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Shirzadi Z, Schultz SA, Yau WW, Joseph-Mathurin N, Fitzpatrick CD, Levin R, Kantarci K, Preboske GM, Jack CR Jr, Farlow MR, Hassenstab J, Jucker M, Morris JC, Xiong C, Karch CM, Levey AI, Gordon BA, Schofield PR, Salloway SP, Perrin RJ, McDade E, Levin J, Cruchaga C, Allegri RF, Fox NC, Goate A, Day GS, Koeppe R, Chui HC, Berman S, Mori H, Sanchez-Valle R, Lee JH, Rosa-Neto P, Ruthirakuhan M, Wu CY, Swardfager W, Benzinger TL, Sohrabi HR, Martins RN, Bateman RJ, Johnson KA, Sperling RA, Greenberg SM, Schultz AP, Chhatwal JP, Dominantly Inherited Alzheimer Network and the Alzheimer’s Disease Neuroimaging Initiative. Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease. JAMA Neurol. 2023 Dec 1;80(12):1353-1363. PubMed.
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Columbia University
I am delighted to see that consideration of the role and meaning of white-matter hyperintensities (WMH) continues to be part of our conversation about Alzheimer’s disease. The paper by Shirzadi and colleagues showcases the powerful approach of combining data from many cohorts with different participant characteristics to examine the correlates of WMH as they appear in AD. Their study confirms that WMH are a prominent feature of AD, that they are related to other pathophysiological indicators, like atrophy and cerebral microbleeds, and that they are not accounted for entirely by vascular risk factors. The authors conclude that, in the context of AD, WMH should be considered a reflection of “AD-intrinsic” factors like amyloid pathology and neurodegeneration, and not an indicator of small vessel cerebrovascular disease.
There are many strengths to this study. I think at the top of the list is the utilization of data from individuals with autosomal-dominant forms of AD from the Dominantly Inherited Alzheimer Network (DIAN). Individuals with autosomal-dominant AD tend to be much younger than those with late-onset AD and, importantly, have low levels of vascular risk factors, so consideration of the role of WMH without the confound of exposure to vascular risk factors is possible. Even in this younger, healthier, and genetically “pure” form of AD, the authors observed increased WMH that seemed to covary with other aspects of AD.
We took a similar approach in 2016, showing that WMH are increased among mutation carriers in DIAN about 20 years prior to expected symptom onset (Lee et al., 2016) and that these changes, while related, were not mediated entirely by cerebral microbleeds, a marker of cerebral amyloid angiopathy (Lee et al., 2018). Similarly, in older adults with Down’s syndrome, another population at genetic risk for developing AD with very low amounts of vascular risk factors, we observed increased WMH in addition to several other markers of cerebrovascular disease, like microbleeds, enlarged perivascular spaces, and frank infarcts that were not attributable entirely to vascular risk factors (Lao et al., 2020). The cerebrovascular indicators, rather, were related to protein markers that suggest inflammatory processes, particularly in early stages of AD (Moni et al., 2022).
These studies, along with myriad others in late-onset AD, converge toward a similar conclusion drawn by Shirzadi and colleagues: WMH are not entirely attributable to exposure to vascular risk factors in AD, so they must be due to “something else.”
Showing that WMH are not related to vascular risk factors and that they are related to aspects of AD pathophysiology tells us two things: that WMH are not due exclusively to (modifiable) risk factors and that there is a relationship between WMH with other markers of AD. But do these observations prove the etiology of WMH? I do not think this question has been settled. Emerging work implicates inflammatory processes and vascular changes, including aspects of blood-brain barrier dysfunction, at the level of the endothelium in the pathogenesis and progression of AD. This emerging literature points to “vascular intrinsic factors” that may be part of AD pathogenesis; these changes could be amplified by exposure to vascular risk factors, but vascular risk factors are not necessary for there to be a vascular component to AD pathogenesis.
A potential role of intrinsic vascular factors would induce correlations among factors implicated in AD pathogenesis and progression (and minimize correlations with risk factors). Demonstrating a relationship among biomarkers in AD, as in the paper by Shirzadi and colleagues, shows a codependency among pathophysiological factors related to AD and even highlights that WMH are a core feature of AD, but falls short of proving causality.
Shirzadi and colleagues caution us not to overinterpret increases of WMH as evidence of mixed vascular and AD pathology, but the autopsy literature would suggest that the vast majority of AD cases in fact comprise mixed pathology (Kapasi et al., 2017), suggesting we should amplify our consideration of multiple pathologies in AD. We need more specific biomarkers to detect the different vascular factors that may be playing a role in AD and increases in efforts to understand how vascular factors contribute to AD.
The paper by Shirzadi and colleagues is a wonderful contribution to the literature, which I hope inspires continued conversation around these critical questions.
References:
Lee S, Viqar F, Zimmerman ME, Narkhede A, Tosto G, Benzinger TL, Marcus DS, Fagan AM, Goate A, Fox NC, Cairns NJ, Holtzman DM, Buckles V, Ghetti B, McDade E, Martins RN, Saykin AJ, Masters CL, Ringman JM, Ryan NS, Förster S, Laske C, Schofield PR, Sperling RA, Salloway S, Correia S, Jack C Jr, Weiner M, Bateman RJ, Morris JC, Mayeux R, Brickman AM, Dominantly Inherited Alzheimer Network. White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network. Ann Neurol. 2016 Jun;79(6):929-39. Epub 2016 Apr 27 PubMed.
