Protective genetic variants against Alzheimer's disease

Abstract

Genetic studies can offer powerful insights for the development of disease-modifying therapies for Alzheimer's disease. Protective genetic variants that delay the onset of cognitive impairment have been found in people with sporadic Alzheimer's disease and in carriers of mutations that usually cause autosomal-dominant Alzheimer's disease in mid-life. The study of families who carry autosomal dominant mutations provides a unique opportunity to uncover genetic modifiers of disease progression, including rare variants in genes such as APOE and RELN. Understanding how these variants confer protection can help identify the biological pathways that contribute to cognitive resilience, such as the heparan-sulphate proteoglycan-APOE receptor pathway, the TREM-2-driven signalling pathways in the microglia, and phagocytosis. Therapies able to replicate the beneficial effects of these natural defences could provide novel strategies for slowing or preventing the progression of Alzheimer's disease.

Figure 1:. The ApoE–Reelin pathway of resilience in neurons

The intraneuronal pathway is activated upon interaction between Reelin or ApoE and heparan sulphate proteoglycans, followed by binding to the ApoE receptor. Once the Reelin–ApoE receptor complex is internalised, the rapid phosphorylation of DAB1 leads to AKT activation and subsequent inhibition of GSK3β, thus resulting in reduced tau phosphorylation. pDAB1 activity is controlled by fast ubiquitination and degradation. HSPG=heparan sulfate proteoglycans. Figure created with BioRender.com.

Figure 2:. Differences between individuals susceptible or resilient to Alzheimer’s disease.

(A) ApoE3 and Reelin variants contribute to maintain the homoeostatic balance between glia and neuronal transmission. In people with autosomal-dominant Alzheimer’s disease or sporadic Alzheimer’s disease, microglia, astrocytes, and synaptic transmission are severely affected. APOE4 contributes to impaired Reelin activity due to increased binding affinity to heparan sulphate proteoglycans, thus contributing to tau hyperphosphorylation. The effects of Alzheimer’s disease-inducing pathological variants are counterbalanced by the presence of protective variants such as APOE3Ch. Reelin-COLBOS contributes to preserved microglia, astrocytes, and neuronal function thanks to up-regulated reelin activity and reduced tau phosphorylation. (B) Representative fluorodeoxyglucose PET scans of the brain of an individual with autosomal-dominant Alzheimer’s disease (left) and the brain of a Reelin-COLBOS resilient individual (right) showing that the metabolic activity of the brain is severely affected in the presence of Alzheimer’s disease pathology, whereas in the presence of protective variants, metabolism is preserved. Adapted from Lopera et al. APOE3CH=APOE3 Christchurch (Arg136Ser) variant. HSPG=heparan sulfate proteoglycans. Figure created with BioRender.com.

Figure 3:. The protective role of TREM-2 in microglia

(A) Increased TREM-2 activity leads to preserved microglia activity, whereas the crosstalk of TREM-2 with ApoE leads to preserved astrocyte function, increased phagocytosis, and preserved neuronal activity in individuals with resilience. (B) The loss of function of TREM-2 activity leads to impaired microglia activity that, along with degenerating astrocytes, contributes to neurodegeneration in people with Alzheimer’s disease. Figure created with BioRender.com.