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A 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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