9 November 2010. Compared to the vast majority of the population carrying the more common E3 and E4 isoforms of ApoE, the few who have an ApoE2 allele enjoy reduced risk of late-onset Alzheimer’s disease. Now, a new study sheds light on the underpinnings of this protection. Analyzing cognitively normal subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), researchers report that E2 carriers not only have biomarker signatures indicating less AD pathology, but also lower hippocampal atrophy rates, relative to E3 homozygotes. Cognitive decline did not differ between the two groups over the study’s 24-month timeframe, however. The work “provides evidence that the protective effect of the ApoE2 genetic polymorphism is detectable in vivo, before there is evidence of cognitive impairment,” the authors write. Gloria Chiang of the University of California, San Francisco, and colleagues published the findings online October 27 in the journal Neurology.
Only 5 percent of the population carries an E2 allele (see Huang, 2006). Those who do are less likely to develop late-onset AD (Corder et al., 1994) and seem to have slower rates of cognitive decline (Wilson et al., 2002). “We were trying to find a structural biological basis for these observations,” Chiang told ARF.
Of the 193 normal ADNI participants with reliable magnetic resonance imaging (MRI) data, 27 were E2 carriers (i.e., E2/E3 or E2/E2) and 111 were E3/3. The researchers compared hippocampal atrophy and cognitive decline in both groups, and also analyzed cerebrospinal fluid (CSF) biomarkers in those who agreed to spinal taps—about half the participants. This paper did not report on PiB-PET imaging in these volunteers.
The study found that, relative to E3 homozygotes, E2 carriers had baseline CSF profiles reflecting little or no AD pathology—that is, higher Aβ and lower phospho-tau levels. This confirms another recent study that found higher CSF levels of Aβ42 in normal E2-positive seniors (Morris et al., 2010), and seems to jibe with data linking E2 to decreased Aβ accumulation (Kim et al., 2009).
“What is new (in the present study) is that the rate of neurodegeneration, as marked by hippocampal atrophy, was lower in E2-positive people,” noted David Holtzman, Washington University School of Medicine, St. Louis, Missouri, in an e-mail to ARF. Atrophy rates averaged 0.5 percent per year among E2 carriers, compared with 1.3 percent for the E3/3 group. Taken together with the CSF data, Holtzman wrote, the findings suggest “that ‘preclinical’ AD pathology, which is less in E2-positive people, is associated with reduced downstream brain injury.”
On cognition, Chiang said she “expected to find some trend, maybe not in global measures, but at least in episodic memory,” since this was the cognitive domain that distinguished E2 carriers from E3/3 and E3/4 groups in a previous eight-year prospective study (Wilson et al., 2002). However, E2 carriers’ annual decline in overall cognition (measured by the ADAS-cog) and episodic memory (measured by delayed paragraph recall in the Wechsler Memory Scale-Revised) was statistically indistinguishable from the E3/3 group.
Chiang attributes this in part to the study’s short timeframe (two years), but also to the fact that the participants came in with normal brain function. “We wouldn’t expect their cognition to change substantially in a couple of years,” she said. The authors note, in addition, that the ADNI cohort was “more highly educated, and had fewer comorbidities than a community population at this age”—factors that may have further slowed cognitive decline in this study. Other researchers have also noted that ADNI volunteers may not be representative of the general population.
In an accompanying commentary, Richard Caselli and Amylou Dueck of Mayo Clinic Arizona, Scottsdale, highlight several lines of research that complicate analysis of the current findings. One is the recent work of Allen Roses, Duke University, Durham, North Carolina, and colleagues, which “clouds the interpretation of all ApoE-based analyses,” Caselli and Dueck write. Roses and colleagues have identified a gene, Tomm40, that is co-inherited with APOE, and appears to predict LOAD onset age (Roses et al., 2009; ARF related Las Vegas conference story; ARF related Honolulu conference story). ApoE/Tomm40 interactions in LOAD may stem from the role of these two proteins in mitochondrial dynamics (see Roses’ comment below), though this interpretation is controversial, as other scientists point out that an alternative explanation has less to do with Tomm40 function and more with variation in ApoE4 expression.
Another intriguing observation, from the 90+ Study of nonagenarians, seems to turn the tables on the apparent link between the E2 isoform and reduced AD pathology. Non-demented E2 carriers had higher amyloid load than did E3/3 individuals (Berlau et al., 2009). Furthermore, in studies with a new AD mouse strain made by coupling ApoE targeted replacement mice with Bob Vassar’s 5xFAD model, Mary Jo LaDu and colleagues at the University of Illinois, Chicago, have also found more extracellular Aβ deposition in ApoE2 TR/5xFAD mice relative to E3- and E4-TR counterparts. In contrast, intracellular Aβ, which may be more toxic, was most abundant in the E4 mice. Katherine Youmans, a graduate student in the LaDu lab, reported the findings earlier this summer at a one-day ApoE symposium in St. Louis, Missouri (see ARF related conference story and Youmans comment below).
On a broader level, Yadong Huang of the Gladstone Institute of Neurological Disease, San Francisco, notes that the ApoE2 allele is understudied. This is not surprising for research in humans, because the allele is so rare. Even animal studies tend to be few and far between, he said, possibly because E2’s impact on cognition is small and often hard to measure. “In our own experience, we rarely get clear cognitive differences between E2 and E3 animals. And there is no place to publish negative results,” Huang said. In light of these difficulties, the “current paper adds good evidence to support that E2 is a protective allele,” he said. “It’s a very important study.”
In a follow-up to the current study, Chiang and colleagues await further longitudinal data to see whether E2 carriers ultimately show slower rates of mental decline, compared to people with E3 or E4 alleles.—Esther Landhuis.
Chiang GC, Insel PS, Tosun D, Schuff N, Truran-Sacrey D, Raptentsetsang ST, Jack CR Jr, Aisen PS, Petersen RC, Weiner MW; For the Alzheimer's Disease Neuroimaging Initiative. Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal. Neurology. 2010 Oct 27. Abstract
Caselli RJ and Dueck AC. APOE epsilon2 and presymptomatic stage Alzheimer disease: How much is not enough? Neurology. 2010 Oct 27. Abstract