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White matter hyperintensities (WMH) are areas of increased lucency visualized on T2‐weighted magnetic resonance imaging (MRI), including fluid attenuated inversion recovery (FLAIR) sequences. Over the past 15 years we have been examining WMH in studies of cognitive aging among clinical, community‐based, and populations at genetic risk to understand the role of vascular brain injury in Alzheimer’s disease (AD) onset, symptom progression, and pathogenesis. Our findings suggest that regional WMH, particularly when distributed in posterior areas, increase risk for clinical AD and contribute to the clinical course of the disease, even among genetic population with relatively low rates of vascular risk factor, like adults with Down syndrome and with autosomal dominant genetic mutations for AD. While these observations suggest a role of endogenous cerebrovascular disease as a driver or core feature of AD, there has been considerable discussion about the underlying pathophysiology of WMH. Some authors argue that WMH in the context of AD reflect white matter changes secondary to neurodegeneration (so‐called “Wallerian degeneration”). We have argued against this possibility based on four observations. First, experimental data from animal models of vascular brain injury suggest that hypoperfusion injury gives rise white matter injury and downstream tau pathology and neurodegeneration. Second, the anatomical distribution of WMH in AD more closely aligns with the brain’s perfusion patterns and the vulnerability of whatershed regions to changes in blood supply and small vessel injury than with proximity to cortical neuronal injury. Third, the temporal evolution of WMH in the context of AD suggests a contribution of WMH that precedes expected neurodegenerative changes. Finally, we do not view an observed relationship between WMH and risk factors, such as hypertension, as a requirement to establish a cerebrovascular basis of WMH; rather, in total, findings suggest an “endogenous” cerebrovascular component, perhaps mediated by inflammatory changes, genetics, or blood brain barrier breakdown. Understanding the pathophysiological basis of WMH with respect to underlying vasculature may point to novel directions for disease prevention or intervention.

Alzheimer’s disease (AD) is conceptualized as a progressive consequence of two hallmark pathological changes in grey matter: extracellular amyloid plaques and neurofibrillary tangles. However, over the past several years, neuroimaging studies have implicated micro- and macrostructural abnormalities in white matter in the risk and progression of AD, suggesting that in addition to the neuronal pathology characteristic of the disease, white matter degeneration and demyelination may be also important pathophysiological features. Here we review the evidence for white matter abnormalities in AD with a focus on myelin and oligodendrocytes, the only source of myelination in the central nervous system, and discuss the relationship between white matter changes and the hallmarks of Alzheimer’s disease. We review several mechanisms such as ischemia, oxidative stress, excitotoxicity, iron overload, Aβ toxicity and tauopathy, which could affect oligodendrocytes. We conclude that white matter abnormalities, and in particular myelin and oligodendrocytes, could be mechanistically important in AD pathology and could be potential treatment targets.

As the older adult segment of the population increases, Alzheimer’s disease (AD) has emerged as a significant public health epidemic. Over the past 3 decades, advances in the understanding of the biology of AD have led to a somewhat unified hypothesis of disease pathogenesis that emphasizes the precipitating role of beta amyloid protein. However, several lines of evidence suggest that multiple pathologies are necessary for clinical manifestation of the disease. Our focus over the past several years has been on the contribution of small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on magnetic resonance imaging, to AD. White matter hyperintensity volume, particularly in parietal regions, is elevated among individuals with and at risk for AD, predicts future diagnosis of AD, predicts the rate of progression of cognitive symptoms among individuals with AD, and increases over time among individuals destined to develop AD. White matter hyperintensities may represent an independent source of impairment and/or may interact more fundamentally with “primary” AD pathology. Future work should focus on more inclusive models of that better define “normal” vs “pathological” aging.

AbstractObjectiveTo evaluate trials of drugs that target amyloid to determine whether reductions in amyloid levels are likely to improve cognition.DesignInstrumental variable meta-analysis.Setting14 randomized controlled trials of drugs for the prevention or treatment of Alzheimer’s disease that targeted an amyloid mechanism, identified from ClinicalTrials.gov.PopulationAdults enrolled in randomized controlled trials of amyloid targeting drugs. Inclusion criteria for trials vary, but typically include adults aged 50 years or older with a diagnosis of mild cognitive impairment or Alzheimer’s disease, and amyloid positivity at baseline.Main outcome measuresAnalyses included trials for which information could be obtained on both change in brain amyloid levels measured with amyloid positron emission tomography and change in at least one cognitive test score reported for each randomization arm.ResultsPooled results from the 14 randomized controlled trials were more precise than estimates from any single trial. The pooled estimate for the effect of reducing amyloid levels by 0.1 standardized uptake value ratio units was an improvement in the mini-mental state examination score of 0.03 (95% confidence interval −0.06 to 0.1) points. This study provides a web application that allows for the re-estimation of the results when new data become available and illustrates the magnitude of the new evidence that would be necessary to achieve a pooled estimate supporting the benefit of reducing amyloid levels.ConclusionsPooled evidence from available trials reporting both reduction in amyloid levels and change in cognition suggests that amyloid reduction strategies do not substantially improve cognition.

