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NEUROLOGY 2004;62:925-931
© 2004 American Academy of Neurology

Early Aß accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain

M. Ingelsson, MD PhD, H. Fukumoto, PhD, K. L. Newell, MD, J. H. Growdon, MD, E. T. Hedley–Whyte, MD, M. P. Frosch, MD PhD, M. S. Albert, PhD, B. T. Hyman, MD PhD and M. C. Irizarry, MD

From the Harvard Medical School, Massachusetts General Hospital, Boston.

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 ß-peptide (Aß) 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 Aß, 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 Aß 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 Aß measures. Accumulation of Aß, 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 Aß reaches a "ceiling" early in the disease process, whereas NFT formation, synaptic loss, and gliosis continue throughout the course of the illness.

Received June 27, 2003. Accepted in final form November 26, 2003.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the March 23 issue to find the title link for this article.

Drs. Ingelsson and Fukumoto contributed equally to this work.




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