Answer is C (NFTs appear extracellularly before intracellular appearance):NFTs are typically seen intracellularly within the soma and proximal dendrites of neurons. Neurofibrillary Tangles (NFTs) are intracellular accumulations of hyperphosphorylated 'tau' proteins.Neurofibrillary Tangles are Intracellular AccumulationsNeurofibrillary Tangles are intracellular accumulations of hyperphosphorylated microtubule binding protein 'tau'.Paired helical filaments of tau protein (NFTs) form intracellularly within the soma and proximal dendrites of neurons.These cytoskeletal protein tangles (NFTs), initially impede cellular metabolism and axosplasmic transpo leading to impaired synaptic function and eventually to neuronal death.These neurofibrillaty tangles may be seen as extracellular tangles after degeneration of the neuron as evidence of the neuronal cell's demiseNeurofibrillary Tangles are intracellular accumulations that may appear extracellularly alter degeneration of neuron (neuronal death)Histopathological Hallmarks of Alzheimer's DiseaseAmyloid Plaques (Extracellular)Amyloid Neuritic Plaques are formed by extracellular accumulation of beta amyloid deposits within the neutropil'Neuritic' or 'Senile' I3-amyloid plaques are an early histopathological sign of Alzheimer's disease (that occur rarely in healthy subjects)The amyloid 13-protein accumulated in single neuritic plaques is toxic to surrounding structures and adjacent neurons.Clinicopathological studies have shown that amy/aid burden does not directly correlate with severity or duration of dementia.Neurofibrillary Tangles (Intracellular)Neurofibrillary tangles arc formed by intracellular accumulation of hyperphosphorylated microtubule binding protein 'tau'.NFT's occur in many neurodegenerative diseases and /or a group of diseases called laupathies'.These include Frontotemporal dementia, Pick's disease etc. The cooccurance of fi-amyloid plaques with NFT's suggests a diagnosis of AD.The NFT's are toxic to the neurons and neurons with NFT's eventually die and degenerate leaving a residual `ghost tangle', in the extracellular space reminding of the pyramidal cell body in which it was initially formed.Clinicopathological studies have shown that dementia correlates more strongly with NFT's than with senile plaques (3-amyloid)