure to external stressors (like viral or toxic molecules) or internal problems (like DNA damage). And some of them are unintentional (“non-programmed”), which often involves the premature breakdown of cell membranes and loss of cell contents.
Their evidence spanned multiple human data sets of postmortem AD brains and mouse models (5XFAD), and showed that markers for necroptosis (MLKL, RIP1, RIP3) were often significantly correlated with the degree of AD neuropathology seen in those brains.
Notably, their data didn’t provide strong evidence to exclude apoptosis and non-necroptosis necrotic cell death pathways as also contributory to cell death in AD.
So, another study that would also be interesting would be to see a more global comparison of all different types of cell death, to see which markers correlate the strongest with AD neuropathologic changes.
On the other hand, the authors note in their discussion that there is a lot of cross-talk between necrosis and apoptosis, which means that it may be difficult or not make sense to distinguish between them in this way.
Even if necroptosis is the mechanism of cell death in AD, that doesn’t mean that we can just turn off this cell death pathway and rescue neurons and memory. If anything, it suggests that the neurodegeneration itself is intentional, likely helpful to mitigate even more damage, and that changes to stop AD will have to occur much farther up to pathogenic cascade.
Still, it’s critical to understand exactly what is the pathway of degeneration in AD so that we can figure out what to target, and this study might be an important part of that.
Many articles include the premise that Alzheimer’s disease (AD) neuropathology is unique to humans. However, there is a large body of literature suggesting that the characteristic neuropathology of AD, including diffuse amyloid plaques, neuritic amyloid plaques, and abnormally phosphorylated tau, are also seen in some non-human primates.
One of the only exceptions where AD pathology has not been commonly reported is coexisting amyloid plaques and neurofibrillary tangles, although even this has been reported in one chimpanzee.
On the genetic level, tau is identical between chimps and humans, while APP is 99% identical.
It is not that surprising that chimps would have the most similar neuropathology as humans, because chimps (and bonobos) are among the most similar non-human primates to humans.
Now, a nice article from Edler et al examines neuropathology from 20 chimpanzees aged 37-62 to directly interrogate the presence of AD neuropathology in a large sample.
The authors scored neuropathology in all 20 chimpanzees in 4 brain regions (PFC, MTG, CA1, CA3) using the following scoring system:
Here were some of their findings:
All of the chimps had APP/Aβ and Aβ-positive blood vessels, while only 2/3rds had plaques not associated with vessels, suggested that Aβ accumulation near blood vessels may be an early or precursor lesion in chimps.
Cerebral amyloid angiopathy, which is seen in 80% of AD patients, had a strong association with tau pathology in their chimps, especially pretangle density:
On the other hand, Aβ42 levels were not correlated with tau pathology.
Pretangle and NFT staining in chimps followed the pattern of Braak staging seen in humans.
In reviewing the literature, they note that only subtle, but not profound, age-related memory decline has been demonstrated in chimps. This may be because chimps have differences in APOE and other factors, but it is also the case that very few studies have directly addressed this question.
Overall, the most important finding from this study confirmed the previous 2008 report from a single chimp that amyloid and tau can coexist species other than humans.
These non-human primate studies shine an important light on the true biology of AD, which is especially important to consider when evolutionary or environmental explanations are invoked to explain the disease.