Mitochondrial Dysfunction and Immune Activation are Detectable in Early Alzheimer's Disease Blood.

Alzheimer's disease (AD), like other dementias, is characterized by progressive
neuronal loss and neuroinflammation in the brain. The peripheral leukocyte
response occurring alongside these brain changes has not been extensively
studied, but might inform therapeutic approaches and provide relevant disease
biomarkers. Using microarrays, we assessed blood gene expression alterations
occurring in people with AD and those with mild cognitive changes at increased
risk of developing AD. Of the 2,908 differentially expressed probes identified
between the three groups (p < 0.01), a quarter were altered in blood from mild
cognitive impairment (MCI) and AD subjects, relative to controls, suggesting a
peripheral response to pathology may occur very early. There was strong evidence
for mitochondrial dysfunction with decreased expression of many of the
respiratory complex I-V genes and subunits of the core mitochondrial ribosome
complex. This mirrors changes previously observed in AD brain. A number of genes
encoding cell adhesion molecules were increased, along with other immune-related
genes. These changes are consistent with leukocyte activation and their increased
transition from circulation into the brain. In addition to expression changes, we
also found increased numbers of basophils in people with MCI and AD, and
increased monocytes in people with an AD diagnosis. Taken together this study
provides both an insight into the functional response of circulating leukocytes
during neurodegeneration and also identifies potential targets such as the
respiratory chain for designing and monitoring future therapeutic interventions
using blood.