Approved Research

Does homozygous Christchurch mutation in apoE3 delay onset of Alzheimer's disease

Lay summary

Scientific rationale: a Colombian woman inherited the autosomal-dominant E280A mutation in presenilin 1 but stayed cognitively well for decades past this mutation's typical age of disease onset. Called Paisa, this mutation causes A! overproduction, triggering neurodegeneration and cognitive decline by a person's 40s. Yet this woman stayed alert for three decades after that. Now in her 70s, she struggles with short-term memory but still remains independent. Amyloid PET scanning revealed a massive buildup of amyloid plaques in her brain, far higher than those seen in young mutation carriers who are cognitively impaired. Despite all this amyloid, she has very little tau pathology, mostly confined to the medial temporal lobe, and her brain glucose metabolism is almost normal. It's as if the chain of pathogenic events is broken after amyloid. The woman is homozygous for the ApoE Christchurch mutation, which seemed to block secondary tau pathology. This protective effect is similar to, but greater than, that of homozygosity for ApoE2.

Project aims: We wish to confirm whether homozygosity for the ApoE Christchurch mutation in persons homozygous for ApoE3 can protect against Alzheimer's disease. If so, our results may lead to new treatments.

Project duration: one year 

Public health impact: Our study may hasten new treatments for Alzheimers disease.

Current Scope:A Colombian woman who inherited the autosomal-dominant E280A mutation in presenilin 1 stayed cognitively well for decades past this mutation's typical age of disease onset. Called Paisa, this mutation causes Amyloid-beta overproduction, triggering neurodegeneration and cognitive decline by a person's 40s. The Colombian woman inherited two copies of an ApoE variant, known as the Christchurch mutation. The protective effect is similar to, but greater than, that of ApoE2. (Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nature Medicine 2019). We wish to use UK Biobank data to corroborate this finding. We will look at data from persons over 60 hetero or homozygous for the Christchurch mutation and compare cognitive measurements to determine if homozygotes are protected.

New Scope: I was originally interested in the christchurch mutation and Alzheimer's disease. I now wish to broaden the scope of my application to neurodegeneration, especially as it might relate to oncology. I have looked at the effects of cannabis because of its relationship to impaired cognition and possible detrimental effects with extensive use.

Research aims for the scope extension: I now wish to broaden the scope of my application to neurodegeneration and cancer. I aim to analyze neurodegeneration in multiple forms of cancer as well as genes, agents used to treat cancer that might be related to neurodegeneration such as cannabis, oncologic drugs, bisphosphonates, oncogenes, viruses.

Only 7 subjects with christchurch mutation were in the UK Biobank sample, too few for any analysis. I think a broader scope would be more worthwhile. No one knows the cause of Alzheimer's or other forms of neurodegeneration. Oncology drugs have been tested in these conditions, most recently tasigna, without success. I hope to turn up information that will help others working in this area and ultimately people with neurodegenerative diseases.