Albert, Marilyn

Abstract INTRODUCTION New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. METHODS Harmonized amyloid PET data from 4216 participants were used in genome‐wide survival, tissue‐specific gene expression, and genetic covariance analyses of EAOA. RESULTS Variants in apolipoprotein E ( APOE ), ABCA7 , and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7 , associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7 , which was associated with increased amyloid pathology at autopsy. Multiple immune‐related diseases shared genetic covariance with EAOA. DISCUSSION APOE , ABCA7 , and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue‐specific expression analyses, offering insights into intervenable targets at early stages of AD. Highlights Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E ( APOE ) , ABCA7 , and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue‐specific expression analyses.

AbstractBackgroundCerebral small vessel disease (SVD) related vascular contributions represent a major factor contributing to cognitive decline and dementia (VCID) in older adults. However, there has not been a validated biomarker for the diagnosis and treatment monitoring of this condition. Recently, the US National Institute on Neurological Disorders and Stroke (NINDS) funded the MarkVCID Consortium to identify and validate clinical‐trial‐ready biomarkers for VCID. Cerebrovascular reactivity (CVR) MRI is one of the selected biomarkers that underwent multi‐site testing in the Consortium. The present study aimed to report the relationship between CVR and cognitive function at independent sites, based on a pre‐specified hypothesis.MethodCVR, the ability of cerebral small vessels to dilate upon stimulus, is thought to directly reflect physiological function of the brain microvasculature. Based on previous single‐site findings, the pre‐defined hypothesis was that CVR will be associated with the global cognitive function measured by Montreal Cognitive Assessment (MoCA) after adjusting for age, sex, and education, and this association will be observed in data collected and analyzed at each individual site.A total of 264 older participants from three sites were included (Table 1). Each site performed an identical CVR MRI procedure using 5% CO2 inhalation, and a standardized clinical and cognitive evaluation. Multi‐linear regression analysis was conducted on a site‐by‐site basis to examine the pre‐defined hypothesis.ResultGray‐matter CVR showed a positive association with MoCA score after adjustment for age, sex, and education, in which participants with higher CVR had higher MoCA scores. This relationship was reproduced at each site (Figure 1, p<0.05 for each), confirming our pre‐specified hypothesis.In the secondary analysis of all data together, higher gray‐matter CVR was found to be significantly associated with better executive function measure of item response theory (IRT) score (β=2.87, p=0.003).ConclusionThe present study evaluated the relationship between CVR and cognition in a multi‐center setting. CVR was found to be positively associated with global cognitive function measured by the MoCA, which was shown to be reproducible across different sites with diverse cohorts. These findings support the utility of CVR as a biomarker in future clinical trials of SVD and VCID.

Abstract INTRODUCTION Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi‐site study, using a predefined hypothesis. METHODS We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. Highlights This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

AbstractINTRODUCTIONThe contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated.METHODSWe analyzed neuropsychological testing results in dementia‐free participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined associations of index domain–specific neuropsychological test performance with incident dementia using cumulative incidence curves and Cox proportional hazards models.RESULTSAmong 5296 initially dementia‐free participants (mean [standard deviation] age of 75.8 [5.1] years; 60.1% women, 22.2% Black) over a median follow‐up of 7.9 years, the covariate‐adjusted hazard ratio varied substantially depending on the pattern of domain‐specific performance and age, in an orderly manner from single domain language abnormalities (lowest risk) to single domain executive or memory abnormalities, to multidomain abnormalities including memory (highest risk).DISCUSSIONBy identifying normatively defined cognitive abnormalities by domains based on neuropsychological test performance, there is a conceptually orderly and age‐sensitive spectrum of risk for incident dementia that provides valuable information about the likelihood of progression.Highlights Domain‐specific cognitive profiles carry enhanced prognostic value compared to mild cognitive impairment. Single‐domain non‐amnestic cognitive abnormalities have the most favorable prognosis. Multidomain amnestic abnormalities have the greatest risk for incident dementia. Patterns of domain‐specific risks are similar by sex and race.

