Case of Resistance to Autosomal Dominant Alzheimer's Disease Suggests New Direction for Treatment
Key findings
- Researchers identified an individual with the presenilin 1 E280A mutation, known to cause early-onset Alzheimer's disease, who did not develop mild cognitive impairment until after 70, nearly three decades after her estimated age of symptom onset
- The woman was found to have two copies of a rare mutation in the APOE gene, the most common gene associated with late-onset Alzheimer's disease, called APOE3 Christchurch mutation (APOE3ch)
- Neuroimaging revealed that her resistance to autosomal dominant Alzheimer's disease was associated with an unusually high amyloid-ß plaque burden, but a limited downstream burden of neurofibrillary tangles and neurodegeneration
- In vitro experiments suggested that the beneficial effect of APOE3ch is related to its altered affinity for heparan sulfate proteoglycans (HSPGs), which are thought to promote amyloid-ß accumulation and neuronal uptake of tau
- A gene therapy that would alter APOE or a drug that would reduce APOE–HSPG binding could be a new way to treat or even prevent Alzheimer's disease
The study of autosomal dominant Alzheimer's disease (ADAD) has substantially improved the understanding of the pathophysiology of the disease. Yakeel T. Quiroz, PhD, director of the Familial Dementia Neuroimaging Lab and the Multicultural Alzheimer's Prevention Program at Massachusetts General Hospital, and colleagues previously characterized approximately 1,200 members of the world's largest known extended family with ADAD in Colombia, South America, who carry a missense mutation encoding a glutamate-to-alanine substitution at codon 280 in the presenilin-1 gene (PSEN1) E280A.
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The PSEN1 E280A mutation leads to overproduction of amyloid-β42, and affected people generally develop mild cognitive impairment (MCI) at a median age of 44 and develop dementia at a median age of 49.
In Nature Medicine, Dr. Quiroz, Joseph F. Arboleda-Velasquez, PhD, MD of the Schepens Eye Research Institute of Mass Eye and Ear, and an international team of researchers report on one such mutation carrier who was cognitively unimpaired until her seventies, when she met criteria for MCI, nearly three decades after the typical age of onset. Her case is vitally important because it suggests new directions for treating and even preventing AD.
A Rare Gene Variant
Whole-exome sequencing and DNA sequencing revealed that the woman had two copies of the rare Christchurch mutation in APOE3 (APOEch). This is an arginine-to-serine substitution at amino acid 136 (R136S), corresponding to codon 154. APOE is the principal susceptibility gene for late-onset AD.
In a review of medical literature, the researchers were unable to find a report of any other PSEN1 E280A mutation carrier who was homozygous for the APOE3ch mutation. Some members of the team had previously identified seven members of the Colombian family who had one copy of APOE3ch, including four who progressed to MCI, but the onset of memory impairment occurred at an average age of 45, as usual.
The researchers thus propose that APOE3ch homozygosity is required for the delayed clinical onset of ADAD.
Neuroimaging Findings
Neuroimaging revealed that the subject had an unusually high amount of amyloid-β plaque, but a limited downstream tau pathology and neurodegeneration, including preserved brain volume and glucose metabolism. In fact, her tau measurements were mainly restricted to the medial temporal and occipital regions, with relative sparing of other regions characteristically affected in the clinical stages of Alzheimer's disease (AD).
Mechanism of Resistance
What could limit tau aggregation and neurodegeneration despite a high amyloid-β plaque burden?
The researchers considered that the APOE3 Christchurch mutation R136S is located in a region of APOE that's known to have a role in binding to heparan sulfate proteoglycans (HSPGs). Those molecules are thought to promote amyloid-β accumulation and neuronal uptake of tau. In laboratory studies, the researchers observed that APOE3ch displayed lower heparin-binding than the three other APOE isoforms—even lower than APOE2, which is relatively protective against AD.
APOE As Treatment Target
The research team then generated a monoclonal antibody against APOE amino acids 130 to 143, including R136S. The antibody reduced wild-type APOE3 heparin binding to a level similar to that of the APOE3ch protein.
The researchers propose that the beneficial effect of APOE3ch is related to its altered affinity for HSPGs or other APOE receptors. Rather than reduce brain pathology, a new approach to the treatment of AD would be to promote resistance to the pathology. Possibilities might be to edit APOE to imitate APOE3ch, lower the expression of APOE or develop drugs that change APOE–HSPG interactions to reproduce the apparently protective effect of APOE3ch.
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