Distinct Pools of β-Amyloid in Alzheimer Disease-Affected Brain: A Clinicopathologic Study

Steinerman, Joshua R.; Irizarry, Michael; Scarmeas, Nikolaos; Raju, Susan; Brandt, Jason; Albert, Marilyn; Blacker, Deborah; Hyman, Bradley; Stern, Yaakov

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.


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Taub Institute
American Medical Association
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January 28, 2016