My previous posting on Alzheimer’s focused on ways to avoid the most dire consequences of the disease in the absence of proven pharmaceutical interventions. The common assumption about disease management is that treatment begins when we develop symptoms. Then we go to the doctor, who most likely prescribes a course of treatment which probably includes taking a drug. The treatment may not make the illness go away totally, but at least it will help with the symptoms.

At this time, that is not the pattern with Alzheimer’s disease (AD). The treatment options now available at best slow the progression just a little, and no treatment has shown any signs of reversing the disease process. Because of the lack of effective treatment options, the best bet for us at this point is to do what we can to prevent the development of AD in the first place. I described two approaches that can (at least in many cases) work towards that goal.

One was minimizing chronic inflammation, since chronic inflammation contributes significantly to the accumulation of amyloid beta (Aβ) and tau neurofibrillary tangles. Both of those impede the transmission of information between brain cells. We can think of them as brain gunk that gums up the works. Chronic inflammation can be minimized through diet. The Mediterranean diet tends to avoid the most inflammatory foods and emphasizes anti-inflammatory foods. We’ll look at inflammation in more detail in a future offering.

The other was increasing what experts have called our “cognitive reserve,” which has been found to be reinforced by several factors, chief among which are education, mental activity and physical activity. Keep both the mind and body active, and you’ll improve your chances of keeping your wits about you.

However, there are models of disease management that might be made to work with Alzheimer’s. For example, there are several instances where disease management doesn’t begin with the symptoms, but with indicators that the individual is under threat of developing a disease. Just about everybody gets their blood pressure monitored fairly often, and many, many people have blood tests that measure blood sugar. In that way, heart disease and diabetes can be spotted before their most damaging consequences take effect. Women have mammograms to identify breast cancer in the early stages, and some intelligent men still have tests for prostate specific antigens (PSA).

If there were reliable tests that would predict the development of Alzheimer’s disease, it’s possible that some of the pharmaceutical treatments that, at this point, only confer a very small benefit to patients with established AD, might have a significant effect in preventing the full-fledged disease and its dire consequences – if treatment was to be initiated early enough.

The Lumipulse test

Identifying the factors that predict which individuals are likely to develop AD has been the subject of a great deal of investigation. Most recently, on May 4th this year, the FDA permitted the marketing a rapid test for the early detection of the amyloid beta (Aβ) plaques that are present in the brains of persons diagnosed with Alzheimer’s. The test, Lumipulse G β-Amyloid Ratio (1-42/1-40) test is intended to be used in adult patients, aged 55 years and older, presenting with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline. The availability of this test is considered to be a highly valuable advance, since up to this point confirming that such patients actually have AD could only be done via PET scans, which are expensive, cumbersome and time-consuming.

The FDA’s decision was based on a clinical study in which the Lumipulse test measured the balance between two specific proteins – Aβ I-42 and Aβ I-40 – in the cerebrospinal fluid (CSF) of 292 individuals with cognitive impairment. It has been determined that Aβ I-42 favors the formation of Aβ. In that clinical study, 97% of individuals with ratio of the two proteins was higher in Aβ I-42 demonstrated the presence of amyloid plaques confirmed by PET scan, whereas 84% of individuals with results higher in Aβ I-40 had a negative amyloid PET scan.

The Lumipulse test is important because it permits the identification of individuals who are on the way to developing Alzheimer’s disease based on the presence of amyloid beta. This test has the potential to enable the identification of those individuals many years before any signs of cognitive impairment appear. While the Lumipulse study was conducted in persons who already showed signs of cognitive impairment, there is evidence that in some persons, amyloid beta deposits are present as long as 20 years before any symptoms of cognitive impairment, and tau protein tangles as long as 6 years before cognitive symptoms.

