**8. Neurofibrillary tangles (NFT)**

Tau, a protein associated with microtubules, is required for normal neuronal development and axonal expansion. However, frontal association cortices, the lateral parietotemporal area, and the mesial temporal lobe (especially the hippocampus) neurons are where hyperphosphorylated tau protein aggregates are most frequently found as helical filamentous NFT. The relationship between the density and distribution of tau NFT and the symptoms and severity of AD dementia emphasizes the critical role of NFT in AD pathology.

### **9. Loss of neurons and synapses**

Synapse loss and neuronal cell death have a similar distribution to NFT. Due to the death of neurons in the nucleus basalis of Meynert, acetylcholine (Ach), a neurotransmitter linked to memory, is decreased in typical AD. Most current therapies seek to remedy this cholinergic deficit. Serotonin and norepinephrine deficits result from the loss of neurons in the brainstem's locus ceruleus and median raphe. Dysfunctional serotonergic and adrenergic activity in the brain is probably the root cause of dysphoria and insomnia in AD [38, 39].
