Alzheimer sites were buzzing last week, describing the brief communication / case report of a very unique woman; she has a heavy burden of brain amyloid, but only mild cognitive symptoms. Investigators found a rare double mutation in the gene pair for a fat metabolism protein, APOE3 (she does have high blood cholesterol). Does this case challenge the prevailing Amyloid Cascade Hypothesis, or NIA-AA Research Framework? Does it imply that a high amyloid burden is not sufficient nor perhaps even necessary as a factor causing cognitive impairment and neurodegeneration in Alzheimer Disease (AD)? Reading through the paper in Nature Medicine, that question doesn’t come up directly.
The woman comes from a family afflicted with many cases of AD, most with early onset. Dr. Francisco Lopera from Medellin, Columbia and others have studied this family for decades. She indeed carries the presenilin 1 (PSEN1) gene mutation, thought to be the main culprit; most of those affected will have mild symptoms by age 44, and AD by age 49. This woman didn’t have mild symptoms identified until her 70’s, but the authors weren’t sure if it was a prolonged mild phase or truly later onset.
Her imaging studies included PET scans for amyloid beta plaques, tau tangles, and glucose utilization in the brain. They showed an amyloid burden higher than expected, with lower than expected tau, and “preserved” glucose utilization; the latter implies that her brain metabolism is unexpectedly healthy. Other imaging and a blood test for neurodegeneration were both better than expected.
The authors suggest that the regional distribution of findings, at least for tau, was unusual, so some context for the images in the usual trajectory of this kindred would have been nice. Many use the term “biomarkers” when discussing this kind of workup. Using the proposed Research Framework nomenclature (linked above) this person would presumably be [A+T-(N)-], considered an early stage on the “continuum,” which, reading between the lines, surprised the authors, given the unusual findings and her daunting family history.
The researchers found a few in the family with a single, rather than double mutation in APOE3; those folks sadly had early onset AD as predicted. Is the specific “APOE3ch” mutation, that this woman exhibits, (named after Christchurch, NZ where it was found) just a random association, or is it really involved?
The APOE isoform group is already the subject of quite some study in AD, with papers stating that APOE2 might be protective against AD, while APOE4 is thought to increase the risk for AD. APOE3 is thought to be “neutral.” The investigators in this paper developed ideas about what the APOE3ch mutation does, and report some of their basic science work. They used in vitro assays for amyloid beta aggregation, and suggest the mutation shows less aggregation.
Another way that APOEs could work in the brain is through a presumptive interaction with molecules known as HSPGs, which contain heparin. They found that recombinant APOE3ch had low heparin binding; they then created a blocking monoclonal antibody and found that it could affect heparin binding of native APOE3 in a similar way.
Where does this lead? Could the monoclonal antibody be a drug? Alzforum.org has a nice technical news item about the paper, with more clinical details not in the paper itself or Extended Data, with quotes from various investigators in the field; their online format allows other investigators to comment.
They report that the woman’s cholesterol was 512 mg/dl, and triglycerides 692 mg/dl, very high in most clinical labs. The case report itself says she has Hyperlipoproteinemia III (usually thought to be related to APOE2) and is on the medication atorvastatin (US trade name Lipitor). Neither the case report nor the Alzforum mentions whether she might have cerebrovascular disease or signs of vascular dementia, but one assumes that her extensive brain imaging didn’t suggest blood vessel problems. Alzforum suggests she doesn’t have overt cardiovascular disease. Perhaps that lack of vascular disease with high blood lipids is just as unique as her lack of a major neurocognitive disorder with high amyloid.
So, if amyloid beta is toxic, could the double mutation of APOE3ch protect really against that directly, or is something else going on? However, if APOE3ch can disrupt amyloid aggregation, why was the PET amyloid scan so intense? The authors suggest it might have been even more intense if not for some factor. Is preserving the brain against tau really the major effect, limiting her neurodegeneration?
Could APOE3ch work to strengthen neurons to resist amyloid toxicity, rather than affect amyloid itself? Could her high lipids, or some other downstream factor, be working to delay her impairments? Does this person’s medication play a role? There have been studies looking at statins as preventatives against AD, but the results seem mixed. Interesting reports always generate more questions, don’t they!
Biotech companies have been working on APOE ideas for awhile; earlier this year two researchers shared their thoughts from an industry perspective. The Alzforum piece also mentions some therapeutic ideas that might feed off this case report, and the commenters there go way beyond this little posting. They refer to other APOE mutations that might lower risk or delay AD, the idea that neuronal endosomes might be involved, and ideas about inflammation.
This single case doesn’t refute the Amyloid Cascade Hypothesis, but it wonderfully suggests that there might be a “work around” to ameliorate, or postpone, the devastating and seemingly inevitable decline predicted for anyone with AD, especially those with positive PET amyloid imaging. So let’s see something ASAP, since the National Alz Project Act deadline looms, in 2025!
(Image credit: Richard Watts, PhD, University of Vermont and Fair Neuroimaging Lab, Oregon Health and Science University, NIH public domain, unrelated false color fMRI image of a brain working on a memory task)