The COLBOS Study

These data came from a study that has been going on in Antioquia, Colombia, South America, led by researchers at Massachusetts General Hospital. The study subjects are members of a very large family of more than 6,000 living members, a high proportion of whom have Alzheimer’s. In this family, a mutation known as Presenilin-1 E280A is very common, and those family members with the mutation are almost certain to develop AD dementia, usually showing signs of mild cognitive impairment in their mid-40s and full-fledged AD by age 50.

The researchers used functional magnetic resonance imaging (fMRI) to look at the connectivity within and between different networks of the brain. In individuals with the Presenelin mutation, disruptions in the brain’s memory network appeared several years before any signs of cognitive impairment. The impairment of the brain’s connective networks was closely aligned with the emerging presence of Aβ and tau protein tangles. (Sanchez, JS et al. Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer’s disease: findings from the Colombia-Boston (COLBOS) biomarker study. Alzheimer’s Res Ther. 2021 Jan 15;13(1):27 )

The COLBOS study, as we saw, used fMRI to identify the individuals with elevated Aβ and tau protein. Would the Lumipulse test, using the proportions between those two proteins as a predictor of Aβ, identify those same individuals, without the need for fMRI? That remains to be seen, but if it did identify those individuals, we would be miles ahead in spotting the persons most in need of intervention.

Another possible pre-AD marker with conflicting implications

This one is an enzyme, phosphoglycerate dehydrogenase (PHGDG), which was found to be consistently upregulated in the brains of persons with AD as compared with controls. Researchers at the University of California San Diego led by Dr Sheng Zhong published these findings on May 3rd in Cell Metabolism . (Chen X. et al, Cell Metab. 2022 May 3;34(5):651-653).

In 11 elderly subjects who developed signs of cognitive impairment, plasma PHGDH consistently exhibited increases as the subjects transitioned from normal to cognitive impairment. In 8 out of 9 subjects who did not develop signs of cognitive impairment, PHGDG remained stable. Researchers suggested that changes in the plasma levels of this enzyme could be useful as a presymptomatic indication of Alzheimer’s.

The researchers also analyzed genetic data collected from post-mortem human brains from subjects in four different research cohorts, each made up of 40 to 50 individuals 50 years and older.

The subjects consisted of Alzheimer’s patients, so-called “asymptomatic” individuals (people without cognitive problems and without an Alzheimer’s diagnosis, but whose post-mortem brain analyses showed early signs of Alzheimer’s-related changes), and healthy controls.

The results showed a consistent increase in PHGDH expression among Alzheimer’s patients and asymptomatic individuals in all four cohorts compared to the healthy controls. Moreover, expression levels were higher the more advanced the disease. The researchers also compared the subjects’ PHGDH expression levels with their scores on two different clinical assessments: the Dementia Rating Scale, which rates a person’s memory and cognitive ability, and Braak staging, which rates the severity of Alzheimer’s disease based on the brain’s pathology. The results showed that the worse the scores, the higher the expression of PHGDH in the brain.
The lead author, Dr Zhong noted, “The fact that this gene’s expression level directly correlates with both a person’s cognitive ability and disease pathology is remarkable. Being able to quantify both of these complex metrics with a single molecular measurement could potentially make diagnosis and monitoring progression of Alzheimer’s disease much simpler.”

But these findings come with a caveat. Along with its link with Alzheimer’s and dementia, PHGDH is also the enzyme that triggers the formation of the amino acid serine, which is currently being promoted as a nutritional supplement to improve memory and cognitive function. There is some evidence for the benefit of serine as a modulator of acute stress and schizophrenia, but evidence for its benefit to improve cognition is sketchy. An important link is that serine is required for the activation of the N-methyl-D-aspartate (NMDA) glutamate receptor, which plays a vital role in several important nervous system processes including brain development and learning. (More about NMDA a bit farther on in this piece.) However, despite that link, the substantial findings that brain levels of PHGDH increase with the severity of AD and dementia call into question the use of serine to improve cognition. In the absence of definitive evidence, the best advice might be to go slow with serine supplements.

