Averting the road to dementia …

Galantamine Reduces
Brain Shrinkage

… and helps prevent Alzheimer’s disease

By Will Block

It is the sweetest spring within the memory of man. So green, so mild, so beautiful! Ah, what a contrast between nature without and my own soul so torn with doubt and terror! It has been an uneventful day, but I know that I am on the edge of an abyss [Emphasis added].

— Arthur Conan Doyle
(creator of the detective Sherlock Holmes, 1859–1930)

D o you know anyone with mild cognitive impairment—also known as MCI? MCI is associated with a impaired cognitive function and typically involves reduced memory and thinking abilities. Compared to the expected mental agility based on one’s age and educational level, MCI is characterized by a worsening of alertness and other cognitive functions such as attention, language and visuospatial skills.

However, MCI does not (yet) meet the clinical criteria for dementia. Nonetheless, with MCI that abyss of dementia is more likely to come. To repeat the opening question: do you know anyone with MCI? The answer is “yes,” and that person is more and more likely to be you. As the pages of time turn, MCI is projected to approach ⅓ or more of the >65 population. (see Fig. 11).

Figure 1. Prevalence (2010) and projected population estimates in 2030 and 2050 for the number of US adults over age 65, with Alzheimer’s dementia, and with cognitive impairment based on US Census Bureau population projections.
LEM1410mainFig1_274.gif
(click on thumbnail for full sized image)

Decreasing the Conversion to Dementia

In a new study using a wealth of unanalyzed data from the Gal-Int-11 trial,2 MCI subjects treated with galantine demonstrated a lower rate of brain degeneration than those receiving placebo.3 Specifically, subjects given galantamine were shown to have a lower rate of whole brain atrophy (shrinkage) compared to those given placebo (adjusted mean difference 0.18% per year).

Maintaining whole brain volume is beneficial because MCI causes a higher rate of conversion to dementia, a disease in which cell damage leads to tissue shrinkage and reduced function in the brain’s frontal and temporal lobes. These lobes control planning and judgment functions, along with emotions, speaking and understanding speech, and certain types of movement. To date, no study has evaluated the effect of galantamine on the rate of changes in brain volume in patients with MCI.


MCI subjects treated with
galantamine demonstrated
a lower rate of whole brain atrophy
(degeneration) than those
receiving placebo.


Protective Effect in Those Most Susceptible

The study extended over a 24-month treatment period, and compared the brain volume from 364 MCI patients who received either (galantamine, n = 176) or placebo (n = 188). The protective effect of galantamine on whole brain atrophy rate in MCI was only present in apolipoprotein E (ApoE) ε4 carriers. Individuals with APOE ε4 carriers are significantly more susceptible to Alzheimer’s disease (AD), the most severe form of dementia. That is why ApoE ε4 is called a risk-factor gene.


Do you know anyone with MCI? The
answer is “yes,” and that person is
more and more likely to be you.


The Injurious ε4 Variant of ApoE

Figure 2. An overview of APOE4’s (aka ApoE ε4 allele) effect on neurons in Alzheimer’s disease.
LEM1410mainFig2_274.gif
(click on thumbnail for full sized image)

ApoE is a class of apolipoproteins found in the chylomicron and intermediate-density lipoprotein (IDLs)—two of the five major groups of lipoproteins, together with VLDL, LDL, HDL (very low density, low density, and high density lipoproteins)—and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents and fat-soluble vitamins. However, defects in the ApoE ε4 allele result in impaired clearance of chylomicron, VLDL and LDL (the bad cholesterol) remnants. VLDL converts to LDL, so it too may be thought of as bad. Studies show that the ε4 variant of ApoE is noticeable for its role in several biological processes not directly related to lipoprotein transport. These disruptions can precipitate immunoregulation and cognition problems, as well as AD (see Fig. 2).


MCI causes a higher rate of
conversion to dementia.


MCI Increases the Risk of Alzheimer’s

Patients with MCI are at increased risk of developing AD, with up to 15% of these patients progressing to dementia per year, compared with up to 2% of the normal elderly population. This represents a 7½ times greater risk of converting to AD. Fortunately, advancements in magnetic resonance imaging (MRI) scanning have added to our understanding of the brain changes associated with both MCI and AD.


To date, no study has evaluated
the effect of galantamine on
the rate of changes in brain volume in
patients with MCI.


Brain Shrinkage Characteristic of Alzheimer’s disease

Brain atrophy is a pathologic change characteristic of AD. Brain imaging studies demonstrate progressive reduction in whole brain volumes and volumes of the amygdala, hippocampus, and parahippocampal gyrus. At a group level, the degree and rate of medial temporal lobe and brain atrophy in individuals with MCI is greater than that in normal controls, and less than that in patients with AD. In MCI subjects, a lower brain or hippocampal volume or a higher rate of brain or hippocampal atrophy is predictive of progression of MCI to AD.


ε4 variant of ApoE can precipitate
immunoregulation and cognition
problems, as well as AD.


