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Introduction: In amyloid-positive individuals, disease-related biomarker heterogeneity is understudied., Methods: We used Subtype and Stage Inference (SuStaIn) to identify data-driven subtypes among cerebrospinal fluid (CSF) amyloid beta (1-42)-positive individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNIGO/2 [n = 376]). Variables included: CSF phosphorylated tau (p-tau181), hippocampal and whole-brain volume, logical memory (LM), composite Trail Making Test score, and white matter hyperintensity (WMH) volumes. CSF amyloid-negative, apolipoprotein E ε4 non-carrier cognitively unimpaired controls (n = 86) were used to calculate z scores., Results: One subtype (n = 145) had early LM changes, with later p-tau and WMH changes. A second subtype (n = 88) had early WMH changes, were older, and more hypertensive. A third subtype (n = 100) had early p-tau changes, and reflected typical Alzheimer's disease. Some amyloid positive (n = 43) individuals were similar to the amyloid-negative group., Discussion: This work identified heterogeneity in individuals who are conventionally considered homogeneous, which is likely driven by co-pathologies including cerebrovascular disease., Highlights: Data-driven modeling identified marker heterogeneity in amyloid-positive individuals. Heterogeneity reflected Alzheimer's disease-like, vascular-like, and mixed pathology presentations. Some amyloid-positive individuals were more similar to amyloid-negative controls. Vascular pathology plays a key role in understanding heterogeneity in those on the amyloid pathway., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine., Methods: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity., Results: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication., Discussion: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies., Highlights: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β 1-42 (Aβ42)-positive status., Methods: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume., Results: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001)., Discussion: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter., Highlights: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aβ42 status in 11 memory clinic cohorts. Aβ42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies., Methods: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (N main  = 2632; N APOE-interaction  = 1810)., Results: Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (β = -3.89 mL [-5.81, -1.97], P adjusted  < 0.05); these were largely attenuated in fully adjusted models (β = -1.59 mL [-3.55, 0.36], P = 0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed., Discussion: We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study., Methods: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses., Results: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains., Discussion: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment., Highlights: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) "typical", (2) "limbic-predominant", (3) "hippocampal-sparing", and (4) "mild atrophy". We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes., Methods: The four subtypes were replicated using a clustering method on MRI data in 260 amyloid-β-positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [ 18 F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline., Results: Voxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline., Discussion: Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD., (© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: To date, the clinical relevance of comorbid amyloid-β (Aβ) pathology in patients with vascular cognitive disorders (VCD) is largely unknown., Methods: We included 218 VCD patients with available cerebrospinal fluid Aβ 42 levels. Patients were divided into Aβ+ mild-VCD (n = 84), Aβ- mild-VCD (n = 68), Aβ+ major-VCD (n = 31), and Aβ- major-VCD (n = 35). We measured depression with the Geriatric Depression Scale, cognition with a neuropsychological test battery and derived white matter hyperintensities (WMH) and gray matter atrophy from MRI., Results: Aβ- patients showed more depressive symptoms than Aβ+. In the major-VCD group, Aβ- patients performed worse on attention (P = .02) and executive functioning (P = .008) than Aβ+. We found no cognitive differences in patients with mild VCD. In the mild-VCD group, Aβ- patients had more WMH than Aβ+ patients, whereas conversely, in the major-VCD group, Aβ+ patients had more WMH. Atrophy patterns did not differ between Aβ+ and Aβ- VCD group., Discussion: Comorbid Aβ pathology affects the manifestation of VCD, but effects differ by severity of VCD., (© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)