Our blood profile as early as age 35 predicts the likelihood of developing Alzheimer’s

This information came from the Framingham Heart Study Offspring. As you may know, the Framingham Heart Study started in 1948 and has continued observing its participants since that date. The Offspring study was initiated in 1971 in order to observe the health characteristics of family members from a relatively young age.

The study subjects were grouped into three cohorts: early adults (ages 35 to 50, median 41), middle adults (ages 51 to 60, median 54), and late adults (ages 61 to 70, median 63.5). There were 271 participants in the study who were diagnosed with Alzheimer’s dementia. People with a diagnosis of non-Alzheimer’s dementia were excluded from the study. The control group consisted of 4,867 cognitively normal subjects.

One of the characteristics of the Framingham studies is that the follow-up periods are much longer than in almost all other studies. In the Offspring study, mean follow-up periods for people in the early, middle, and late age groups were 35.2 years, 25.8 years, and 18.5 years, respectively.

During the observation period, for every 15 mg/dL increase in HDL cholesterol (“good” cholesterol, in common parlance), the likelihood of Alzheimer’s dementia decreased by about 15% in early adulthood, and about 18% in middle adulthood.

And in middle adulthood, for every 15 mg/dL increase in blood glucose there was an increase of about 15% in Alzheimer’s dementia.

In late adulthood, a 10 mm increase in diastolic blood pressure was associated with a 14% increase in Alzheimer’s dementia.

Future development of Alzheimer’s dementia was progressively higher and likely to occur earlier among people who had blood glucose in pre-diabetic (100 to 126 mg/dL) and diabetic (>126 mg/dL) ranges in early adulthood and middle adulthood.

Lindsay Farrer, PhD, co-author of the Offspring study, noted: “While our findings confirm other studies that linked cholesterol and glucose levels measured in blood with future risk of Alzheimer’s disease, we have shown for the first time that these associations extend much earlier in life than previously thought.”

Does this mean that if a 35-year-old is found to have subnormal levels of HCL cholesterol and elevated levels of blood glucose, measures aimed at preventing the onset of AD should be immediately adopted? And, by the way, what measures might those be? The obvious answer, “do something about that person’s lipid balance and cut back on stuff like sugary soft drinks.” In other words, addressing the factors that lead to heart disease and also to type 2 diabetes would likely have the beneficial effect of reducing the chance that the individual will develop Alzheimer’s. This says nothing about the medical treatment of AD itself, but a great deal about the life-style behaviors that increase one’s chances of developing AD and how early in life these behaviors start.

Correcting vision problems may help decrease the prevalence of dementia

Hearing loss was listed as one of the modifiable risk factors in the Lancet Commission’s assessment of the key modifiable risk factors that could materially affect dementia. Vision loss was not included. But many of the ways in which hearing loss contributes to dementia apply also to vision loss. These include changes to brain structure and function, increased stress on cognition as the individual struggles to make sense of the impaired visual information, and also a degree of social isolation and loneliness.

Most vision loss is treatable by non-pharmacological means. Almost three quarters of adults in the US use some form of vision correction – eyeglasses and/or contact lenses. Some wear eyeglasses only for reading or close work; others for distance vision only. But many individuals struggle with uncorrected defective eyesight.

A recent prospective study found that cataract surgery decreased the odds of the person developing dementia by about 30%. The population attributable fraction (the proportion of dementia cases that potentially would be prevented if a risk factor were eliminated) of vision impairment was 1.8% in the 2018 Health and Retirement Study, representing more than 100,000 prevalent cases.

Preventing dementia and Alzheimer’s disease by addressing the risk factors

To cataract surgery and hearing aids as a means of preventing dementia (as well as the immediate aims of improving eyesight and hearing), we might consider adding those other population attributable risk factors as a form of preventive treatment.

