Genetic variant that protects against early Alzheimer's disease discovered

A rare genetic mutation may delay the onset of Alzheimer's disease and could be the key for developing new treatments.

Alzheimer's disease is the most common cause of dementia. Mutations in several genes are known to increase the risk of developing the disease. Researchers studying an extended family that carries a high risk genetic variant associated with early onset Alzheimer's found an individual who appeared resilient to the disease. An additional, very rare genetic mutation protected him from early disease onset and delayed cognitive decline. In 2019, the same team found his sister was also protected from early disease onset by a different genetic variant.

'Extraordinary cases like this one illustrate how individuals and extended families with Alzheimer's disease can help advance our understanding of the disease and open new avenues for discovery.' said co-senior author Dr Yakeel Quiroz-Gaviria from Massachusetts General Hospital, Boston. 'The insights we are gaining from this second case may guide us on where in the brain we need to look to delay and stop disease progression and will help us form new hypotheses about the series of steps that may actually lead to Alzheimer's dementia.'

The male patient carried the 'Paisa' mutation, which would usually result in dementia by the age of 49. Unlike other carriers in the extended family group, he showed no cognitive impairments until his late 60s. A never before reported mutation in the reelin gene was found to be responsible for his resilience. Furthermore, a common disease pathway links both this protective variant, and the one discovered in 2019.

Neurodegeneration in Alzheimer's disease is characterised by increasing accumulation of two misfolded proteins: amyloid beta and tau. During brain imaging it was revealed that despite widespread amyloid-beta plaques, tau tangles were only present in some brain areas. A region called the entorhinal cortex, which plays a critical role in memory and learning, was largely free of tau tangles.

In the study published in Nature Medicine, researchers bred mice that carried the protective reelin variant. The mice showed a similar reduction in tau accumulation in several brain areas, as seen in the protected patient.

The reelin protein plays a role in brain development and function. It binds to similar receptors as the APOE protein. Different variants of the APOE gene are associated with different risks of developing Alzheimer's disease. It is thought that when reelin binds to its receptors, it 'deactivates' tau, while APOE has the opposite effect. The protective mutation increases reelin activity, which could explain the reduction in tau tangles seen in the patient.

'Alzheimer's disease remains a devastating disease with an immense global burden, and this work opens the door to further investigation into how this resilience pathway may lead to an effective therapeutic strategy,' said Professor Joan Miller, chair of ophthalmology at Harvard Medical School, Boston, Massachusetts, who was not involved in the research.

The authors did note that other factors, such as additional genetic variants, may have contributed to the individual's resilience against Alzheimer's disease progression. However, the preclinical experiments support a protective role for the reelin variant, and researchers are looking to develop new treatments targeting the implicated pathway.