SAN DIEGO (FRONTLINE MEDICAL NEWS) – The apolipoprotein E e4 allele is well known for its association with amyloid deposition in Alzheimer’s disease, but now it also appears to help drive the other key pathological process in the disease: deposition of hyperphosphorylated tau protein.

That’s according to the authors of a PET neuroimaging study presented at the annual meeting of the American Neurological Association.

The finding suggests a pathophysiologic mechanism for Alzheimer’s disease cases that predominantly affect memory.

The investigators scanned 67 Alzheimer’s disease (AD) patients using Pittsburgh compound B (PiB) uptake to detect amyloid-beta deposits and uptake of AV1451 to detect phosphorylated tau deposits. The patients had either mild cognitive impairment or dementia, and were a mean age of about 64 years; 35 (52%) were carriers of the apolipoprotein E e4 (APOE4) allele.

The team then compared the results with uptake of the radiotracers in 71 cognitively normal control subjects who were a mean age of 79 years, 23 of whom (32%) were APOE4 carriers.

APOE4 was associated with higher cortical amyloid in the controls, but not tau deposition. Although AV1451 uptake in the temporal lobe was increased in e4 carriers, the effect was not statistically significant after controlling for PiB uptake.

“We saw an APOE4 effect on amyloid but not on tau in normal people,” said senior investigator Gil Rabinovici , MD, a neurologist and professor of memory and aging at the University of California, San Francisco.

All the AD patients had PiB uptake, with no difference in uptake between e4 carriers and noncarriers. However, APOE4 carriers had higher AV1451 uptake in their anterior medial temporal lobes (MTL), a difference that remained unchanged after controlling for PiB.

Carriers of the e4 allele who had AV1451 uptake in their MTLs had a harder time than other AD patients on a test in which they were asked to recall a series of words after a 10-minute break (California Verbal Learning Test), but they did not perform worse on other cognitive measures.

“In cognitively normal individuals, the effect of APOE4 on tau pathology seems to be mediated by the effect of e4 on Ab [amyloid-beta] deposition,” the investigators noted. “However, when assessing amyloid-positive symptomatic AD patients, APOE4 was associated with increased AV1451 binding in the MTL.

“This suggests that, in addition to its effect on Ab pathology, APOE4 might influence the topographical distribution of tau pathology and, potentially, the cognitive symptoms in patients,” the researchers concluded.

“We are very interested in heterogeneity in Alzheimer’s disease – age of onset, rate of progression, which brain areas are affected,” Dr. Rabinovici said. “This study is beginning to dig into some of the factors that might explain that; APOE4 is one potential modifier. It may have a direct effect on tau phosphorylation, and it changes where tau is located in the setting of Alzheimer’s disease.”

The finding of increased MTL tau in APOE4-postive Alzheimer’s patients helps explain why patients who carry the allele tend to have more memory problems, he said, while AD patients who don’t carry the allele tend to have more of a cortical-predominant presentation, with more visual-spatial and language problems.

“I think it’s very likely that APOE4-related disease may be driven by a different mechanism than APOE4-negative disease,” Dr. Rabinovici said. “In the future, APOE4-positive or APOE4-negative might be used to stratify therapy and the measurements used for disease progression. APOE4 itself may be an interesting therapeutic target because it has downstream effects on amyloid and tau.”

Meanwhile, there’s just not a lot of tau pathology in cognitively normal people, which is likely why the effect didn’t show up in the controls, noted lead investigator Renaud La Joie , PhD, a neuroimaging researcher at UCSF.

The work was funded in part by the National Institutes of Health. Avid Pharmaceuticals provided the AV1451. Dr. Rabinovici is an advisor for Genentech, Merck, and Roche, and has research support from Avid Radiopharmaceuticals and Eli Lilly, among others.

SOURCE: La Joie R, et al. Abstract M183, American Neurological Association 2017 annual meeting.


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