This week, another stunning Alzheimer’s Disease (AD) report: a Colombian gentlemen with a mutation causing early dementia, whose scans showed considerable PET-amyloid, escaped dementia for at least twenty years longer than expected!
The case is the second one that begs questions about whether amyloid beta accumulation is really the primary cause of AD. Amyloid clearing was used as a rationale by the FDA in approving drugs aducanumab and lecanemab (donanemab has yet to file again.) The drugs improve scans, but might have questionable “clinical meaningfulness” in really helping patients. The cases may also renew root cause problem analysis in AD and the search for an etiology.
Of course it is more complicated in this patient, as described in the article published in Nature Medicine 15 May 2023, (open access, linked above.) The impressive report includes clinical, imaging, neuropathology, molecular and transgenic “knockin” mouse model data. It was nice to see Prof. F. Lopera listed as first author, since he has long been associated with the kindred in Colombia as a clinician-scientist.
This research collaboration from Medellin and Boston had reported the other case in 2019, showing a Colombian woman with the early dementia mutation, significant amyloid burden on PET scan and relative preservation of cognitive function; link to a discussion here.
AlzGadfly’s take-home messages:
- These cases, and reports from other neuroimaging and neuropathology series, suggest that more is going on than PET-amyloid accumulation. PET-amyloid may be a marker, but the underlying problem is not yet solved. These authors suggest that the sparing of abnormal tau findings in the entorhinal cortex (ERC) area of the brain [center for memory, space and time perceptions?] may be more important.
- Both of these subjects had the PSEN1-E280A familial mutation, which is associated with mild cognitive impairment (MCI) by median age 44, in an autosomal dominant way, yet neither had a diagnosis of MCI until age 70 (the gent did have some symptoms at age 67).
- PET scan imaging of both subjects showed significant amyloid beta. [FDA labels for both aducanumab and lecanemab say: “Confirm the presence of amyloid beta pathology prior to initiating treatment,” i.e. order the PET-amyloid scan.] Yet both had less tau positivity than expected by imaging. In the newer paper, the authors make the point the ERC is relatively spared. The first paper is not as explicit, but the second paper quotes it a such. Both had some brain atrophy on MRI, unclear if it might be age-related.
- Brain autopsy neuropathology results for both cases were fairly typical for AD, with individual variations. Both had significant amyloid beta, both had some sparing of tau related pathology, the first case more than the second.
- Second genetic mutations are thought by the authors to confer protection; on a molecular basis, both may involve changes in the pathway of glycosaminoglycans (certain brain cell receptors or APOE proteins might interact). The first subject was a homozygote for the APOE3ch mutation, while the male was a heterozygote for a Reelin (RELN) gene mutation that the authors call RELN-COLBOS (yeah, that’s Colombia and Boston). The male also had a “non-coding” mutation variant of the amyloid precursor protein (APP) gene, and a calmodulin mutation; neither were thought to be active for dementia, at least “in silico” (is that your AI talking again?)
- The introduction of the RELN-COLBOS mutation into a tauopathy mouse strain (transgenic experiments) were interesting because they suggest a “gain of function” in certain mouse neuro tests (hard to imagine the human correlation of the tail elevation shown in Fig 4f, I just know it’s hard to catch a tiger by its tail), but the mouse neuropathology seems more convincing of protection. There may have been a gender finding that I won’t detail.
- The authors conclude, in the newer paper: “…Regulation of this RELN-protective pathway, particularly in the ERC [entorhinal cortex], may have a profound therapeutic impact on the resistance to Tau pathology and neurodegeneration, and resilience against cognitive decline and dementia in AD.”
These cases may be “exceptions that test the rule” of AD being primarily an Amyloid Cascade Hypothesis problem. [The clinical trials of anti-amyloid gantenerumab failed to reach its endpoints, but it is currently in an extension phase in this genetic population.] Both cases suggest to the authors that tau pathology and its distribution is more important.
Having a mutation with terrible consequences is usually tragic; could a second mutation negate the first problem, or provide the brain with a workaround, like magic? Maybe most of us walking around thinking we are cognitively unimpaired have competing mutations! A bit of Ancient Yin & Yang?
Kudos to the group for its work, and providing some new or perhaps revived insights into other pathways that might help patients. After all, the title of the paper is “Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man”…the Quest for Resilience seems worthy of a new Dr. Indiana Jones wearing a white lab coat, swashbuckling with a micropipette!
P.S. for those who believe that AD starts decades before clinical manifestations, a long comprehensive review with a somewhat aspirational title was also published this week: “Towards a future where AD pathology is stopped before the onset of dementia,” Nature Aging 18 May 2023, not open access, but seems available to read.
Comment: the review takes a practical approach to prevention, patient education, and public health, based on conventional amyloid diagnosis and therapeutic concepts (NIA-AA ATN criteria, dropping the original idea that it was a “research framework.”) It says that when a person has clinical dementia, “…it is too late to rescue the brain…” and has a graphic of the authors’ perception of a patient’s journey; another graphic shows their idea of the trajectory of cognitive decline, along with increasing caregiver burden.
P.P.S Just to be clear, the authors of the case reports above don’t claim to “refute” the Amyloid Cascade Hypothesis, that’s just the blogger being an old Gadfly.