01
On May 15, 2023, the journal Nature Medicine published a research paper titled: Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.
The study reported a very particular case of a patient who carried a mutation in the PSEN1 gene that causes early-onset inherited Alzheimer's disease, which he should normally develop between the ages of 30-50, however, his cognitive abilities remained intact until the age of 67. The research team further identified a new rare mutation in the RELN gene, the RELN H3447R mutation (RELN-COLBOS), which can prevent Alzheimer's disease.
This study found the second human in the world born tolerant of early-onset inherited Alzheimer's disease, thus revealing a previously unknown molecular pathway that may confer resilience to cognitive decline in people at high risk of Alzheimer's disease, pointing a new direction for the development of Alzheimer's disease treatment drugs.
02
The biggest difficulty with Alzheimer's disease is that its pathogenesis is still not well understood. Although the β amyloid (Aβ) hypothesis has been controversial, in the field of Alzheimer's disease new drug development, β amyloid hypothesis is still the most far-reaching theory, the basic idea of the Aβ hypothesis is that the deposition of Aβ is the initiating factor of pathogenesis, and the aggregation of Aβ is neurotoxic.
Extent of damage within the brain in Alzheimer's disease (Source: Scientific Animations)
Aβ contains 39~43 amino acid polypeptides, which are produced by the proteolysis process of transmembrane amyloid precursor protein (APP) by β- and γ-secretase[1].
Based on the Aβ hypothesis, in recent years, Eisai/Biogen's two new Alzheimer's disease drugs, Aducanumab and Lecanemab, have been approved by the FDA, while only sodium oligomannurarate (GV-971) has been approved for marketing and included in medical insurance.
On January 6, 2023, FDA accelerated its approval of Lecanemab's marketing application. The results of the Clarity AD study showed that at 6 months of treatment, CDR-SB in the lecanemab group showed a highly statistically significant change compared with the placebo group (p
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Although the approval of the drug was not based on the Clarity AD study, but on a Phase 2b clinical study that confirmed Lecanemab's superior amyloid clearance efficiency. But the results of the Clarity AD study also confirmed the validity of the Aβ hypothesis.
03
A 2012 study published in The Lancet Neurology looked at a large family of 5,000 people in Colombia, 30 percent of whom carried a gene for early-onset Alzheimer's. 100% of people who carry this gene (presenelin 1 gene) will develop Alzheimer's disease before the age of 60.
Using brain scans and spinal fluid and blood tests, the researchers examined dozens of young adults in the family between the ages of 18 and 26. Among them [3]: members who did not carry the disease-causing gene had normal cerebrospinal fluid and brain scans; Members who carry special 100% disease-causing genes, who will inevitably develop Alzheimer's disease in the future, although their cognitive performance is normal, β-amyloid levels have been elevated and some brain atrophy has appeared.
In 2015, a study published in Brain [4] found that autopsies comparing the brains of 13 deceased people aged 20-66 had found that 20-year-old young people with no cognitive impairment at all had β-amyloid aggregation in their brains.
Accumulation of toxic proteins in the brains of young Alzheimer patients
Returning to the study mentioned above, by comparing the two patients who were able to innately resist Alzheimer's disease, the researchers found that both had extensive and large amounts of amyloid pathology in their brains, which is a pathological feature of Alzheimer's disease. However, tau protein has limited accumulation in the entorhinal cortex, a brain region typically affected by the early clinical stages of Alzheimer's disease, which may be an important target for the treatment of Alzheimer's disease.
In terms of molecular mechanism, APOE and Reelin protein mutations are involved in the protection of Alzheimer's disease, by activating a specific signaling pathway to inhibit the accumulation of tau protein, thereby delaying the cognitive decline of patients.
From the sample size, whether APOE and Reelin protein mutations can directly lead to the reduction of tau protein accumulation in the entorhinal cortex still needs more research to confirm. But the phenotype of tau protein reducing the accumulation of the entorhinal cortex is somewhat interesting, and if more subsequent studies can prove that it can delay cognitive decline, this finding will provide a new hypothesis for the treatment of Alzheimer's disease, and humans are also expected to usher in new treatments.
reference
[1] Kametani F, Hasegawa M. Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease. Front Neurosci. 2018 Jan 30;12:25. doi: 10.3389/fnins.2018.00025. PMID: 29440986; PMCID: PMC5797629.
[2] C.H. van Dyck， C.J. Swanson， P. Aisen， R.J. Bateman， C. Chen， M. Gee， M. Kanekiyo， D. Li， L. Reyderman， S. Cohen， L. Froelich， S. Katayama， M. Sabbagh， B. Vellas， D. Watson， S. Dhadda， M. Irizarry， L.D. Kramer， and T. Iwatsubo， Lecanemab in Early Alzheimer’s Disease， n engl j med 388;1 nejm.org January 5， 2023
[3] https://www.ncbi.nlm.nih.gov/pubmed/23137948
[4] https://news.northwestern.edu/stories/2015/03/alzheimer-amyloid-clump