Also, in ApoE ε4-positive individuals, moderate to severe sleep disordered breathing is associated with poorer performance on cognitive tests that require both memory and executive function engagement.4

Once again, the researchers reinvestigating the data of the Gal-Int-11 trial found that galantamine lowered the rate of brain atrophy in MCI patients who were ApoE ε4 carriers. Compared to non-carriers, these MCI patients are more likely to have underlying AD pathology. Also, the researcher’s results indicate that a potential beneficial effect of galantamine on brain atrophy may be restricted to MCI patients with underlying AD pathology.


In MCI subjects, a higher rate of brain
or hippocampal atrophy is predictive
of progression of MCI to AD.


As readers of this publication know very well, acetylcholinesterase inhibitors (AChE inhibitors) such as galantamine have previously been shown to exhibit a neuroprotective effect via the nicotinic acetylcholine receptor-mediated cascade. However, AChE inhibitors which are not positive allosteric modulators of nicotinic receptors have not shown significant effects on brain or hippocampal volume loss in placebo-controlled studies of 2 to 4 years’ duration in MCI patients.

It has also has been reported that AChE inhibitors hinder the progress of brain atrophy in AD, indicating the lessening of neuronal death in the brain of the patients. The reduced rate of whole brain atrophy observed in the new trial provides clinical evidence of neuroprotection with galantamine treatment.


It has also has been reported that
AChE inhibitors hinder the progress of
brain atrophy in AD, indicating the
lessening of neuronal death in the
brain of the patients.


What is the Prevalence of the ε4 Variant of ApoE?

In a Chinese study, the frequency of the ε4 allele was 19.6 percent for the entire sample of patients who had memory complaints, with greater prevalence in women vs. men (22.6% and 14.9%, respectively).5 In another study, examining the prevalence of the ε4 allele among an AD diagnosed population in Europe, the highest rate was in Northern Europe where it was 61.3%! Depending on which study you read, among the general population in the US, about 20% of the population has at least one ε4 allele, while about 2% have two ε4 alleles. As you’d expect, having two is worse than having one in terms of Alzheimer risk. Be reminded that if anyone in your family has had either memory problems or been diagnosed with AD, you have an increased risk of possessing the dreaded ε4 variant of ApoE.

Can I Be tested for ApoE ε4?

It used to be fairly easy and cheap to be tested for the defective allele ApoE ε4. However, the FDA has ruled that pending a decision (somewhere out there in the distant future), health reports such as the ApoE ε4 test are to be withheld from new customers of genetic services such as 23andMe.* The FDA believes that information can be dangerous.


* https://customercare.23andme.com/entries/23071646-Does-the-23andMe-service-include-analysis-of-the-APOE-gene-



Be reminded that if anyone in
your family has had either memory
problems or been diagnosed with AD,
you have an increased risk of
possessing the dreaded
ε4 variant of ApoE.


No Army Can Stop an Idea Whose Time Has Come

Nonetheless, this may soon change. A recent article in Forbes magazine6 interviews 23andMe CEO Anne Wojcicki, the provider of a $99 test that was declared a new medical device and banned in November of 2013. The bottom line is that you can’t ban information. Quoting Ms. Wojcicki (and echoing Victor Hugo’s famous quote), “So how do you regulate information? That’s one of the issues. I’m not sure you can hold it back.”

In the End

So if you have MCI and are simultaneously saddled with the ApoE ε4 defective gene (by familial suspicion or test), you may avoid conversion to dementia and Alzheimer’s if you are taking galantamine. Sure it’s expensive, but expense is relative if it means saving your mind.

References

  1. Gregory SM, Parker B, Thompson PD. Physical activity, cognitive function, and brain health: what is the role of exercise training in the prevention of dementia? Brain Sci. 2012 Nov 29;2(4):684-708.
  2. Winblad B, Gauthier S, Scinto L, Feldman H, Wilcock GK, Truyen L, Mayorga AJ, Wang D, Brashear HR, Nye JS; GAL-INT-11/18 Study Group. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology. 2008 May 27;70(22):2024-35.
  3. Prins ND, Knol DL, van der flier WA, et al. The effect of galantamine on brain atrophy rate in subjects with mild cognitive impairment is modified by apolipoprotein E genotype: post-hoc analysis of data from a randomized controlled trial. Alzheimers Res Ther. 2014 Jul 21;6(4):47.
  4. Nikodemova M, Finn L, Mignot E, Salzieder N, Peppard PE. Association of sleep disordered breathing and cognitive deficit in APOE ε4 carriers. Sleep. 2013 Jun 1;36(6):873-80.
  5. Wang X, Wang H, Li H, Li T, Yu X. Frequency of the apolipoprotein E ε4 allele in a memory clinic cohort in Beijing: a naturalistic descriptive study. PLoS One. 2014 Jun 10;9(6):e99130.
  6. Hof R. “We Are Going For Change”: A Conversation With 23andMe CEO Anne Wojcicki. Forbes. August 15, 2014. http://www.forbes.com/sites/roberthof/2014/08/15/we-are-going-for-change-a-conversation-with-23andme-ceo-anne-wojcicki / Updated August 15 2014. Accessed August 16, 2014.


Will Block is the publisher and editorial director of Life Enhancement magazine.

Featured Product

  • Learn more about Galantamine benefits and implementation strategies.

Ingredients in this Article

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator