There are 2 separate, important subtypes of AD neuropathologic changes, i.e., neuritic and diffuse amyloid plaques containing Aβ peptide, and NFTs (including pretangles), which develop in different patterns in AD brains Evidence from CPC studies strongly support the existence of a specific, prevalent disease defined by the presence of clinical dementia, neuritic Aβ plaques, and NFTs in the neocortex It is extraordinarily rare for a case with widespread, dense AD-type neocortical lesions to lack documented antemortem cognitive decline With some notable exceptions (e.g. elderly schizophrenia patients, substance abusers, systemic disease), no significant subset of patients with severe age-associated cognitive decline exists that lacks any pathologic substrate when modern methods (i.e. immunohistochemistry) are used in the neuropathologic examination It is best that AD not be regarded as a hippocampal disease because the disease process does not exert its full impact without extension into the neocortex, where correlation is stronger between clinical and pathological observations There are prevalent (more than two thirds of patients) comorbidities, including cerebrovascular diseases, synucleinopathies, tauopathies, frontotemporal lobar degeneration, and TDP-43–related diseases, in the brains of aged persons that inevitably skew correlations between neuropathologic findings and cognition CPC studies, like biomarker studies of living patients, must consider the long prodromal phase of AD during which AD pathology is accumulating but is not yet clinically manifest as overt cognitive impairment
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