'Normal aging' in the brain refers to age-related changes that occur independent of disease, in particular Alzheimer's disease. A major barrier to mapping normal brain aging has been the difficulty in excluding the earliest preclinical stages of Alzheimer's disease. Here, before addressing this issue we first imaged a mouse model and learn that the best MRI measure of dendritic spine loss, a known pathophysiological driver of normal aging, is one that relies on the combined use of functional and structural MRI. In the primary study, we then deployed the combined functional-structural MRI measure to investigate over 100 cognitively-normal people from 20-72 years of age. Next, to cover the tail end of aging, in secondary analyses we investigated structural MRI acquired from cognitively-normal people, 60-84 years of age, who were Alzheimer's-free via biomarkers. Collectively, the results from the primary functional-structural study, and the secondary structural studies revealed that the dentate gyrus is a hippocampal region differentially affected by aging, and that the entorhinal cortex is a region most resistant to aging. Across the cortex, the primary functional-structural study revealed and that the inferior frontal gyrus is differentially affected by aging, however, the secondary structural studies implicated other frontal cortex regions. Together, the results clarify how normal aging may affect the brain and has possible mechanistic and therapeutic implications.

Growing epidemiological evidence suggests an adverse relationship between exposure to air pollutants and cognitive health, and this could be related to the effect of air pollution on vascular health. We aim to evaluate the association between air pollution exposure and a magnetic resonance imaging (MRI) marker of cerebral vascular burden, white matter hyperintensities (WMH). This cross-sectional analysis used data from the French Three-City Montpellier study. Randomly selected participants 65-80 years of age underwent an MRI examination to estimate their total and regional cerebral WMH volumes. Exposure to fine particulate matter ( ), nitrogen dioxide ( ), and black carbon (BC) at the participants' residential address during the 5 years before the MRI examination was estimated with land use regression models. Multinomial and binomial logistic regression assessed the associations between exposure to each of the three pollutants and categories of total and lobar WMH volumes. Participants' ( ) median age at MRI was 70.7 years [interquartile range (IQR): 6.1], and 52% ( ) were women. Median exposure to air pollution over the 5 years before MRI acquisition was 24.3 (IQR: 1.7) for , 48.9 (14.6) for , and 2.66 (0.60) for BC. We found no significant association between exposure to the three air pollutants and total WMH volume. We found that exposure was significantly associated with higher risk of temporal lobe WMH burden [odds ratio (OR) for an (95% confidence interval: 1.41, 2.36) for the second volume tercile, 2.04 (1.59, 2.61) for the third volume tercile, reference: first volume tercile]. Associations for other regional WMH volumes were inconsistent. In this population-based study in older adults, exposure was associated with increased risk of high WMH volume in the temporal lobe, strengthening the evidence on adverse effect on the brain. Further studies looking at different markers of cerebrovascular damage are still needed to document the potential vascular effects of air pollution. https://doi.org/10.1289/EHP12231.

Inflammation plays a major role in cognitive aging. Most studies on peripheral inflammation and cognitive aging focused on selected major inflammatory biomarkers. However, inflammatory markers are regulated and influenced by each other, and it is therefore important to consider a more comprehensive panel of markers to better capture diverse immune pathways and characterize the overall inflammatory profile of individuals. We explored 23 circulating inflammatory biomarkers using data from 1,743 participants without dementia (≥ 65 years-old) from the community-based, multiethnic Washington Heights Inwood Columbia Aging Project. Using principal component analysis (PCA), we developed six inflammatory profiles (PC-1 to PC-6) based on these 23 biomarkers and tested the association of resulting inflammatory profile with cognitive decline, over up to 12 years of follow-up. PC-1 described a pro-inflammatory profile characterized by high positive loadings for pro-inflammatory biomarkers. A higher PC-1 score was associated with lower baseline cognitive performances. No association of this profile with cognitive decline was observed in longitudinal analysis. However, PC-5 characterized by high PDGF-AA and RANTES was associated with a faster cognitive decline. Among older adults, a circulating pro-inflammatory immune profile is associated with lower baseline cognitive performance, and some specific pro-inflammatory cytokines might be associated with faster cognitive decline.

This study provides causal evidence demonstrating that consuming a high flavanol diet improves dentate gyrus function and dentate gyrus–dependent cognitive functions in aged humans. The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50–69-year-old subjects who consumed either a high or low cocoa flavanol–containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.

Cerebral embolization during transcatheter aortic valve implantation (TAVI) can lead to a spectrum of clinically relevant manifestations, ranging from overt stroke to mild neurologic or cognitive deficits and subclinical cerebral infarcts. This study sought to determine the frequency of neurologic injury, cerebral ischemic lesions, and cognitive dysfunction in subjects undergoing contemporary commercial TAVI in the United States. Neuro-TAVR is the first prospective, multicenter study to use serial systematic neurologic and cognitive assessments and diffusion-weighted magnetic resonance imaging (at 4 ± 2 days after procedure) to investigate the incidence and severity of neurologic injury after contemporary unprotected TAVI in the United States. A total of 44 consecutive patients underwent TAVI at 5 US sites. Diffusion-weighted magnetic resonance imaging lesions were detected in 94%, with a mean of 10.4 ± 15.3 lesions per subject and a median total lesion volume of 295 mm3 (interquartile range 71.6 to 799.6 mm3). New neurologic impairment (worsening in National Institutes of Health Stroke Scale score from baseline with new cerebral lesions) occurred in 22.6% (7 of 31) of subjects at discharge and 14.8% (4 of 27) at 30 days. In addition, cognitive decrements from baseline were identified by the Montreal Cognitive Assessment in 33% (12 of 36) of subjects at discharge and 41% (13 of 32) at 30 days. In conclusion, this contemporary cohort of US patients confirms that TAVI results in cerebral infarction in most patients and that 1 in 5 patients have measurable neurologic impairment and 1 in 3 patients have decrease in cognitive measures by Montreal Cognitive Assessment score after TAVI, reinforcing the need for methods to mitigate the risk of brain injury during TAVI.

Adults with Down syndrome have a genetic form of Alzheimer’s disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer’s Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25–72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.