Genes, IQ, and Benadryl Dementia

BGI Cognitive Genetics is a Chinese institute hard at work teasing out the connections between genes and IQ. Robert Plomin at King’s College London is on a similar quest, studying the DNA of 2,000 participants from the long-running Study of Mathematically Precocious Youth, sharing findings with the Chinese BGI group. Very recently, another multi-disciplinary study comprising researchers from Europe, the US, and Australia, has revealed significant associations between specific genes and cognitive ability from a sample of 50,000 individuals using GWAS (genome wide association study) techniques.

Excerpt from study abstract:

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis…

… The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C. __IQ Genes

More from Brian Wang

The idea is to find the gene variants that account for the lion’s share of variation of cognitive ability. It is a highly complex and time-consuming task, requiring the skills of a wide variety of intelligent, imaginative, and well-trained persons. The goal is slowly being approached by the world’s global contingent of scientists and cognitive/genetic technologists.

Human intelligence evolved via natural selection just as did other human characteristics such as shape, size, strength, and speed. Different semi-isolated breeding groups in different parts of the world, evolved somewhat differently in all of those characteristics, and more.

IQ by Race North America _ Wikipedia

IQ by Race North America _ Wikipedia

The famous overlapping distribution curves of IQ for four North American populations — Asian, European, Hispanic, and Black — reveals how general cognitive ability seems to have evolved differently over time, with significant interaction between genes and environment.

There is significant variation of intelligence within broad breeding populations as well as between breeding populations — just as there is variation in other inherited characteristics within and between population groups and gender. That only highlights the genetic complexity involved in the heritability of cognitive aptitude.

Politically Correct Illustration of Gene/Environment Interaction in Generating Cognitive Achievement

Politically Correct Illustration of Gene/Environment Interaction in Generating Cognitive Achievement

As you can see in the politically correct image above, genes set the bounds for cognitive achievement, and environment creates the conditions that determine where a person lands within those genetic bounds.

Now let’s look at cognitive developments at the farther end of the age spectrum:

Recent Concerns about Common Anticholinergics and Dementia

Not all of us were jackpot winners in the grand genetic cognitive lottery, but we would like to keep as much of what we have for as long as possible. So even if not all of us are natural born geniuses, we cannot help but be disturbed when we are told that common anticholinergic drugs such as Benadryl, tricyclic antidepressants, and bladder antispasmodics may accelerate the onset of dementia.

See JAMA Network Study for more details of recent study.

One of the problems with such studies up until now, is that they were likely to confuse the reversible symptoms of dementia with irreversible dementia itself. For example, here is one criticism of previous claims linking anticholinergics such as Benadryl with dementia:

A study with internal validity only to African-Americans over the age of 70 which “suggested” that anticholinergic use may be linked to mild cognitive impairment had, through the evolution of information, been applied to the general population and concluded that medications like Benadryl caused memory loss. __ Clinical Misinformation

The most recent JAMA Network study was better designed than earlier studies, and answered some of the previous complaints. The researchers in the recent study controlled for several of the shortcomings of previous studies. This study was a “prospective cohort study,” meaning that participants were free of disease at recruitment, and followed over time to compare “exposed” vs. “non-exposed” individuals. In this study, different levels of cumulative exposure allowed authors to posit a “dose-response” relationship between anticholinergic exposure and dementia diagnosis.

Although we at Al Fin have been recommending for over 15 years that older persons avoid the use of anticholinergic drugs (for this reason), it is not clear to me that this one study has demonstrated a cause and effect relationship. For one thing, anticholinergics are apt to “unmask” symptoms of dementia earlier in the course of disease without actually causing the disease process in the brain to be more advanced. For another thing, anticholinergic delirium is not uncommonly misdiagnosed as dementia by some practitioners. Further, although the cholinergic system is clearly involved in the symptoms and early treatment of Alzheimer’s disease, the underlying pathophysiological process is far more complex than currently understood. It is too easy to fixate upon one component of a complex system and neglect other factors which may be far more important in the long run.