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Lao PJ, Gutierrez J, Keator D, Rizvi B, Banerjee A, Igwe KC, Laing KK, Sathishkumar M, Moni F, Andrews H, Krinsky-McHale S, Head E, Lee JH, Lai F, Yassa MA, Rosas HD, Silverman W, Lott IT, Schupf N, Brickman AM. Alzheimer-Related Cerebrovascular Disease in Down Syndrome. Ann Neurol. 2020 Dec;88(6):1165-1177. Epub 2020 Oct 9 PubMed.
Moni F, Petersen ME, Zhang F, Lao PJ, Zimmerman ME, Gu Y, Gutierrez J, Rizvi B, Laing KK, Igwe KC, Sathishkumar M, Keator D, Andrews H, Krinsky-McHale S, Head E, Lee JH, Lai F, Yassa MA, Rosas HD, Silverman W, Lott IT, Schupf N, O'Bryant S, Brickman AM. Probing the proteome to explore potential correlates of increased Alzheimer's-related cerebrovascular disease in adults with Down syndrome. Alzheimers Dement. 2022 Feb 24; PubMed.
Kapasi A, DeCarli C, Schneider JA. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. 2017 Aug;134(2):171-186. Epub 2017 May 9 PubMed.
View all comments by Adam BrickmanRush Alzheimer's Disease Center
This very important study emphasizes the danger of equating WMH with systemic vascular risk in older persons. It also highlights cerebral amyloid angiopathy as an important factor in the evolution of WMH, and that WMHs may appear before the evolution of imaging evidence of CMBs.
It is also important to note caveats, as reported by the authors.
First, the cohorts do not reflect a generalized population of vascular risk, especially diabetes. Of note, the DIAN cohort is young and with low vascular risk. This is noted as a limitation by the authors, who also did sensitivity analyses investigating the higher-tiered group for vascular risk.
Second, the FRS is a scale derived to determine vascular risk in middle-aged persons but, in a study of FRS and brain vascular pathology in a community cohort, there was a relatively low correlation of FRS and actual brain vascular pathologies, and the FRS had a low discrimination on an individual level. (Oveisgharan et al., 2021).
Use of a new vascular risk score in an older age groups will be important.
Finally, these findings also emphasize that CAA, a common but variable feature of AD, is often included in the “vascular disease” category; however, risk factors for CAA are linked to AD, rather than traditional systemic vascular risk factors. Nonetheless, CAA is related to downstream “vascular” disease effects like WMH, microinfarcts and microbleeds.”
References:
Oveisgharan S, Yu L, Capuano A, Arvanitakis Z, Barnes LL, Schneider JA, Bennett DA, Buchman AS. Late-Life Vascular Risk Score in Association With Postmortem Cerebrovascular Disease Brain Pathologies. Stroke. 2021 Jun;52(6):2060-2067. Epub 2021 Apr 12 PubMed.
View all comments by Julie SchneiderClinic of Cardiovascular Diseases named after Most Holy John Tobolsky
When considering the causes of AD development, it should be taken into account that this disease occurs not only due to impaired metabolism of Aβ and tau protein in the cerebral tissue and vascular wall, but also because of specific disorders of cerebral blood supply.
In our earlier studies, we identified vascular and microvascular changes that appear in the brain in AD, which were named dyscirculatory angiopathy of Alzheimer's type (DAAT). Regardless of the nature of AD, DAAT affects the microcirculatory arterial as well as venous bed and is classified as cerebral small vessel disease (CSVD). The lesion occurs at an early age and is congenital and hereditary in nature.
DAAT develops only in patients with AD, not in other neurodegenerative and ischemic cerebral lesions. It is not associated with the atherosclerotic process. The lesion is manifested by increased tortuosity of the distal intracerebral arterial branches, the specific reduction of the capillary bed in the temporal and frontoparietal region, the development of arteriovenous shunts, early discharge of arterial blood through these shunts into the venous bed, the development of abnormal large venous trunks, and subsequent stagnation of venous blood. Our data are confirmed by the studies of others.
As a result, the cerebral blood supply is completely rebuilt, which leads to damage to tissue structures. In the brain, the neurovascular unit (NVU) is damaged. In cells, mitochondria die, and neurons degenerate and die. This is accompanied by impaired metabolism of Aβ, which leads to a decrease in its excretion and an increase in its accumulation. In its turn, the deposition of Aβ in cerebral tissue and vascular wall reduces the elasticity of microvessels, causing an even greater narrowing of their lumen, which, secondarily, further reduces cerebral blood flow. A decrease in blood flow contributes to an even greater deposition of Aβ, which jointly contributes to the development of progressive neurovascular dysfunction, neurodegeneration, cerebral atrophy, dementia and the development of AD.
DAAT, in combination with progressive deposition of amyloid beta, defines white-matter hyperintensities (WMHs).
References:
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View all comments by Ivan MaksimovichBanner Sun Health Research Institute
Agree that it is no longer correct to assume that white matter rarefaction is equivalent to or completely accounted for by small vessel disease. Our comprehensive postmortem study suggests that neuofibrillary tangles are statistically a much greater predictor of white matter rarefaction.
References:
Beach TG, Sue LI, Scott S, Intorcia AJ, Walker JE, Arce RA, Glass MJ, Borja CI, Cline MP, Hemmingsen SJ, Qiji S, Stewart A, Martinez KN, Krupp A, McHattie R, Mariner M, Lorenzini I, Kuramoto A, Long KE, Tremblay C, Caselli RJ, Woodruff BK, Rapscak SZ, Belden CM, Goldfarb D, Choudhury P, Driver-Dunckley ED, Mehta SH, Sabbagh MN, Shill HA, Atri A, Adler CH, Serrano GE. Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy. J Neuropathol Exp Neurol. 2023 May 25;82(6):457-466. PubMed.
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