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. 2024 Nov 22;6(6):fcae369.
doi: 10.1093/braincomms/fcae369. eCollection 2024.

Cerebral amyloid angiopathy impacts neurofibrillary tangle burden and cognition

Dana Godrich  1 , Jeremy Pasteris  1   2 , Eden R Martin  1   2 , Tatjana Rundek  3 , Gerard Schellenberg  4 , Tatiana Foroud  5 , Jeffery M Vance  1   2 , Margaret A Pericak-Vance  1   2 , Michael L Cuccaro  1   2 , William K Scott  1   2 , Walter Kukull  6 , Thomas J Montine  7 , Gary W Beecham  1   2
Affiliations

Cerebral amyloid angiopathy impacts neurofibrillary tangle burden and cognition

Dana Godrich et al. Brain Commun. .

Abstract

Cerebral amyloid angiopathy commonly co-occurs with amyloid β plaques and neurofibrillary degeneration and is proposed to contribute to cognitive impairment. However, the interplay among these pathologic changes of Alzheimer disease is not well understood. Here we replicate and extend findings of a recent study that suggested the association of cerebral amyloid angiopathy and cognitive impairment is mediated by neurofibrillary degeneration. We employed similar approaches but in a larger, clinical-based (as opposed to community-based) set of 4915 autopsied National Alzheimer's Coordinating Center participants (60% with dementia). Neuropathologic lesions were measured ordinally; longitudinal change in cognition was used to measure cognitive impairment. Statistical analyses included ordinal logistic regression, mediation analyses and extension of models to include presence of APOE e4. We show a statistical interaction between cerebral amyloid angiopathy and neuritic plaques that impacts the burden of neurofibrillary tangles. Mediation analyses show that cerebral amyloid angiopathy is associated with cognitive impairment, but only by modifying the impact of neurofibrillary tangles on cognition. We expanded the mediation analysis to include APOE e4 and show similar results. Findings indicate that cerebral amyloid angiopathy plays an important role in the burden and impact of neurofibrillary degeneration contributing to cognitive impairment.

Keywords: Alzheimer’s disease; dementia; neurodegeneration; neuropathology.

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Conflict of interest statement

M.L.C. and J.P. reports no conflicts of interest. E.R.M., M.A.P.-V., J.M.V. and G.W.B. report grant funding through the NIH. G.S. reports grant funding through the NIH and an honorarium from the BrightFocus Foundation for grant review. W.K.S. reports grant funding through the NIH and an honorarium from the University of Chicago for speaking at a seminar. W.K. 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. T.J.M. 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. D.G. is an unpaid member of the American Society for Human Genetics career development committee.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Illustration of path models. A illustrates the hypothetical relationship between APOE, amyloid (neuritic) plaques, CAA, neurofibrillary tangle (NFT) progression and rate of cognitive change (adapted from Rabin et al.). Briefly, APOE increases amyloidosis (NP and CAA) while also potentially having other direct effects on NFT and cognition. CAA may have direct effects on cognition but may also operate through NFT indirectly (dashed lines), while also interacting with other effects such as APOE and plaques. Operationally, we tested this model through mediation analyses subset by NP severity. B and C illustrate the mediation analyses. The first (B) tests both the direct effect and indirect effect of CAA on change in cognition. The second (C) tests the same effects, but also accounts for APOE e4 dosage, to assess the role of APOE pleiotropic effects. NFT, neurofibrillary tangles; CAA, cerebral amyloid angiopathy; APOE e4, Apolipoprotein E e4 allele.
Figure 2
Figure 2
Correlation and trends of neurofibrillary tangles and neuritic plaque levels by CAA burden. (A) Bar plot of NFT burden by CAA burden. (B) Bar plot of NP burden by CAA burden. (C) NFT burden by CAA burden, grouped into no/low and intermediate/high NP groups. (D) Correlation (Kendall’s τ) between lesions (CAA, NFT, NP) and APOE e4. NFT, neurofibrillary tangles; NP, neuritic plaques; CAA, cerebral amyloid angiopathy; APOE e4, Apolipoprotein E e4 allele.
See this image and copyright information in PMC

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