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Shirzadi, Zahra; Schultz, Stephanie A.; Yau, Wai-Ying W.; Joseph-Mathurin, Nelly; Fitzpatrick, Colleen D.; Levin, Raina; Kantarci, Kejal; Preboske, Gregory M.; Jack, Clifford R.; Farlow, Martin R.; Hassenstab, Jason; Jucker, Mathias; Morris, John C.; Xiong, Chengjie; Karch, Celeste M.; Levey, Allan I.; Gordon, Brian A.; Schofield, Peter R.; Salloway, Stephen P.; Perrin, Richard J.; Mcdade, Eric; Levin, Johannes; Cruchaga, Carlos; Allegri, Ricardo F.; Fox, Nick C.; Goate, Alison; Day, Gregory S.; Koeppe, Robert; Chui, Helena C.; Berman, Sarah; Mori, Hiroshi; Sanchez-Valle, Raquel; Lee, Jae-Hong; Rosa-Neto, Pedro; Ruthirakuhan, Myuri; Wu, Che-Yuan; Swardfager, Walter; Benzinger, Tammie L. S.; Sohrabi, Hamid R.; Martins, Ralph N.; Bateman, Randall J.; Johnson, Keith A.; Sperling, Reisa A.; Greenberg, Steven M.; Schultz, Aaron P. and Chhatwal, Jasmeer P. (2023): Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease. In: JAMA Neurology, Vol. 80, No. 12: pp. 1353-1363

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Importance Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN;February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI;July 2007 to September 2021), and the Harvard Aging Brain Study (HABS;September 2010 to December 2019). Main Outcome and Measures The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years;137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years;274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years;194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001];ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = -3.1 [P = .002];ADNI: t = -5.6 [P < .001];HABS: t = -2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001];ADNI: t = 9.1 [P < .001];HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40];ADNI: t = 0.6 [P = .50];HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63;95% CI, 1.72-4.03;P < .001). Conclusions and Relevance The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

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