Previous research established that white matter hyperintensities (WMH), a biomarker of small vessel cerebrovascular disease, are strong predictors of cognitive function in older adults and associated with clinical presentation of Alzheimer’s disease (AD), particularly when distributed in posterior brain regions. Secondary prevention clinical trials, such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, target amyloid accumulation in asymptomatic amyloid positive individuals, but it is unclear the extent to which small vessel cerebrovascular disease accounts for performance on the primary cognitive outcomes in these trials. The purpose of this study was to examine the relationship between regional WMH volume and performance on the Preclinical Alzheimer Cognitive Composite (PACC) among participants screened for participation in the A4 trial. We also determined whether the association between WMH and cognition is moderated by amyloid positivity status.

We assessed demographic, amyloid PET status, cognitive screening, and raw MRI data for participants in the A4 trial and quantitated regional (by cerebral lobe) WMH volumes from T2-weighted FLAIR in amyloid positive and amyloid negative participants at screening. Cognition was assessed using PACC scores, a z-score sum of four cognitive tests: The Mini-Mental State Examination (MMSE), the Free and Cued Selective Reminding Test, Logical Memory Test, and Digit Symbol Substitution Test. We included 1329 amyloid positive and 329 amyloid negative individuals (981 women; mean age=71.79 years; mean education=16.58 years) at the time of the analysis. The sample included Latinx (n=50; 3%), non-Latinx (n=1590; 95.9%), or unspecified ethnicity (n=18; 1.1%) individuals who identified as American Indian/Alaskan Native (n=7; 0.4%), Asian (n=38; 2.3%), Black/African American (n=41; 2.5%), White (n=1551 ; 93.5%), or unspecified (n=21; 1.3%) race. We first examined the associations of total and regional WMH volume and amyloid positivity on PACC scores (the primary cognitive outcome measure for A4) using separate general linear models and then determined whether amyloid positivity status and regional WMH statistically interacted for those WMH regions that showed significant main effects.

Both increased WMH, in the frontal and parietal lobes particularly, and amyloid positivity were independently associated with poorer performance on the PACC, with similar magnitude. In subsequent models, WMH volume did not interact with amyloid positivity status on PACC scores.

Regionally distributed WMH are independently associated with cognitive functioning in typical participants enrolled in a secondary prevention clinical trial for AD. These effects are of similar magnitude to the effects of amyloid positivity on cognition, highlighting the extent to which small vessel cerebrovascular disease potentially drives AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered explicitly when evaluating outcomes in trials, both as potential effect modifiers and as possible targets for intervention or prevention. The findings from this study cannot be generalized widely, as the participants are not representative of the overall population.

Neuropsychiatric symptoms concerning mood are common in Alzheimer's disease (AD), but it is unclear if they are etiologically related to AD pathophysiology or due to factors considered to be non-pathogenic, such as small vessel cerebrovascular disease. New generation clinical trials for AD often enroll participants with evidence of AD pathophysiology, indexed by amyloid PET scanning, but who are cognitively asymptomatic. We used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to examine the extent to which depressive symptoms are associated with amyloid pathophysiology and small vessel cerebrovascular disease, in the form of white matter hyperintensities (WMH).

The A4 study randomizes cognitively healthy older adults with evidence of amyloid pathophysiology on PET scanning. We used screening data, which included amyloid status (positive, negative) by visual read, amyloid PET standard uptake value ratio (SUVR) in cortical regions, and MRI data acquired in a subset (n=1,197, mean age 71.6 +/- 4.8 years, 57% women) to quantitate total WMH volume. Depressive symptoms were evaluated with the 15-item Geriatric Depression Scale, which we used both as a continuous variable and to define 'depressed' and 'non-depressed' groups, based on a cut score of > 5. We examined whether 1) depressive symptoms and proportion of depressed individuals differed between amyloid positive and negative groups, 2) there is a relationship between amyloid SUVR and depressive symptoms that differs as a function of amyloid positivity status, and 3) there is a relationship between WMH volume and depressive symptoms that differs as a function of amyloid positivity status.

