Science investigation casts doubt on claims about “protective” genes in Alzheimer’s disease
Science investigation casts doubt on claims about “protective” genes in Alzheimer’s disease
On August 13, Science published an investigation by Charles Piller and Jennie Erin Smith into rare gene variants found in a large Colombian family. Carriers of the inherited PSEN1 E280A mutation usually develop mild problems with memory and thinking at around 44 years of age. Two reports of much later disease onset made other genes potential candidates for therapeutic development.
A 2019 paper described a woman with PSEN1 E280A whose cognitive function remained intact until she was 70. She carried two copies of the rare APOE3 Christchurch variant. Her scans showed a high amyloid burden, meaning accumulations of a protein characteristic of Alzheimer’s disease, but relatively little deposition of tau, another protein associated with the disease. This single unusual case suggested a hypothesis: the APOE variant might delay the onset of symptoms.
A 2023 study added a man from the same family. He retained his cognitive abilities until he was 67, and he was diagnosed with mild cognitive impairment at 70. Among the changes in his genome, the authors identified the H3447R variant in the RELN gene and named it COLBOS. The RELN gene encodes the protein reelin. In primary mouse neurons, this variant increased the activation of Dab1, an intracellular protein that transmits the reelin signal. The authors first observed an unusually late disease onset in a person, then selected a candidate gene and tested the function of its protein.
A cell experiment can explain how a protein functions. Whether a variant is associated with later disease onset must be tested using human data.
The investigation brought this initial test back to the center of the discussion. Science reports that its authors reviewed more than a thousand scientific papers, patents, grant records, and items of correspondence, and spoke with independent experts and members of the Colombian research group GNA. The publication raises questions about changes made to patient data and about suspicious or duplicated images in several papers. GNA responded that the image concerns involve only a limited subset of the publications and do not affect the authenticity of the underlying data, the quantitative analyses, or the scientific conclusions of those studies.
An independent analysis should compare genotypes, ages at symptom onset, and patient selection criteria across the cohort. Once that check has been completed, cell experiments can help explain how a candidate variant affects the protein and the cell before researchers rely on it in developing treatments.