Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.
BACKGROUND
Pathologic changes in the Alzheimer disease (AD) brain occur in a hierarchical neuroanatomical pattern affecting cortical, subcortical, and limbic regions.


OBJECTIVE
To define the time course of pathologic and biochemical changes-amyloid deposition, amyloid beta-peptide (Abeta) accumulation, neurofibrillary tangle (NFT) formation, synaptic loss, and gliosis-within the temporal association cortex of AD cases of varying disease duration, relative to control brains.


METHODS
Stereologic assessments of amyloid burden and tangle density as well as ELISA-based measurements of Abeta, synaptophysin, and glial fibrillary acidic protein (GFAP) were performed in the superior temporal sulcus from a cohort of 83 AD and 26 nondemented control brains.


RESULTS
Relative to control cases, AD brains were characterized by accumulation of NFT and amyloid plaques, increase of tris- and formic acid-extractable Abeta species, reduced levels of synaptophysin, and elevated levels of GFAP. In AD cases, the duration of dementia correlated with the degree of tangle formation, gliosis, and synaptic loss but not with any Abeta measures. Accumulation of Abeta, measured both neuropathologically and biochemically, was markedly increased in AD brains independent of disease duration, even in cases of short duration.


CONCLUSIONS
These data support distinct processes in the initiation and progression of AD pathology within the temporal cortex: Deposition of Abeta reaches a "ceiling" early in the disease process, whereas NFT formation, synaptic loss, and gliosis continue throughout the course of the illness.
Ingelsson
M
M
Harvard Medical School, Massachusetts General Hospital, Boston.
Fukumoto
H
H
Newell
K L
KL
Growdon
J H
JH
Hedley-Whyte
E T
ET
Frosch
M P
MP
Albert
M S
MS
Hyman
B T
BT
Irizarry
M C
MC
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016874:Neurofibrillary Tangles / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism; D011237:Predictive Value of Tests; D013569:Synapses / Q000473:pathology*; D016708:Synaptophysin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; D016708:Synaptophysin; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)