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. 2022 Dec;18(12):2403-2412.
doi: 10.1002/alz.12516. Epub 2022 Feb 9.

Neuropathological lesions and their contribution to dementia and cognitive impairment in a heterogeneous clinical population

Dana Godrich  1 , Eden R Martin  1   2 , Gerard Schellenberg  3 , Margaret A Pericak-Vance  1   2 , Michael Cuccaro  1   2 , William K Scott  1   2 , Walter Kukull  4 , Thomas Montine  5 , Gary W Beecham  1   2
Affiliations

Neuropathological lesions and their contribution to dementia and cognitive impairment in a heterogeneous clinical population

Dana Godrich et al. Alzheimers Dement. 2022 Dec.

Abstract

Introduction: Alzheimer disease (AD) and related dementias are characterized by damage caused by neuropathological lesions in the brain. These include AD lesions (plaques and tangles) and non-AD lesions such as vascular injury or Lewy bodies. We report here an assessment of lesion association to dementia in a large clinic-based population.

Methods: We identified 5272 individuals with neuropathological data from the National Alzheimer's Coordinating Center. Individual lesions, as well as a neuropathological composite score (NPCS) were tested for association with dementia, and both functional and neurocognitive impairment using regression models.

Results: Most individuals exhibited mixed pathologies, especially AD lesions in combination with non-AD lesions. All lesion types were associated with one or more clinical outcomes; most even while controlling for AD pathology. The NPCS was also associated with clinical outcomes.

Discussion: These data suggest mixed-type pathologies are extremely common in a clinic-based population and may contribute to dementia and cognitive impairment.

Keywords: Alzheimer disease; Lewy bodies; amyloid angiopathy; cognitive decline; dementia; hippocampal sclerosis; neuritic plaques; neurofibrillary; neuropathology; tangles; vascular dementia.

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Conflict of interest statement

MC reports no conflicts of interest.

ERM, MAPV, and GWB report grant funding through the NIH.

GS reports grant funding through the NIH and an honorarium from the BrightFocus Foundation for grant review.

WKS reports grant funding through the NIH and an honorarium from the University of Chicago for speaking at a seminar.

WK reports grant funding through the NIH, honoraria for serving on external advisory committees (Boston U ADRC, USC ADRC, UCI ADR, Mt. Sinai ADRC), honoraria for grant review (NIH: NIA/CSR), and travel support from the Alzheimer Association for participation in a symposium.

TM reports grant funding through the NIH and Farmer Family Foundation, royalty payments from UpToDate, honoraria and travel support for invited lectures, and has patents pending on novel chemical matter for treatment or imaging of neurodegenerative diseases.

DG is an unpaid member of the American Society for Human Genetics career development committee.

Figures

FIGURE 1
FIGURE 1
Flow chart of exclusion criteria and analyses. The flowchart shows exclusion criteria and sample sizes in the dataset. The primary dataset allows three or fewer missing lesions to be imputed and analyzed. The clinical outcomes have varying sample sizes as we do not impute the outcome variables. The “complete” data do not allow any missing lesions and were only used in some of the sensitivity analyses. Abbreviations: CDR‐SOB, Clinical Dementia Rating Sum of Boxes; MMSE, Mini‐Mental State Examination; NACC, National Alzheimer's Coordinating Center
FIGURE 2
FIGURE 2
Distributions of neuropathology composite score (NPCS) and lesion severity. (A) Shows the overall distribution of the NPCS (N = 5272). The dashed line notes the mean NPCS of 2.98 (±1.7 SD). This histogram represents the distribution of the NPCS from one imputation with the multivariate imputation by chained equation (MICE) package in R software. Other distributions will vary slightly in number per bin, but will follow the same general shape of this distribution. (B) Shows the distribution of individual lesions, split by quartile of the NPCS. Abbreviations: ARTE, arteriolosclerosis; CAA, cerebral amyloid angiopathy; DP, diffuse plaques; HS, hippocampal sclerosis; LB, Lewy bodies; NFT, neurofibrillary tangles; NP, neuritic plaques; NPCS, neuropathology composite score; VBI, vascular brain injury
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