The neuropathology of probable Alzheimer disease and mild cognitive impairment

Abstract

Objective: Mixed pathologies are common in older persons with dementia. Little is known about mixed pathologies in probable Alzheimer disease (AD) and about the spectrum of neuropathology in mild cognitive impairment (MCI). The objective of this study was to investigate single and mixed common age-related neuropathologies in persons with probable AD and MCI.

Methods: The study included 483 autopsied participants from the Religious Orders Study and the Rush Memory and Aging Project with probable AD (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria), MCI (amnestic and nonamnestic), or no cognitive impairment. We excluded 41 persons with clinically possible AD and 14 with other dementias. We documented the neuropathology of AD (National Institute on Aging-Reagan criteria), macroscopic cerebral infarcts, and neocortical Lewy body (LB) disease.

Results: Of 179 persons (average age, 86.9 years) with probable AD, 87.7% had pathologically confirmed AD, and 45.8% had mixed pathologies, most commonly AD with macroscopic infarcts (n = 54), followed by AD with neocortical LB disease (n = 19) and both (n = 8). Of the 134 persons with MCI, 54.4% had pathologically diagnosed AD (58.7% amnestic; 49.2% nonamnestic); 19.4% had mixed pathologies (22.7% amnestic; 15.3% nonamnestic). Macroscopic infarcts without pathologically diagnosed AD accounted for 4.5% of probable AD, 13.3% of amnestic MCI, and 18.6% of nonamnestic MCI. Pure neocortical LB disease was uncommon in all persons with cognitive impairment (<6%). Microscopic infarcts (without macroscopic infarcts) were common as a mixed pathology, but rarely accounted for a clinical diagnosis of probable AD (n = 4) or MCI (n = 3).

Interpretation: Clinically diagnosed probable AD and MCI, even amnestic MCI, are pathologically heterogeneous disorders, with many persons exhibiting mixed pathologies.

Figure

Pathology by clinical status proximate to death. Blue shades: Pathologic diagnosis of Alzheimer's disease. Clockwise: light blue - pathologic diagnosis of Alzheimer's disease only (AD); dark blue - pathologic diagnosis of Alzheimer's disease and neocortical Lewy bodies (AD+LB); medium blue - pathologic diagnosis of Alzheimer's disease and cerebral infarcts (AD+I); aqua - pathologic diagnosis of Alzheimer's disease, cerebral infarcts and neocortical Lewy bodies (AD+I+LB). Red shades: Cerebral infarcts and/or neocortical Lewy bodies (with no pathologic diagnosis of AD). Clockwise: pink - cerebral infarcts or neocortical Lewy bodies (I ± LB); red - cerebral infarcts and neocortical Lewy bodies (I+LB). White: No pathologic diagnosis of Alzheimer's disease, no cerebral infarcts, no neocortical Lewy bodies.