Take a look at an analysis of data from the Health and Retirement study, which evaluated 16,690 participants, 54% of whom were female, 52% age 65 or older, 11% black, and 80% white.

The model included 12 dementia risk factors. The researchers calculated the population attributable fraction based on the prevalence and relative risk of dementia for each risk factor. (The population attributable fraction is the percentage of the total population of demented persons that can be attributed to an individual risk factor.)

Hypertension had the highest weighted population attributable fraction for dementia (12.4%), followed by obesity (9.2%), depression (9.1%), hearing loss (7.0%), traumatic brain injury (6.1%), diabetes (5.1%), smoking (3.2%), physical inactivity (3.1%), less education (3.1%), social isolation (1.9%), vision loss (1.8%), and excessive alcohol consumption (0.3%). (Varadaraj V et al. JAMA Netw Open 2021 Jul 1;4(7)

I am not clear as to how traumatic brain injury could be classified as a modifiable risk factor. It seems to me that more accurate terms might be “avoidable risk factors” or “external risk factors”.

Arriving at the individual percentages for each of these risk factors must have been an exceedingly complex process, since many individuals share several of those risk factors. There are certainly many persons with hypertension, obesity, depression, hearing loss, diabetes, smoking, and excessive alcohol consumption, and many of those individuals are in the less educated cohort. In such cases, do the percentages add up? According to my calculations, an individual with those characteristics would have a total risk factor of 49.4%.

A survey in 140,076 adults age 34 and older conducted by the CDC’s National Center for Chronic Disease Prevention and Health Promotion found that adults with subjective cognitive decline were likely to have a large number of modifiable risk factors for dementia. What is meant by “subjective cognitive decline” is that the individual says that he/she is experiencing more frequent confusion or memory loss.

More than one in three of these adults – 34.3% – had at least four of eight modifiable risk factors for dementia. In contrast, only 13.1% of the individuals without subjective cognitive decline had four of eight modifiable risk factors.

The eight modifiable risk factors in the CDC survey included high blood pressure, physical inactivity, obesity, diabetes, depression, smoking, hearing loss, and binge drinking. In persons with no risk factors, prevalence of subjective cognitive decline was 3.9%.

We should note that the modifiable risk factors used in the CDC study omit several of the modifiable risk factors used in the Health and Retirement Study, notably traumatic brain injury, less education, social isolation, and vision loss.

A study based on data from the Framingham Heart Study found that the factors associated with developing dementia varied by age. The study was based originally on 4,889 dementia-free participants, followed from age 55 to age 80, at which point there were 2,386 dementia-free participants.

• At age 55, diabetes and high systolic blood pressure were the most important predictors of future dementia.
• At 65, cardiovascular disease was the most important risk factor predicting 10-year dementia.
• For people in their 70s, diabetes and stroke topped the list.
• At 80, diabetes, stroke history, and antihypertensive use most strongly predicted 10-year dementia.

This study particularly focused on the relationship between cardiovascular risk factors and dementia, as would be expected from its origin in the Framingham Heart Study. What is especially valuable in this study is the 25-year period of observation, which permitted verification of the predicted incidence of dementia. The hazard ratios, which attempt to quantify by how much the risk factors increased the incidence of dementia, ranged from tripling the incidence in the case of diabetes at age 55 to doubling the risk in cases of cardiovascular disease or stroke at later ages. (McGrath ER. Neurology 2022 May 18:10.1212/WNL0200521)

What these studies point to is that, although at present there is no pill that will effectively reduce the progress of Alzheimer’s disease/dementia, there are measures that we can adopt that will greatly reduce the odds of developing that condition.

When it comes to searching for a possible drug that slows AD, researchers are not randomly going through the enormous number of possible compounds to see if any of them affects Alzheimer’s. What they are doing is looking for the mechanisms that result in those brain changes that are known to be associated with AD. This is like trying to prevent heart disease by treating some of the known causes of heart disease, such as high blood pressure and elevated low density cholesterol.

