APOE Epsilon 2 Allele Linked to Milder AD Symptoms, Pathology

Susan Jeffrey

April 23, 2015

WASHINGTON, DC — The apolipoprotein E (APOE) ε2 allele, previously shown to be associated with a lower risk for Alzheimer's disease (AD), is also associated with milder AD pathology after death and less severe cognitive impairment in life compared with ε3 and ε4 alleles, an analysis from a large autopsy cohort shows.

"Surprisingly, APOE ε2 was associated with a lower Braak neurofibrillary tangles stage," lead author Alberto Serrano-Pozo, MD, PhD, from the Department of Neurology at Massachusetts General Hospital, Boston, concluded. "We think this is a novel observation that warrants further investigation," he said, both at the experimental level and now in vivo, given the availability of tau positron emission tomography (PET).

APOE ε2 doesn't appear to have a direct effect on cognition, he added, but rather seems to have an indirect effect by influencing AD pathology.

The results were presented here at the American Academy of Neurology (AAN) 67th Annual Meeting, and were published in the Annals of Neurology.

Risk Allele

The association of APOE with sporadic AD is "the strongest of any known risk gene," the authors write in their publication. Compared with the major ε3 allele, carrying one copy of the APOE ε4 allele increases the risk for AD by 3 to 4 times; two copies increase the risk by 8 to 12 times. Conversely, the ε2 allele reduces the risk for AD by almost half, they note.

Many studies have shown the ε4 allele correlates with increased amyloid plaque deposition, as well as increased vascular amyloid deposition in the form of cerebral amyloid angiopathy (CAA), they note, findings supported by recent PET amyloid imaging studies in patients with AD and in cognitively normal people. Some have suggested that ε4 is also linked to increased neurofibrillary tangles (NFTs), but others have not.

"In contrast to APOE ε4 carriers, APOE ε2 carriers are thought to bear fewer amyloid plaques, and possibly also fewer NFTs," they write. "However, in part because of the relative rarity of this allele, sufficiently powered and detailed post-mortem studies examining the effects of the APOE ε2 allele in the pathobiology of AD are still lacking."

In this study, they used data from the large National Alzheimer's Coordinating Center (NACC) autopsy cohort, a multicenter longitudinal cohort study of aging, to overcome this lack of statistical power.

Patients were included in this analysis if they had no primary neuropathologic diagnosis other than AD found at autopsy, they had had a final clinical evaluation within 2 years of death, they were 50 years of age or older, and their APOE genotype was available.

"We allowed for the presence of incidental Lewy body pathology and vascular pathology, as long as the severity was not enough to warrant a diagnosis of vascular dementia or Lewy body disease," Dr Serrano-Pozo noted.

They were excluded if they had a neuropathologic diagnosis other than AD, had had cognitive impairment linked to alcohol use, depression, medications or medical illness, had the APOE ε2/ε4 genotype since they hoped to study the separate effects of these alleles, and those who were cognitively intact at the last clinical evaluation, "in order to prevent artificially significant results due to the 'anchoring' effect of cognitively intact subjects, who typically have low levels of AD pathology and are less likely to care the APOE ε4 allele," they write.

A total of 793 patients met these criteria. Of these, only 1 (0.1%) had ε2/ε2, 40 (5.0%) had ε2/ε3, 339 (42.7%) had ε3/ε3, 320 (40.3%) had ε3/ε4, and 93 (11.7%) had ε4/ε4.

Dr Serrano-Pozo reported that compared with the APOE ε3/ε3 genotype, APOE ε2 was independently associated with lower Braak NFT stages, and possibly fewer neuritic plaques, but had no direct effect on CAA.

APOE ε4, on the other hand, was associated with more neuritic plaques and CAA but had no independent effect on Braak NFT stage in this analysis.

Unadjusted analyses showed cognitive performance on their last clinical examination using the Clinical Dementia Rating Sum of boxes and the Mini-Mental State Examination in these patients were markedly different by genotype, with ε2 scoring higher than ε3 scoring higher than ε4.

Mediation analysis suggested this difference was largely explained through the effects on pathology.

"Even when adjusted for age of onset, symptom duration and other variables, APOE ε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOE ε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOE ε2 in AD," the authors conclude.

Questions Remain

Heather M. Snyder, PhD, director of medical and scientific operations for the Alzheimer's Association, was asked for comment on these findings.

"The interesting thing about this study is it's looking at a specific population," of people whose data are collected from the large National Institute on Aging–funded NACC, and found those with APOE ε2 had a less severe clinical presentation and fewer neuropathologic changes, she said.

The results "match some of the population studies we've seen where there is less of a presence of APOE ε2 in people with Alzheimer's disease, but it also underscores that there's a lot here we don't understand," Dr Snyder told Medscape Medical News.

"There are people with APOE ε4 who do not have Alzheimer's disease and people with APOE ε2 who do have Alzheimer's disease, and what might be happening at the very basic biology inside the brain is something we just don't totally understand. … [T]here's clearly a need to further investigate what might be happening in the brain, and that could potentially open the door for new therapies or new avenues for research for therapies that would target a particular area."

The study was supported by the Massachusetts Alzheimer's Research Center. The NACC database is supported by the National Institutes of Health/National Institute on Aging. Dr Serrano-Pozo has disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 67th Annual Meeting. Abstract S16.005. Presented April 21, 2015.

Ann Neurol. Published online January 26, 2015. Abstract

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