Updated 17 June 2003
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Neuropathology of Alzheimer Disease and Clinical Relevance
By Kurt Jellinger
Kurt Jellinger's presentation.
Alzheimer disease (AD) morphologically shows extracellular deposition of Ab amyloid (Ab),
paired helical filaments (hyperphosphorylated tau) in neurofibrillary tangles, neuropil threads, and dystrophic neurites. These of lesions
showing a distinct sequence of spreading are associated with loss of cortical synapses and neurons causing disruption
of neuronal circuits as major correlates of dementia and AD variants. Current diagnostic criteria are based on age-correlated
(semi)quantitative assessment of plaques (NIA), neuritic plaques (CERAD), topographic staging of neuritic changes (Braak),
and a combination of CERAD and Braak staging (NIA-RI criteria), but their reliability and clinical relevance are yet to be determined.
While Ab plaques are a poor indicator for dementia, its degree correlates best with the severity and extent
of neuritic pathology and loss of synapses/synapse markers. Evaluation of these criteria with clinical scores identified all cases with
severe dementia, but may fail in moderately demented individuals. NIA-RI criteria assigned most nondemented to the low or intermediate
categories, but studies in those with no or mild cognitive impairment showed a wide variety of AD-related pathology: 7-50% met one or
more of the AD criteria or had tau pathology in the perforant path target zone and loss of entorhinal neurons. Only 20% were free of
considerable AD-related lesions. Even the combined use of all current AD criteria often cannot distinguish between questionable and
definite dementia. Recent demonstration of a distinct sequence of Ab depositions suggests that nondemented subjects with
Ab or neuritic plaques may represent early stages of AD. Additional difficulties arise from frequent
concurrence of other, e.g. vascular and Lewy body, pathologies that may interact in "unmasking" or promoting cognitive impairment.
Future studies should try to subdivide nondemented elderly ("normal aging") without from those with AD-related pathology (preclinical AD).
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