Abstract: For many decades, Alzheimer’s disease research has primarily focused on impairments within cortical and hippocampal regions, which are thought to be related to cognitive dysfunctions such as memory and language deficits. The exact cause of Alzheimer’s disease is still under debate, making it challenging to establish an effective therapy or early diagnosis. It is widely accepted that the accumulation of amyloid-beta peptide in the brain parenchyma leads to synaptic dysfunction, a critical step in Alzheimer’s disease development. The traditional amyloid cascade model is initiated by accumulating extracellular amyloid-beta in brain areas essential for memory and language. However, while it is possible to reduce the presence of amyloid-beta plaques in the brain with newer immunotherapies, cognitive symptoms do not necessarily improve. Interestingly, recent studies support the notion that early alterations in subcortical brain regions also contribute to brain damage and precognitive decline in Alzheimer’s disease. A body of recent evidence suggests that early Alzheimer’s disease is associated with alterations (e.g., motivation, anxiety, and motor impairment) in subcortical areas, such as the striatum and amygdala, in both human and animal models. Also, recent data indicate that intracellular amyloid-beta appears early in subcortical regions such as the nucleus accumbens, locus coeruleus, and raphe nucleus, even without extracellular amyloid plaques. The reported effects are mainly excitatory, increasing glutamatergic transmission and neuronal excitability. In agreement, data in Alzheimer’s disease patients and animal models show an increase in neuronal synchronization that leads to electroencephalogram disturbances and epilepsy. The data indicate that early subcortical brain dysfunctions might be associated with non-cognitive symptoms such as anxiety, irritability, and motivation deficits, which precede memory loss and language alterations. Overall, the evidence reviewed suggests that subcortical brain regions could explain early dysfunctions and perhaps be targets for therapies to slow disease progression. Future research should focus on these non-traditional brain regions to reveal early pathological alterations and underlying mechanisms to advance our understanding of Alzheimer’s disease beyond the traditionally studied hippocampal and cortical circuits.

Key words: Alzheimer’s disease, AMPA receptors, amygdala, epilepsy, gamma-aminobutyric acid, glutamate, hippocampus, neurodegeneration, neuronal excitability, N-methyl-D-aspartate receptors, non-cognitive, nucleus accumbens