Addressing the mechanisms that result in the development of Alzheimer’s disease: Formation of amyloid beta

Since amyloid beta (Aβ) has been observed in the brains of persons with Alzheimer’s dementia and is assumed to be at least one of the causes of the decline in brain processing, it is eminently reasonable that targeting the formation of Aβ would be a principal strategy in preventing Alzheimer’s disease.

The formation of amyloid beta takes place when a protein known as the amyloid precursor protein is cleaved by an enzyme, beta (β) secretase (BACE). A class of drugs called BACE inhibitors blocks this process and can prevent the formation of Aβ, and therefore block or at least slow the development of Alzheimer’s by this means. Therefore, BACE inhibitors have been the focus of research by several pharmaceutical companies – however, without much success to date. BACE inhibitors are very large molecules, and they have great difficulty in passing through the blood-brain barrier in enough concentration to be at all effective. It was this unfortunate limitation that led to the poor performance of aducanumab/ Aduhelm and the ensuing fiasco, which we have discussed amply in these missives.

However, it is by no means impossible that another pathway might exist through which the actions of beta (β) secretase could be blocked, preventing the formation of Aβ and the resulting clogging of neuronal pathways. Research on this matter continues.

Another likely mechanism: NMDA receptors and synaptic dysregulation

NMDA is N-methyl-D-aspartate, which stimulates glutamate receptors in the brain, glutamate being the chief neurotransmitter in the brain, responsible for fast transmission of neuronal communications. But excessive stimulation of glutamine signaling can result in toxicity in the brain, thus pointing to a potential role for agents that would to some degree block NMDA receptors and thus dial down excessive glutamine signaling.

An agent that blocks NMDA receptors, craftily named namenda (Memantine, AbbVie) was approved by the FDA back in 2003. The best that can be said of namenda/Memantine is that it slows the progression of dementia in persons with Alzheimer’s disease – slows that progression to some degree, but not very much. If the progression of AD is tracked by the deposition of amyloid beta, namenda/ Memantine has no effect on the progression of the disease itself.

Memantine is also used in persons with Parkinson’s disease to slow the progression of the mental effects of that disease – dementia, and also depression. Again, as with AD, those effects of Parkinson’s are slowed, but not halted.

NMDA consists of seven different glutamine signaling sub-units which are active at distinct binding sites in the brain. These sub-units have differing functions and evolve at different rates. The most recently identified of these sub-units, GluN3A and GluN3B, were identified in 2010. The interaction of these sub-units is only now beginning to be understood. More sub-units may yet be discovered and the specific functioning of all glutamate signaling is in the process of being elucidated.

As understanding of NMDA and glutamine signaling progresses, it is likely that avenues will be identified to dial down excessive activity leading to neuronal harm and dementia. Namenda/Memantine will not be the only agent that has a beneficial effect in that area.

Most of the information about NMDA came from an excellent review paper, “The Role of NMDA Receptors in Alzheimer’s Disease.” (Liu J, Frontiers in Neuroscience. 2-19;13: Article 43)

Is there hope for simufilam?

Several readers have asked Doc Gumshoe for his views on this prospective drug. Hopes for simufilam (Cassava Biosciences) were soaring in late summer last year but have dimmed significantly since that time. However, as we know, hope springs eternal!

The mechanism whereby simufilam may deliver some benefit to persons with Alzheimer’s / dementia is definitely interesting and perhaps promising. Simufilam addresses a protein called filamin (hence simufilam’s name). Filamin interacts with Aβ I-42, which is the form of amyloid beta associated with Alzheimer’s disease. The binding of Aβ I-42 with acetylcholine receptors in the hypocampus and prefrontal cortex results in amyloid deposition and the phosphorylation of tau protein, two interactions that produce the plaque and fibrillary tangles that have been observed in the brains of patients with AD and are assumed to be the basic causes of the disease.