Purpose: Population-based evidence in the interrelationships among hearing, brain structure, and cognition is limited. This study aims to investigate the cross-sectional associations of peripheral hearing, brain imaging measures, and cognitive function with speech-in-noise performance among older adults. Method: We studied 602 participants in the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) brain magnetic resonance imaging (MRI) ancillary study, including 427 ACHIEVE baseline (2018–2020) participants with hearing loss and 175 Atherosclerosis Risk in Communities Neurocognitive Study Visit 6/7 (2016–2017/2018–2019) participants with normal hearing. Speech-in-noise performance, as outcome of interest, was assessed by the Quick Speech-in-Noise (QuickSIN) test (range: 0–30; higher = better). Predictors of interest included (a) peripheral hearing assessed by pure-tone audiometry; (b) brain imaging measures: structural MRI measures, white matter hyperintensities, and diffusion tensor imaging measures; and (c) cognitive performance assessed by a battery of 10 cognitive tests. All predictors were standardized to z scores. We estimated the differences in QuickSIN associated with every standard deviation ( SD ) worse in each predictor (peripheral hearing, brain imaging, and cognition) using multivariable-adjusted linear regression, adjusting for demographic variables, lifestyle, and disease factors (Model 1), and, additionally, for other predictors to assess independent associations (Model 2). Results: Participants were aged 70–84 years, 56% female, and 17% Black. Every SD worse in better-ear 4-frequency pure-tone average was associated with worse QuickSIN (−4.89, 95% confidence interval, CI [−5.57, −4.21]) when participants had peripheral hearing loss, independent of other predictors. Smaller temporal lobe volume was associated with worse QuickSIN, but the association was not independent of other predictors (−0.30, 95% CI [−0.86, 0.26]). Every SD worse in global cognitive performance was independently associated with worse QuickSIN (−0.90, 95% CI [−1.30, −0.50]). Conclusions: Peripheral hearing and cognitive performance are independently associated with speech-in-noise performance among dementia-free older adults. The ongoing ACHIEVE trial will elucidate the effect of a hearing intervention that includes amplification and auditory rehabilitation on speech-in-noise understanding in older adults. Supplemental Material: https://doi.org/10.23641/asha.25733679

AbstractThe temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-β42 (Aβ42), Aβ40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-β with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5–6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18–45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45–50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50–55 years and an accelerated decrease for hippocampal volume at the baseline age of 55–60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65–70 years. Another acceleration in the rate of change occurred at the baseline age of 65–70 years for Aβ42/Aβ40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18–45 years at baseline, significant increases in Aβ42 and Aβ42/Aβ40 ratio and decreases in PiB SUVR occurred in APOE ɛ4 non-carriers but not carriers. After age 45 years, APOE ɛ4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE ɛ4. These findings may better inform the design of prevention trials on Alzheimer disease.

AbstractBackgroundPrior evidence has suggested associations between hearing loss and smaller brain volumes particularly in the temporal lobe where the primary auditory cortex is located, probably due to changes in cortical organization associated with reduced auditory stimulation. Evidence regarding associations of central auditory processing with brain volumes is relatively limited. The study aims to investigate cross‐sectional associations of central auditory processing with brain volumes in older adults.MethodWe studied 587 cognitively normal (Mini‐Mental State Exam ≥23 if high school degree or less and ≥25 if above high school degree) older adults (mean age: 77±4 years, 56% female, 17% black), including 426 with hearing loss from the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) baseline (2018‐19), which is an ancillary randomized controlled trial of the Atherosclerosis Risk in Communities (ARIC) Study and 161 with normal hearing, comparable age and cognitive status from the ARIC Visit 6/7 (2016‐17/2018‐19). Brain volumes were measured by magnetic resonance imaging (MRI) scans and were transformed to z‐scores. Central auditory processing was measured by the Quick Speech‐in‐Noise (QuickSIN) test. Total scores range from 0 to 30 with lower scores indicating worse speech‐in‐noise performance. Multivariable‐adjusted linear regression was used to estimate cross‐sectional differences in standardized brain volumes associated with differences in QuickSIN score. Models adjusted for age, sex, race, education, cohort, body mass index, smoking, hypertension, diabetes, stroke, intracranial volume, and pure‐tone average.ResultEvery 5‐point decrease in QuickSIN score (worse performance) was associated with smaller volumes of the temporal lobe (‐0.07SD, 95% CI: ‐0.13, ‐0.01). QuickSIN score was also associated with subregions of the temporal lobe related to auditory processing, memory and emotion, including amygdala (‐0.13SD, 95% CI: ‐0.21, ‐0.04), middle (‐0.08SD, 95% CI: ‐0.15, ‐0.00) and superior temporal gyri (‐0.08SD, 95% CI: ‐0.15, ‐0.01).ConclusionPoorer central auditory processing was associated with smaller temporal lobe volumes, including but not limited to subregions important for auditory processing. The ongoing collection of ACHIEVE data with longitudinal MRI data will facilitate understanding of association between hearing loss and brain atrophy as well as the potential promising effects of hearing treatment in mitigating brain aging.

AbstractIntroductionMotoric cognitive risk (MCR), a clinical syndrome characterized by slow gait speed and subjective cognitive complaints, has been associated with dementia risk. The neuropathological features underlying MCR remain poorly understood.MethodsThe Atherosclerosis Risk in Communities (ARIC) community‐based cohort study classified participants using standardized criteria as MCR+/– and mild cognitive impairment (MCI)+/– at study baseline (2011–2013). We examined the 5‐year dementia risk and baseline brain structural/molecular abnormalities associated with MCR+ and MCI+ status.ResultsOf 5023 nondemented participants included, 204 were MCR+ and 1030 were MCI+. Both MCR+ and MCI+ participants demonstrated increased dementia risk. The pattern of structural brain abnormalities associated with MCR+ differed from that of MCI+. Whereas MCI+ was associated with comparatively smaller volumes in brain regions vulnerable to Alzheimer's disease pathology, MCR+ status was associated with smaller volumes in frontoparietal regions and greater white matter abnormalities.DiscussionMCR may represent a predementia syndrome characterized by prominent white matter abnormalities and frontoparietal atrophy.