Overall heritability of DLB is 31 percent!?

This email is about DLB (dementia with Lewy bodies) genetics.  The headline is:  “These calculations put DLB’s genetic component at 31 percent, close to that of PD and half that of AD.”  If I understand this correctly, this means that 31 percent of DLB cases can be explained by genetics.  Two of these genetics research papers utilized brain tissue of DLB donors where we assisted with the brain donations!

A week ago, Brain Support Network handled four brain donations in 24 hours.  (We often see this in early January and late December.)  One of the cases was of a gentleman with a Parkinson’s Disease.  His sister suspects DLB.  Almost exactly two years ago, we handled the brain donation of their brother, also with a clinical Parkinson’s diagnosis.  In the brother’s case, DLB was confirmed through brain donation.  It seems that something genetic may be going on in this family.  So, the sister and I thought we’d ask the brain bank to run a genetics test for the alpha-synuclein gene on both brothers.  I went to the web to see what the latest was about that alpha-synuclein gene so I could correctly present the case to the brain bank.

I found an update on fascinating DLB genetics research published in November 2015, and presented at the International Dementia with Lewy Body Conference in December 2015.  Let me point out that this research is only possible through brain donation.  Many of the DLB brain donations we’ve helped with over the last several years have contributed to two of these research papers!  (Bras paper and Murray paper)

Here’s an excerpt of the update:

“Jose Bras of University College London, U.K., reminded the audience that late-onset Alzheimer’s and Parkinson’s were not considered genetic diseases until recently. By now some 30 genes are known to be involved in each of them, and their overall heritability is estimated at 60 and 28 percent, respectively. At the level of GWAS, the known common genetic risk factors for AD and PD do not overlap. Yet there is DLB, a clinical hybrid of the two…”

“To date, scientists have implicated four genes in DLB. They are:
* SNCA (encoding the α-synuclein protein)…
* A locus on chromosome 2 in a large family…
* GBA, variants of which drive up a person’s risk of developing DLB…”

Note that these four genes are not specific to DLB.  They are implicated in either Alzheimer’s (AD) or Parkinson’s (PD).

“Bras and collaborators in Europe, Australia, and across North America have thus far pooled 1,400 cases confirmed by neuropathology to have had DLB. This is still a far cry from the nearly 100,000 people whose samples are available for AD/PD GWAS, but it’s a first step toward a comprehensive look at the genetic signature of DLB, Bras said.”

“Samples of this size support heritability estimates. These calculations put DLB’s genetic component at 31 percent, close to that of PD and half that of AD, Bras told the audience. They also enable estimates of the genetic overlap among AD, DLB, and PD–diseases already known to overlap at the clinical and the neuropathological level. Genetically speaking, DLB correlates strongly with AD, though much of that is due to ApoE. Subtracting ApoE leaves DLB equally correlated to AD and PD, Bras reported.”

“Cyrus Zabetian of the University of Washington, Seattle, presented a comparison of candidate genes in a smaller sample of 348 neuropathologically confirmed DLB cases and 102 PDD cases from seven centers in the United States. Finding broadly similar results, this study suggested that ApoE4 is more common in DLB, the disease that is arguably closer to AD, than in PDD, the disease nearer to PD. ‘If you carry ApoE4, it pushes you toward an earlier presentation of dementia, hence you are more likely to be classified as having DLB. GBA mutations, on the other hand, push you toward alpha-synucleinopathy, so you are more likely to be classified as having PDD,’ Zabetian said.”

“Another hint that ApoE4 puts its finger firmly on the AD end of the DLB scale came from a study relating ApoE genotype to neuropathology in large series of people who had had a diagnosis of DLB during life. Melissa Murray from the Mayo Clinic in Jacksonville, Florida, reported that while ApoE4 carriers tended to have worse alpha-synuclein pathology than non-carriers, that link was due to the presence of amyloid pathology. About 90 percent of patients with DLB have AD pathology, as well. In AD research, ApoE4 is increasingly seen as an indicator that amyloid is present in the brain with age, and several presentations in Fort Lauderdale, including Murray’s, pointed in the same direction for DLB.”

“‘In the clinic, by and large DLB is not an inherited disorder,’ agreed Ian McKeith of Newcastle University, U.K.”

Here’s a link to the research update:  www.alzforum.org/news/conference-coverage/genetics-dlb-setting-fill-mostly-empty-canvas

If you reach different conclusions than I have, please let me know!