10 Oct 2014

Not everyone who accumulates Aβ in the brain goes on to develop dementia. Could genetic factors influence how quickly amyloid starts to degrade learning and memory? In the October 7 Molecular Psychiatry online, scientists led by Colin Masters and Paul Maruff at the University of Melbourne, Australia, report that ApoE4 and brain-derived neurotrophic factor (BDNF) jointly accelerate cognitive decline threefold more than ApoE4 alone. “This is the first longitudinal study to show this effect. If validated it has major implications for clinical trial design and for prognosis,” Masters wrote to Alzforum in an email.

The BDNF protein promotes neuron survival and supports synaptic plasticity, making it important for learning and memory. A common polymorphism replaces the amino acid valine at position 66 with a methionine. About 37 and 70 percent of Caucasians and Asians, respectively, carry at least one copy of this BDNFmet variant, while a respective 5 and 21 percent of those populations are homozygous for it, according to AlzGene.

Some research suggests that this variant impairs BDNF’s intraneuronal sorting, transport to dendrites, and activity-dependent secretion (see Jan 2003 news story). Other studies suggest the mutation weakens hippocampal function (see Nov 2011 news story).

Previous work from Masters and colleagues hints that BDNFmet speeds cognitive decline in people who accumulate amyloid in their brain (see Lim et al., 2014). Since ApoE4 also does this (see Mormino et al., 2014), first author Yen Ying Lim, now at Brown University, Providence, Rhode Island, wanted to test whether the two gene variants conspire to hasten cognitive decline even more in amyloid-positive people.

Lim and colleagues checked for a genetic relationship in 333 cognitively normal adults, average age 70, from the Australian Imaging, Biomarkers, and Lifestyle study (AIBL). A blood sample revealed whether they carried ApoE4 and/or BDNFmet alleles, and amyloid imaging with Pittsburgh Compound B (PiB), florbetapir, or flutemetamol divulged their amyloid status. Each participant underwent medical, psychiatric, and neuropsychological testing at baseline, then at 1½, 3, and 4½ years. A composite score combined standardized scores from tests of verbal and visual episodic memory, executive function, language, and attention.

Of these 333 volunteers, 109 carried at least one copy of ApoE4, and 123 carried one or more BDNFmet isoforms. At baseline, 84 tested positive for Aβ, of whom 27 carried ApoE4, 11 carried BDNFmet, and 14 carried both. The key finding of the study is that those 14 deteriorated fastest on cognitive tests, followed by those with only ApoE4. People who had only the BDNFmet allele barely deteriorated over those 4½ years, as did those who carried neither polymorphism. People whose amyloid scan was negative did not decline.

In three years, people with both polymorphisms met the criteria for clinically significant memory impairment—a composite score of 1.5 standard deviations below that of the Aβ-/ApoE4- group. By extrapolation, the authors calculated that people who carry only ApoE4 would take 10 years to deteriorate as much, while those with only amyloid would get there in 27 years.

Clinical trials aim to detect and treat Alzheimer’s disease as early as possible; therefore researchers are seeking ways to predict clinical decline in cognitively healthy people. “Stratifying individuals according to amyloid status, APOE, and BDNF Val66Met may provide additional power,” Maruff and Lim wrote to Alzforum in an email. Paul Thompson, University of Southern California, Los Angeles, agreed. He said that if these results are replicated in other cohorts, treatment trials might increase their power by screening for ApoE4 and BDNFmet. These findings could inform post hoc comparisons, he added. The data also support the idea that modifying neurotrophic factors like BDNF may slow AD-related cognitive decline (Lu et al., 2013), the authors wrote.

Though this study implies that BDNFmet helps drive cognitive decline, genetic association studies do not flag it as a risk factor for Alzheimer’s (see AlzGene; Honea et al., 2013). Why not? Lim noted that the interaction they observed between BDNF and ApoE alleles was lost in cross-sectional analysis, and would be missed by most genetic studies.

