Gene May Increase Risk of Late-Onset Alzheimer's

There has been reason to think that brain-derived neurotrophic factor (BDNF) and the BDNF gene might play a role in late-onset Alzheimer's. For example, BDNF is critical for neuronal plasticity and facilitates processes that are important for learning and memory.

In patients with Alzheimer's, BDNF gene expression is markedly reduced in the hippocampus and entorhinal cortex—two of the brain regions affected earliest by the disease. And altered levels of BDNF in blood and cerebrospinal fluid have been found in Alzheimer's patients and linked with disease severity and impaired episodic memory performance.

Now a new study bolsters the possibility that the BDNF gene might play a role in late-onset Alzheimer's. It found that the gene confers risk for late-onset Alzheimer's, but only in an age-dependent manner.

The study was headed by Aristotle Voineskos, M.D., Ph.D., an assistant professor of psychiatry at the University of Toronto, and the findings were published in the February Archives of General Psychiatry.

Voineskos and his colleagues conducted a study to assess the effect of the BDNF gene on neural structures and cognitive functions that are disrupted in Alzheimer's. The study included 69 healthy volunteers ranging in age from 19 to 82.

The subjects were genotyped for the BDNF gene. Twenty-eight had either two copies of the Met variant or a copy of the Met variant plus a copy of the Val variant. Forty-one had two copies of the Val variant.

The scientists then used brain imaging to examine the thickness of subjects' temporal-lobe structures as well as white matter fiber integrity, since the thickness of temporal lobe structures, especially of the entorhinal cortex, is reduced in Alzheimer's and white matter fibers are also disrupted in the illness. The scientists also tested the subjects' episodic memory, since impairment of such memory is characteristic of Alzheimer's. Finally they looked to see whether any BDNF gene variants could be linked with temporal-lobe, white-matter tract, or memory deficiencies—in other words, whether they conferred a risk for late-onset Alzheimer's.

The researchers found that such a link did exist, but it depended on age. Those individuals with the Met/Met or Met/Val gene variant were at risk earlier in life for reduced cortical thickness, reduced white matter integrity, and reduced episodic memory performance, whereas individuals with the Val/Val gene variant were at risk later in life for such deficits. This situation contrasts with that for the APOE gene, in which APOE e4 carriers are at a disadvantage for Alzheimer's even in early adult life.

Thus it looks as if the BDNF gene may be a mechanism that increases susceptibility to Alzheimer's, but only when it interacts with age.

"I think the genotype-by-age interaction is fascinating," Voineskos told Psychiatric News. "One might think that a risk allele is always a risk allele at all points in the lifespan, but that may not necessarily be the case, as indicated by our findings."

"I also think that while our findings are not applicable to the individual person at this point, they really shed light on the importance of BDNF in the memory centers and circuitry of our brains," Voineskos said.

And if BDNF and the BDNF gene do play a role in Alzheimer's, there may be therapeutic implications as well, Voineskos and his colleagues noted in their paper. Indeed, some promising research in that domain is already being conducted by Mark Tuszynski, M.D., Ph.D., a professor of neurosciences at the University of California, San Diego, and his colleagues, they pointed out.

Specifically, Tuszynski and his team have found that BDNF therapy can reverse age-related cognitive impairment in primates and that BDNF gene delivery can reverse synaptic loss, improve cell signaling, and restore learning and memory in a rodent model of Alzheimer's. "The plan [now] is to begin clinical trials" to see whether BDNF might help patients with Alzheimer's, Tuszynski told Psychiatric News.

The study was funded by the Canadian Institutes of Health Research, American Psychiatric Association/American Psychiatric Institute for Research and Education AstraZeneca Young Minds in Psychiatry Award, and Center for Addiction and Mental Health.

An abstract of "The Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Prediction of Neural Risk for Alzheimer Disease" is posted at <http://archpsyc.ama-assn.org/cgi/content/short/68/2/198>.