Cerebral amyloid angiopathy pathology and cognitive domains in older persons

Abstract

Objective: To examine the relation of cerebral amyloid angiopathy (CAA) to cognitive domains in older community-dwelling persons with and without dementia.

Methods: Subjects were 404 persons in the Religious Orders Study, a cohort study of aging, who underwent annual clinical evaluations, including 19 neuropsychological tests from which 5 cognitive domain and global summary scores were derived, and brain autopsy at time-of-death (mean age-at-death 86). Using amyloid-β immunostaining, CAA severity was graded in 5 regions (midfrontal, inferior temporal, angular, calcarine, and hippocampal cortices), as 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe. Because severity was related across regions (all r(s) > 0.63), and almost all persons had some CAA, we averaged regional CAA scores and created class variable predictors for no-to-minimal (<0.5), mild-to-moderate (0.5-2.5) and moderate-to-very severe CAA (>2.5).

Results: CAA was very common (84.9%; 94 had no-to-minimal, 233 mild-to-moderate, and 76 moderate-to-very severe disease) and was related to AD pathology (r(s) = 0.68). In linear regression analyses controlling for age, sex, education, AD pathology, infarcts, and Lewy bodies, moderate-to-very severe CAA was associated with lower perceptual speed (p = 0.012) and episodic memory (p = 0.047), but not semantic memory, working memory, visuospatial skills, or a composite of all cognitive measures. No associations of mild-to-moderate CAA with cognition were found. Dementia did not modify these findings.

Interpretation: CAA pathology is very common in older community-dwelling persons and is associated with AD pathology. Moderate-to-very severe CAA, but not mild-to-moderate CAA, is associated with lower performance in specific cognitive domains, most notably perceptual speed, separately from the effect of AD pathology.

Figure

Immunostaining of CAA showing increasing severity of CAA. All panels are shown in original magnification ×200. (A) Mild severity (grade 1) showing incomplete circumferential staining of leptomeningeal blood vessels in a case with sparse positivity. (B) Moderate severity (grade 2) showing strong circumferential staining of leptomeningeal blood vessels. (C) Severe (grade 3) with multiple blood vessels with strong circumferential staining in a case with widespread positivity. (D) Very severe (grade 4) with amyloid positivity emanating from the blood vessels into surrounding neuropil, in a case with widespread circumferential staining. CAA = cerebral amyloid angiopathy.