Neurodegenerative basis of age-related cognitive decline

Abstract

Objective: To assess the contribution of dementia-related neuropathologic lesions to age-related and disease-related change in cognitive function.

Methods: A total of 354 Catholic nuns, priests, and brothers had annual clinical evaluations for up to 13 years, died, and underwent brain autopsy. The clinical evaluations included detailed testing of cognitive function from which previously established composite measures of global cognition and specific cognitive functions were derived. As part of a uniform neuropathologic evaluation, the density of neurofibrillary tangles was summarized in a composite measure and the presence of Lewy bodies and gross and microscopic cerebral infarction was noted.

Results: During follow-up, rate of global cognitive decline was gradual at first and then more than quadrupled in the last 4 to 5 years of life consistent with the onset of progressive dementia. Neurofibrillary tangles, cerebral infarction, and neocortical Lewy bodies all contributed to gradual age-related cognitive decline and little age-related decline was evident in the absence of these lesions. Neurofibrillary tangles and neocortical Lewy bodies contributed to precipitous disease-related cognitive decline, but substantial disease-related decline was evident even in the absence of these lesions.

Conclusion: Mild age-related decline in cognitive function is mainly due to the neuropathologic lesions traditionally associated with dementia.

Figure 1 Neuropathologic lesions and global cognitive decline Predicted path of global cognitive decline at high (75th percentile, red line) and low (25th percentile, green line) levels of neurofibrillary tangles (A); with chronic gross (B) and microscopic (C) infarction present (red line) or absent (green line); with Lewy bodies present (neocortical, red line; nigral/limbic, blue line) or absent (green line) (D).

Figure 2 Neurofibrillary tangles and decline in specific cognitive domains Relation of high (75th percentile, red line) and low (25th percentile, green line) levels of neurofibrillary tangles to decline in episodic memory (A), semantic memory (B), working memory (C), and perceptual speed (D).

Figure 3 Lewy bodies and decline in specific cognitive domains Relation of Lewy bodies (neocortical, red line; nigral/limbic, blue line; absent, green line) to decline in episodic memory (A), semantic memory (B), working memory (C), and perceptual speed (D).