Although depressive symptom severity did not differ between groups (t=0.14, p=0.88), a greater proportion of individuals were classified as depressed in the amyloid negative group than the amyloid positive group (3.5% vs. 1.9%, X2=4.60, p=0.032). Increased amyloid SUVR was associated with increased GDS scores among amyloid positive individuals (r=0.117, p=0.002) but not among amyloid negative individuals (r=0.006, p=0.68, Positivity Status x SUVR interaction on GDS: ß=0.817, p=0.029). Increased WMH was associated with higher GDS scores (ß=0.105, p=0.017) but not differentially in amyloid positive and negative participants (Positivity Status x WMH interaction on GDS: ß=-0.010, p=0.243).

These analyses have several implications. First, individuals who are screened to participate in a clinical trial but do not have evidence of amyloidosis may be misattributing concerns about underlying AD pathophysiology to depressive symptoms. Second, the severity of AD pathophysiology, indexed by amyloid PET SUVR, may drive a small increase in depressive symptomatology among individuals over visual diagnostic thresholds. Third, small vessel cerebrovascular changes are additionally associated with depressive symptoms but in a manner that is independent of AD pathophysiology. Overall, depressive symptoms and depression are likely multiply determined among prospective clinical trial participants for preclinical AD.

Alzheimer’s disease (AD) pathophysiology, including β-amyloid (Aβ), can be appreciated with molecular PET imaging. Among older adults, the distribution of Aβ standard uptake value ratios (SUVR) is typically bimodal and a diagnostic cut is applied to define those who are amyloid ‘positive’ and ‘negative’. However, it is unclear whether the dynamic range of SUVRs in amyloid positive and negative individuals is meaningful and associated with cognition. Previous work by Insel and colleagues (2020) used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) trial to demonstrate subtle associations between a cortical summary SUVR and cognition, particularly on the Free and Cued Selective Reminding Test (FCSRT). We followed up this study to determine the extent to which regional SUVR is associated with performance on the FCSRT in amyloid positive and negative participants screened for participation in the A4 study.

We accessed regional Aβ SUVR, including anterior cingulate, posterior cingulate, parietal, precuneus, temporal, and medial/orbital frontal regions, along with FCSRT15 and demographic data from 4492 A4 participants at screening. Participants were coded as amyloid positive (n=1329; 30%) or amyloid negative (n=3169; 70%) based on a summary SUVR of greater than or equal to 1.15. We used separate general linear models to examine the association of total or regional SUVR, amyloid positivity status, and the interaction of SUVR and amyloid status with FCSRT scores. We compared model fits across regions with the Akaike Information Criterion (AIC). We ran post hoc correlational analyses examining the relationship between SUVR and FCSRT scores stratified by amyloid status in the case of significant interactions. Results were similar with and without demographic adjustment.

There was a significant interaction of summary and all regional SUVR with FCSRT scores in addition to main effects of amyloid positivity. In all models, there were small negative associations between SUVR and memory in amyloid positive individuals. For amyloid negative individuals, there was a significant and very small negative association between SUVR and FCSRT scores only in the parietal lobes and precuneus regions. Model fits were generally similar across the different analyses.

In this sample of individuals screened for a secondary prevention trial of AD, there were consistent associations between Aβ SUVR in all regions and memory for those considered amyloid positive. However, for individuals considered amyloid negative, there were only very small associations between SUVR and memory in parietal and precuneus regions. We conclude that the dynamic range of amyloid may be relevant among those with diagnostic evidence of amyloidosis, but that subtle Aβ accumulation in posterior regions may relate to declining memory in “subthreshold” states.

