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Distinct Pools of β-Amyloid in Alzheimer Disease–Affected BrainA Clinicopathologic Study
Joshua R. Steinerman, MD;
Michael Irizarry, MD;
Nikolaos Scarmeas, MD;
Susan Raju, PhD;
Jason Brandt, PhD;
Marilyn Albert, PhD;
Deborah Blacker, MD;
Bradley Hyman, MD, PhD;
Yaakov Stern, PhD
Arch Neurol. 2008;65(7):906-912.
Objective To determine whether β-amyloid (Aβ) peptides segregated into distinct biochemical compartments would differentially correlate with clinical severity of Alzheimer disease (AD).
Design Clinicopathologic correlation study.
Participants Twenty-seven patients from a longitudinal study of AD and 13 age- and sex-matched controls without a known history of cognitive impairment or dementia were included in this study.
Interventions Temporal and cingulate neocortex were processed using a 4-step extraction, yielding biochemical fractions that are hypothesized to be enriched with proteins from distinct anatomical compartments: TRIS (extracellular soluble), Triton (intracellular soluble), sodium dodecyl sulfate (SDS) (membrane associated), and formic acid (extracellular insoluble). Levels of Aβ40 and Aβ42 were quantified in each biochemical compartment by enzyme-linked immunosorbent assay.
Results The Aβ42 level in all biochemical compartments was significantly elevated in patients with AD vs controls (P < .01). The Aβ40 levels in the TRIS and formic acid fractions were elevated in patients with AD (temporal, P < .01; cingulate, P = .03); however, Triton and SDS Aβ40 levels were similar in patients with AD and in controls. Functional impairment proximal to death correlated with Triton Aβ42 (r = 0.48, P = .02) and SDS Aβ42 (r = 0.41, P = .04) in the temporal cortex. Faster cognitive decline was associated with elevated temporal SDS Aβ42 levels (P < .001), whereas slower decline was associated with elevated cingulate formic acid Aβ42 and SDS Aβ42 levels (P = .02 and P = .01, respectively).
Conclusion Intracellular and membrane-associated Aβ, especially Aβ42 in the temporal neocortex, may be more closely related to AD symptoms than other measured Aβ species.
Author Affiliations: Departments of Neurology (Drs Steinerman and Scarmeas), Psychiatry (Dr Stern), and Psychology (Dr Stern), Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York; Departments of Neurology (Drs Irizarry, Raju, and Hyman) and Psychiatry (Dr Blacker), Massachusetts General Hospital, Charlestown; and Departments of Psychiatry and Behavioral Sciences (Dr Brandt) and Neurology (Dr Albert), Johns Hopkins School of Medicine, Baltimore, Maryland. Dr Irizarry is now with GlaxoSmithKline, Research Triangle Park, NC.
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