In mid-November New York magazine ran a cover story on a group of 540 Ashkenazi Jews who, as the headline trumpets, carry "DNA You Wouldn't Believe." This group of happy oldsters, all of them over 95, might hold the key to extreme longevity, the article suggests. There is the 105-year-old stockbroker who still goes to work everyday and a peripatetic 109-year-old woman.

The article—"What Do a Bunch of Old Jews Know about Living Forever?"—highlights research from the Albert Einstein College of Medicine in the Bronx that points to several genes that might help explain the secret of a Methuselah-like existence. One, in particular, stands out, the Einstein researchers assert. The oldest of the old who bear a certain version of the cholesteryl ester transfer protein gene, (CETP I405V) end up with lower levels of the CETP protein but higher levels of the "good" cholesterol, and larger particles of these high-density lipoproteins (HDLs). The carriers of two copies of this gene variant—one from ma, one from pa— appear to have a lower risk of dementia, failing memories and heart disease.

There is a problem with this halcyon picture. A few weeks after the New York article hit the presses, a report by researchers from Rush University Medical Center in Chicago in a respected journal, Aging Cell, identified the CETP variant as a gene that may increase the risk of Alzheimer's. The same version of the same gene: in one study it slows dementia, in the other it promotes cognitive decline.

What is going on here? Two groups of well-regarded researchers come to the exact opposite conclusion. Welcome to the wild-and-wooly world of gene-association studies that attempt to tie DNA to disease. Unless the link between a gene and a disease or phenotype is a very strong one, researchers who try to follow up on initial studies often get different results the second or third time around.

In this instance, the researchers at Rush had decided to investigate this gene after reading a January study published in JAMA The Journal of the American Medical Association by the Einstein investigators. The JAMA article found that the CETP variant protected a diverse group of older people, aged 70 and older, not just the Ashkenazim, against failing memory and dementia. The JAMA study, though, extended earlier work by the Einstein researchers that showed better cognition and general health in the Ashkenazi super old that carry the gene.

The Rush team, which oversees two well-known longitudinal studies on aging and dementia, decided to see whether they could replicate the JAMA findings. Their analysis of 1,384  participants from the two studies found that the CETP variant was associated with a faster rate of cognitive decline and an increased risk of Alzheimer's. The Chicago researchers then did something that the Einstein team hadn't. They went to pathology information collected on the brains of 590 of the deceased study participants. They found there that those with the relevant CETP variant had a greater density of the plaques characteristic of Alzheimer's than others who didn't.

So who is right? Maybe no one at all. A leader of the Rush team points out the possibility that both results may be due to chance "They got an effect, they reported it; we got an opposite effect, we reported it," said David Bennett, a professor of neurological sciences at Rush and one of the co-authors on the paper. "Maybe the truth is in the middle, which is no effect."

4 Comments

1. 1. barzilaimd 05:43 PM 12/13/11

   Genetic studies are important to point at an important biological pathway. For example the variant of CETP VV is the association with low plasma levels of the CETP gene product and high levels of HDL cholesterol.
   The validation of a single genetic variant is dependent on the genetic structure of the population. For example Asians do not have this variant but have another CETP variant that is associated with the phenotype. In the Rush study the frequency of the VV variant was ~6% while it was ~20% in the EAS (Bronx) population, suggesting different genetic backgrounds (or survival). Thus, association of genotype without the phenotype is not very revealing. The question to both Rush and EAS study is if low CETP levels,high HDL levels (and large lipoprotien sizes) protect against cognitive decline? Analysis of genotypes alone may never reveal the whole truth, and genetecists need to get behind such limitations and the urge to focus on one variant at a time in a diverse populations.

   Reply | Report Abuse | Link to this

2. 2. JacobSilver 03:41 PM 12/14/11

   The problem is that there are many more genes than there are ways in which an individual can exhibit symptoms. So, one gene is often not determinant of a disease. A gene inherited from both parents, and linked to several other genes may be the description of the genetic determinant of a disease. The human body is complex, and complex analysis is often necessary for firm conclusions.

   Reply | Report Abuse | Link to this

3. 3. bucketofsquid 05:51 PM 1/4/12

   I just finished reading another article that explained how environmental factors turn genes off and on. That would tend to make the presence of any given gene only marginally important in a given outcome.
   
   On the plus side, the more we learn about various genes the better we can focus our efforts to find solutions.

   Reply | Report Abuse | Link to this

4. 4. Dov Henis 08:41 AM 2/8/12

   
   “Long-lived people distinguished by DNA”? Ludicrous…
   
   The "long life" DNA expressions are formed by the living mode-culture of the old timers, by the genes “adapting” to their “desirable” circumstances. This is evolution, natural selection, and the genes ARE ORGANISMS.
   
   It's the culture horses that pull-effect the genetic changes, NOT "longevity genes wagon" that pushes-effects long life.
   
   Ask Pavlov. Learn from him...
   
   Dov Henis (comments from 22nd century)
   http://universe-life.com/2011/12/22/rnas-are-earths-primal-organisms/
   

   Reply | Report Abuse | Link to this