The “adjusted hazard ratios” presented by the authors were neither statistically significant nor particularly impressive for the “low” and “moderate” dose cohorts. And although the “high” dose cohort hazard ratio was statistically significant, it was not particularly impressive.

Dementia is a tragic disease which is becoming all too common among the growing cohorts of ageing persons of all population groups. We at Al Fin will continue to caution older persons against the use of strong anticholinergic drugs whenever it is possible to avoid them — and particularly over long periods of time.

It is all about gene expression in the brain

The truth of the matter is that gene expression in the brain sets the limits of cognitive ability in youth and adults. And, surprise! Gene expression in the brain helps determine the risk of Alzheimer’s disease — in conjunction with environmental factors including drugs.

Some persons will be genetically “immune” to the dementiogenic effects of anticholinergic drugs, while others will be particularly sensitive to such effects, genetically. Those who are called upon to advise persons in such areas as lifestyle, career, diet, drug use, etc. will need to keep the individual genetic interactions with environment in mind.

More on the anticholinergics and dementia study:

The main statistically significant finding was in a group taking the equivalent of any of the following medications daily for more than three years:

xybutynin chloride, 5mg
chlorpheniramine maleate, 4mg
olanzapine, 2.5mg
meclizine hydrochloride, 25mg
doxepin hydrochloride, 10mg

… While there are biologically plausible theories, the mechanism by which anticholinergics might contribute to dementia risk is not well understood.

It is important to realise this study was about prescribed medicines. If you have been prescribed anticholinergic medicines, do not stop taking them without speaking to your GP first as everyone’s circumstances are different. The harms of stopping might outweigh any potential benefits. __ Dementia Scare

The article at the above link points out some of the limitations of the JAMA Network study, including lack of control for over the counter medication usage by participants. This oversight could make a significant difference for the interpretation of the results.

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2 Responses to Genes, IQ, and Benadryl Dementia

  1. Anticholinergics have been know (by those with eyes to see) as ‘dumb drugs’ for many decades – and cholinergics have been tried for cognitive enhancement (but without much clinical success) for the same period.

    However this kind of article has a hidden agenda of trying to kill rival over the counter and old off patent medications. Benadryl (diphenhydramine) is in fact an SSRI (discovered to be such by Nobel Laureate Arvid Carlsson in 1969) which was the chemical basis for synthesizing Prozac/ fluoxetine – and there is a danger that the general public might realize this and self treat with the OTC drug instead of continuing to be prescribed expensive alternatives (some of which are also anticholinergic).

    references are here:

    As for the Tricyclic Antidepressants – they are used for moderate to severe melancholic/ endogenous depression for which SSRIs are ineffective – indeed these old TCAs are the only drugs with solid evidence for effectiveness in melancholia – and the only alternative is electroshock. They have sever side effects, but the illness itself is even more severe – so it would be silly and harmful to demonize them.

    I don’t suppose many people have ever harmed themselves significantly with over the counter anticholinergics – because most people stop taking an OTC drug which makes them feel bad. By contrast, prescribed anticholinergics cause massive cognitive problems, because people (such as in-patients and elderly people in residential care) are forced to take them, or else people feel they ought to take them despite the drugs effect on confusing them.

    In sum, this kind of research is a long term strategy to preserve the profitability of on-patent drugs by demonizing killing off patent and OTC drugs – it has been going on at least since the 1960s with many valuable drugs killed such as Miltown, Dexamyl, Pemoline.

    Nowadays, the great majority of the medical research literature is both dishonest and incompetent – being more focused on marketing than science.

    See Pharmageddon by David Healy, or Anatomy of an Epidemic by Robert Whitaker

    • alfin2101 says:

      Thanks, good observations.

      Despite their side effects, sometimes the older drugs are better than the alternatives, as you say.

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