Research led by Columbia University in New York has uncovered a genetic variant in the gene encoding fibronectin 1 (FN1) that protects against Alzheimer’s disease in carriers of the high risk APOE4 allele.
It appears to do this by preventing excessive build-up of fibronectin in the blood brain barrier, something commonly seen in people with Alzheimer’s disease.
Normally people who have one or two copies of the APOE4 allele are at significantly increased risk of developing Alzheimer’s disease compared with the rest of the population, but there are still some elderly carriers of this allele that are cognitively normal.
Badri Vardarajan, an assistant professor in the department of neurological science at Columbia University, and colleagues decided to test a theory that cognitively normal carriers of APOE4 may also have other genetic variants that protect them from the negative neurological impact of this allele.
To study this further, they looked at whole genome sequence data from cognitively healthy people who were over the age of 70 and were carriers of two APOE4 alleles and who were participating in one of three studies related to Alzheimer’s disease: the National Institute on Aging Alzheimer’s Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and the Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts.
Overall, 1,840 Hispanic and 590 non-Hispanic White individuals were in the overall cohort. Of these, 1,148 had Alzheimer’s disease and 1,282 did not. Of the APOE4 homozygotes, 269 had Alzheimer’s and 105 did not, with 42 of the latter group meeting the age criteria of 70 years or older.
Overall, Vardarajan and colleagues identified 510 rare genetic variants in the healthy APOE4 homozygote group. They then did another search in a large group of over 7,000 APOE4 homozygotes and verified that carriers of a variant in the FN1 gene had 71% reduced Alzheimer’s risk compared with non-carriers. It also appeared to delay disease onset by over three years in those who did go on to develop Alzheimer’s.
Fibronectin is normally present in the brain in small amounts, but if larger amount build up, as seen in Alzheimer’s patients, it can be problematic. The genetic variant discovered by the researchers in this study seems to help stop fibronectin build up at the blood–brain barrier.
“It’s a classic case of too much of a good thing. It made us think that excess fibronectin could be preventing the clearance of amyloid deposits from the brain,” said Caghan Kizil, associate professor of neurological sciences at Columbia University and co-lead author of the study describing the work in Acta Neuropathologica, in a press statement.
The team now wants to assess if replicating the effect of the FN1 genetic variant could help provide new treatments for Alzheimer’s disease.
“There’s a significant difference in fibronectin levels in the blood-brain barrier between cognitively healthy individuals and those with Alzheimer’s disease, independent of their APOEE4 status,” said Kizil.
“Anything that reduces excess fibronectin should provide some protection, and a drug that does this could be a significant step forward in the fight against this debilitating condition.”
