A Colombian brother and sister staved off autosomal-dominant Alzheimer’s disease for 20 years past the age of onset expected based on their inheritance of the E280A Paisa presenilin mutation, according to a new case report. That is thanks to a rare variant in Reelin, an extracellular matrix protein that binds to the ApoE receptor, say Yakeel Quiroz at Massachusetts General Hospital and Joseph Arboleda-Velasquez of Massachusetts Eye and Ear, both in Boston; Diego Sepulveda-Falla of the University Medical Center Hamburg-Eppendorf, Germany; and Francisco Lopera of the University of Antioquia, Medellín, Colombia.
- Man carrying both the H3447R Reelin and E280A PS variants remained dementia-free 20 years after expected symptom onset.
- Brain amyloid load was high, entorhinal neurofibrillary tangles sparse.
- The variant boosts Reelin signaling, quelling tau phosphorylation.
Joachim Herz of the University of Texas Southwestern Medical Center, Dallas, who has studied Reelin in the brain for decades, was unsurprised that a variant was protective, though the magnitude of protection in the siblings struck him. “I was shocked that it could stave off cognitive decline for 20 to 30 years in someone with such a strong mutation like Paisa PSEN1,” he told Alzforum.
These researchers previously discovered a protective APOE3 variant in a woman from the same Colombian cohort. In the May 15 Nature Medicine, they report that the brother had a high amyloid load, yet fewer tau tangles, especially in his entorhinal cortex, than expected upon his death. The Reelin variant both he and his sister carried, dubbed COLBOS for the Colombian-Boston collaboration, was more active than the wild-type, modulating downstream kinases to hinder tau phosphorylation. His sister also seemed protected, though a history of brain trauma complicates her case. Exactly how this variant protects might inform the search for new therapeutics.
“It is really exciting to have a second protective variant to understand why some people are resilient to such an aggressive form of AD,” Guojun Bu, SciNeuro Pharmaceuticals, Rockville, Maryland, told Alzforum. Jason Ulrich, Washington University in St. Louis, agreed that protective genetic factors in ADAD carriers can generate new insight into how amyloid pathology can facilitate the onset of tau aggregation and subsequent neurodegeneration (comment below).
Four years ago, the case of a woman carrying the APOE3 Christchurch variant captivated researchers’ attention. Despite carrying the E280A presenilin 1 mutation, which triggers massive amyloid accumulation, neurodegeneration, and cognitive decline by age 45, she stayed cognitively intact until her 70s (Nov 2019 news; Sep 2022 news). Since then, Quiroz and colleagues have been searching for others “escapees,” identifying the brother and sister with uncharacteristic resilience to dementia.
The man remained sharp until age 70, when he was diagnosed with mild cognitive impairment. He had mild dementia by age 72 and died two years later of pneumonia. His sister's memory began slipping at age 58; she had severe dementia upon clinical evaluation at age 64 and died at age 73. However, she also had multiple co-morbidities, including a severe head injury after a fall, hypertension, and depression, all possibly contributing to earlier dementia onset than her brother.
Resilient Reelin. PET scans of the man with both the Paisa PSEN1 mutation and the H3447R Reelin variant (left) show more amyloid plaques (top) yet fewer neurofibrillary tangles (bottom) than does a typical Paisa carrier with early dementia (right). [Courtesy of Lopera et al., Nature Medicine, 2023.]
Shortly after his dementia diagnosis, the brother traveled to Boston for amyloid and tau PET scans. He had 48 percent more amyloid plaques than do typical Paisa carriers with early dementia, yet his global tau tangle burden was low (image below). Tangles were sparse in his entorhinal cortex, where tau drastically accumulates in Paisa mutation carriers. This likely spared neurons because, upon postmortem analysis, the researchers counted a higher neuron density in his entorhinal cortex than in others in this cohort. “This is key to protecting against cognitive impairment, despite the continued accumulation of tau and Aβ in the rest of the brain,” noted Inmaculada Cuchillo Ibañez of Spain’s Instituto de Neurociencias (comment below).