According to previous work from the AIBL group, BDNF does not affect how much Aβ the brain deposits (see Lim et al., 2013), Maruff and Lim said. Instead, they propose that the valine allele may help the brain tolerate existing amyloid by supporting neural transmission and plasticity. James Vickers, University of Tasmania, Australia, agreed that BDNFVal may help the brain resist Alzheimer's pathology. He recently reported that ApoE4 and BDNFmet interact to impair episodic memory in cognitively healthy older adults, though this study did not take amyloid status into account (see Ward et al., 2014).

Thompson said that hidden genetic or environmental factors could explain why BDNFmet has a “checkered history” as an Alzheimer’s risk gene: “For some genes, whether they are harmful depends on other genes being present.” The finding supports a model of sporadic AD whereby multiple insults interact. “Perhaps you need to exceed a threshold of risk factors to get overt symptoms,” Thompson said. Scientists might examine data from the Alzheimer’s Disease Neuroimaging Initiative to see if they detect this same pattern, he said.

John Hardy, University College London, agreed that replication is needed. “Interactions are notoriously difficult to prove in genetic analysis and require very large numbers of cases and controls to be certain,” he wrote to Alzforum in an email. “We will need to see confirmation of this effect to be sure of what is going on.”

This report extends the previous finding that people who have amyloid in their brain fare better without an ApoE4 allele (see Mormino et al., 2014). “Aβ-positive ApoE4 non-carriers showed minimal cognitive decline, and it is likely that their cognitive function will remain within normal limits for over 20 years,” Lim and Maruff wrote. For that reason, amyloid positivity alone may not predict cognitive decline, they said. Beth Mormino, Harvard Medical School, Boston, said this could have implications for secondary prevention trials, such as the A4 (see Jan 2013 news story). “This finding (along with others) suggests ApoE4 status is important to consider,” she wrote to Alzforum in an email. However, whether therapies will be more or less effective for each isoform is unclear. “Given this uncertainty, it will be important to examine how ApoE4 status relates to treatment effects in A4 participants in post-hoc analyses.” She said the same goes for BDNF genotype.

The AIBL group will continue to follow participants to see whether ApoE4 and BDNFmet carriers progress faster to mild cognitive impairment and AD. AIBL’s 72-month follow-up visits have been collected, and 90-month visits will finish by the end of next year.—Gwyneth Dickey Zakaib

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Lim YY, Villemagne VL, Laws SM, Ames D, Pietrzak RH, Ellis KA, Harrington K, Bourgeat P, Bush AI, Martins RN, Masters CL, Rowe CC, Maruff P, AIBL Research Group. Effect of BDNF Val66Met on memory decline and hippocampal atrophy in prodromal Alzheimer's disease: a preliminary study. PLoS One. 2014;9(1):e86498. Epub 2014 Jan 27 PubMed.
Mormino EC, Betensky RA, Hedden T, Schultz AP, Ward A, Huijbers W, Rentz DM, Johnson KA, Sperling RA, Alzheimer's Disease Neuroimaging Initiative, Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing, Harvard Aging Brain Study. Amyloid and APOE ε4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology. 2014 May 20;82(20):1760-7. Epub 2014 Apr 18 PubMed.
Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 2013 Jun;14(6):401-16. PubMed.
Honea RA, Cruchaga C, Perea RD, Saykin AJ, Burns JM, Weinberger DR, Goate AM, . Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration. PLoS One. 2013;8(9):e76001. PubMed.
Lim YY, Villemagne VL, Laws SM, Ames D, Pietrzak RH, Ellis KA, Harrington KD, Bourgeat P, Salvado O, Darby D, Snyder PJ, Bush AI, Martins RN, Masters CL, Rowe CC, Nathan PJ, Maruff P, . BDNF Val66Met, Aβ amyloid, and cognitive decline in preclinical Alzheimer's disease. Neurobiol Aging. 2013 Nov;34(11):2457-64. PubMed.
Ward DD, Summers MJ, Saunders NL, Janssen P, Stuart KE, Vickers JC. APOE and BDNF Val66Met polymorphisms combine to influence episodic memory function in older adults. Behav Brain Res. 2014 Sep 1;271:309-15. Epub 2014 Jun 16 PubMed.

Do Neurotrophin and ApoE Together Exacerbate Alzheimer's?

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