Synaptic Excitatory to Inhibitory imbalance in Alzheimer’s Disease
Alzheimer’s disease is the most common cause of dementia worldwide, and it is characterized by progressive impairment of cognitive performance, brain atrophy, neuronal and synaptic loss, and abnormal aggregation of amyloid beta and tau proteins. Notably, prodromal Alzheimer’s disease is characterized by mild cognitive impairment, increments in the occurrence of seizures and abnormal electroencephalographic activity. Clinical and animal model studies suggest that hyperexcitability and cognitive impairment may be mechanistically linked, through synaptic abnormalities that disturb the excitatory/inhibitory balance (E/I ratio) in circuits vulnerable to Alzheimer’s disease pathology. We measured electrophysiological, anatomical, transcriptional, and cellular E/I ratios in human brain. Our findings establish a strong correlational link between E/I imbalance and loss of cognition; and showed a pro-excitatory shift of this balance in brain regions known to be hyperactive in Alzheimer’s disease subjects.