To compare this man’s brain to that of the previously identified APOE3 Christchurch carrier, co-first author Nelson David Villalba-Moreno of UMC Hamburg-Eppendorf looked at their autopsies. The reelin case had a similar amyloid burden, more phospho-tau, and microglia that were less activated, as determined by their size and circularity, than did the Christchurch case (see image below). Both had distinctly less ApoE staining inside their cortical and hippocampal neurons than did others in this kindred who had died in their 50s or 60s.
Reelin versus Christchurch. While amyloid pathology was similar in Reelin-COLBOS and ApoE Christchurch carriers (left), the former had more phospho-tau (right). [Courtesy of Lopera et al., Nature Medicine, 2023.]
How might this variant protect? Mouse amyloidosis models that lack Reelin more quickly accumulate plaques, tangles, which are unusual in amyloidosis models, and learning and memory problems, suggesting Reelin protects neurons from AD (Jul 2015 news; Jul 2010 news). A recent genome-wide association study linked a mutation in Dab 1, a kinase downstream of Reelin, to faster AD progression in APOE4 carriers, suggesting that the Reelin-Dab1 pathway helps stave off late-onset AD, too (Bracher-Smith et al., 2022).
Indeed, the H3447R variant ramped up Reelin signaling, as indicated by high levels of phosphorylated Dab1 in primary mouse cortical neurons. Likewise, 6- to 12-month-old mice into which two copies of this variant had been knocked had more phosphorylated Dab1 and more Reelin oligomers, both signs of activated signaling, in their cerebella than did wild-type animals. In the adult brain, expression in the cerebellum is highest. In the context of tauopathy, 18-month-old crosses of the knock-ins with P301L tauopathy mice had 30 percent less p-tau205 in their hippocampi and showed no sign of their typical hindlimb paralysis.
“It’s surprising that a point mutation increases Reelin activity and that such a small difference affects in vivo phenotype,” wrote Mitsuharu Hattori and Takao Kohno from Nagoya City University, Japan (comment below).
The location of the H3447R mutation, near a heparin-binding site in Reelin, might inform potential treatment strategies. The Christchurch mutation also falls within a heparin-binding area of ApoE3 and influences how it interacts with other glycosaminoglycans. GAGs act as scaffolds for signaling ligands, drawing them near receptors to drive binding and boost signaling. “Both the Christchurch and Reelin variants converge on GAG pathways as a mediator of Aβ-related tau pathology, suggesting GAGs as a potential drug target,” said Michael Ewers, Ludwig Maximilian University in Munich.—Chelsea Weidman Burke
- Can an ApoE Mutation Halt Alzheimer’s Disease?
- In Brain With Christchurch Mutation, More ApoE3 Means Fewer Tangles
- Reelin in Aβ Damage?
- Research Brief: Reelin Loss Ramps Up Aβ Pathology
Research Models Citations
- Bracher-Smith M, Leonenko G, Baker E, Crawford K, Graham AC, Salih DA, Howell BW, Hardy J, Escott-Price V. Whole genome analysis in APOE4 homozygotes identifies the DAB1-RELN pathway in Alzheimer's disease pathogenesis. Neurobiol Aging. 2022 Nov;119:67-76. Epub 2022 Jul 29 PubMed.
- Herz J, Chen Y. Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci. 2006 Nov;7(11):850-9. PubMed.
- Lopera F, Marino C, Chandrahas AS, O'Hare M, Villalba-Moreno ND, Aguillon D, Baena A, Sanchez JS, Vila-Castelar C, Ramirez Gomez L, Chmielewska N, Oliveira GM, Littau JL, Hartmann K, Park K, Krasemann S, Glatzel M, Schoemaker D, Gonzalez-Buendia L, Delgado-Tirado S, Arevalo-Alquichire S, Saez-Torres KL, Amarnani D, Kim LA, Mazzarino RC, Gordon H, Bocanegra Y, Villegas A, Gai X, Bootwalla M, Ji J, Shen L, Kosik KS, Su Y, Chen Y, Schultz A, Sperling RA, Johnson K, Reiman EM, Sepulveda-Falla D, Arboleda-Velasquez JF, Quiroz YT. Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man. Nat Med. 2023 May;29(5):1243-1252. Epub 2023 May 15 PubMed.