Non-Hispanic Black older adults experience a disproportionate burden of Alzheimer’s Disease and related dementias (ADRD) risk compared to non-Hispanic White older adults. It is necessary to identify mechanisms that may be contributing to inequities in cognitive aging. Psychosocial stressors that disproportionately affect Black adults (e.g., discrimination) have the potential to impact brain health through stress pathways. The brain’s white matter, which appears to be particularly important for ADRD risk among Black older adults, may be uniquely vulnerable to stress-related physiological dysfunction. To further understand whether and how discrimination can affect ADRD risk, this study aimed to examine associations between multiple forms of racial discrimination and white matter integrity, operationalized through diffusion tensor imaging.

Cross-sectional data were obtained from 190 non-Hispanic Black residents aged 65+ without dementia in northern Manhattan. Racial discrimination was self-reported using the Everyday Discrimination and Major Experiences of Lifetime Discrimination scales. Example items from the Everyday Discrimination Scale include: “You are treated with less respect than other people”; “You are called names or insulted.” Example items from the Major Experiences of Lifetime Discrimination Scale include: “At any time in your life, have you ever been unfairly fired from a job?”; “Have you ever been unfairly denied a bank loan?” Racial discrimination was operationalized as experiences attributed to “race” or “skin color.” White matter integrity was assessed using fractional anisotropy (FA) via diffusion tensor imaging. Multivariable regression models evaluated the unique effects of everyday and major experiences of lifetime racial discrimination on mean FA in the whole brain and specific regions. Initial models controlled for age, sex/gender, intracranial volume, and white matter hyperintensities. Subsequent models additionally controlled for socioeconomic and health factors to consider potential confounders or mediators of the relationship between discrimination and white matter integrity.

Major experiences of lifetime discrimination were negatively associated with mean FA within the left cingulum cingulate gyrus and the right inferior fronto-occipital fasciculus. These associations persisted when controlling for additional covariates (i.e., education, depression, and cardiovascular diseases). In contrast, major experiences of lifetime discrimination were positively associated with mean FA within the right superior longitudinal fasciculus (temporal part). This association was attenuated when controlling for additional covariates. Everyday racial discrimination was not associated with mean FA in any regions.

These results extend prior work linking racial discrimination to brain health and provide evidence for both risk and resilience among Black older adults. Major experiences of lifetime racial discrimination, a proxy for institutional racism, may have a stronger effect on white matter integrity than everyday racial discrimination, a proxy for interpersonal racism. Educational opportunities and cardiovascular risk factors may represent mediators between racial discrimination and white matter integrity. White matter integrity within specific brain regions may be a mechanism through which racially patterned social stressors contribute to racial disparities in ADRD. Future research should characterize within-group heterogeneity in order to identify factors that promote resilience among Black older adults.

To compare longitudinal verbal fluency performance among Latinx Spanish speakers who develop Alzheimer’s disease to those who do not develop dementia in absolute number of words produced on each task and their ratio to combine both scores.

Participants included 833 Latinx Spanish-speaking older adults from a community-based prospective cohort in Manhattan. We performed growth curve modeling to investigate the trajectories of letter and semantic fluency, and their ratio (i.e., ‘semantic index’), between individuals who developed Alzheimer’s disease and those who did not (i.e., controls). The semantic index quantifies the proportion of words generated for semantic fluency in relation to the total verbal fluency performance.

Letter fluency performance did not decline in controls; we observed a linear decline in those who developed Alzheimer’s disease. Semantic fluency declined in both groups and showed an increased rate of change over time in the incident Alzheimer’s disease group; in comparison, the control group had a linear and slower decline. There were no group differences in the longitudinal trajectory (intercept and slope) of the semantic index.

A decline in letter fluency and a more rapid and accelerating decline over time in semantic fluency distinguished people who developed Alzheimer’s disease from controls. Using the semantic index was not a superior marker of incident Alzheimer’s disease compared to examining the two fluency scores individually. Results suggest the differential decline in verbal fluency tasks, when evaluated appropriately, may be useful for early identification of Alzheimer’s disease in Latinx Spanish speakers, a historically understudied population.