Injections of simufilam have been reported to prevent the association of filamin and acetylcholine receptors, reducing its effects on Aβ I-42 and tau, and normalizing signaling through those receptors as well as NMDA and insulin receptors. Early simufilam studies were limited to those interactions and did not evaluate the effects of the drug on cognition. However, in 2021 Cassava reported that simufilam treatment had resulted in increases in episodic memory and spatial working memory with effect sizes ranging between 17% and 46%.

Currently, two Phase 3 trials are underway. One is expected to run through October of 2023 and the other through June of 2024. Recruitment of subjects for these clinical trials has run into obstacles, and Cassava has also reported logistical difficulties such as staffing shortages. The two clinical trials were projected to enroll a total of 1750 subjects, but up to this point only 120 have been recruited.

Cassava has been the subject of citizen petitions requesting FDA action to halt simufilam trials, alleging research misconduct having to do with clinical trial biomarker data. In 2021 several independent scientists reported instances of data manipulation in published studies. Cassava denied wrongdoing, but admitted to errors in a poster. In March of this year, the journal PlosOne retracted five papers by a Cassava academic collaborator named Hoau-Yan Wang, and in November of 2021 the journal Molecular Neurodegeration retracted a paper, also by Wang.

The sole clinical trial in which simufilam was reported to produce positive results in cognition has been criticized on the ground that it lacked a placebo group, and also that the patients with Alzheimer’s were not followed long enough to confirm that the reported improvements in cognition were genuine.
It is not beyond belief that Casava knowingly overstated the results of its studies in order to inflate the stock price, which rose to dizzying elevations late last summer before deflating to about one-sixth of its all-time high. (As you know, discussion of stock performances is outside of my purlieu, but there’s clearly a relationship between clinical trial data and stock prices.)

The question that remains is whether the interaction between filamin and those crucial acetylcholine receptors can be targeted as a way of treating AD. Cassava is still engaged in the investigation of simufilam and its effects on that interaction, and it is certainly possible that hopeful data may emerge. We’ll watch for it.

Late breaking: good news for a drug that targets tau protein tangles

We have discussed TauRX and their lead drug, HMTM (hydromethylthionine mesylate) several times in past posts. HMTM so far is the most advanced agent that addresses those neurofibrillary tangles that clog the processing of information in the brains of AD patients. Preliminary results from the LUCIDITY trial, just announced on May 31st, suggest that cognition in participants receiving the drug declines at a rate substantially lower than is typical in patients with AD based on published research. The safety profile is positive. These results are based on a 12-month follow-up period in the blinded phase of the trial, which involved 598 subjects. The 12-month double-blind period will be followed by a one-year open label phase.

As a result of this information, TauRX will now seek regulatory approval for HMTN.

Adding one more means of addressing Alzheimer’s disease to the mechanisms we looked at earlier in this piece is certainly good news. We may be able to attack AD from all sides with the ultimate objective of defeating this aggressor altogether.

* * * * * * * *

By now, all coffee drinkers should be celebrating. A study just published in The Annals of Internal Medicine concluded that people who drank from one-and-a-half to three-and-a-half cups of coffee per day were about 30% less likely to die during the study period (which extended seven years) than non coffee drinkers. This included coffee drinkers who added a teaspoonful of sugar. The cohort that restricted itself to non-sweetened coffee were 16% to 21% less likely to die during the study period. The group with the lowest risk of death drank about three cups per day.

The information was based on data from the UK Biobank, which analyzed demographic, lifestyle, and dietary information from more than 170,000 people over a period of seven years.

I would add that previous studies have found that coffee consumption aligns with a lower risk of Parkinson’s disease, heart disease, Type 1 diabetes, liver cancer, prostate cancer, and other issues.

So, as the song went, “Let’s have another cup of coffee!” I will leave the concluding line, “And let’s have another piece of pie” to be verified or contested by further studies.

Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]