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Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer’s disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer’s disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246–367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51–60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer’s disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61–71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%; P = 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer’s disease risk and the potential value of mean diffusivity and/or multimodal brain signatures., Among cognitively normal adults in their 50 s, an Alzheimer’s brain signature based on grey matter mean diffusivity—but not cortical thickness—significantly improved prediction of progression to mild cognitive impairment 12 years later. Grey matter mean diffusivity signatures may be sensitive to Alzheimer-related changes as early as middle age., Graphical Abstract Graphical Abstract

Exposure to harmful substances and chemicals such as tobacco smoke, chemicals (e.g., herbicides, pesticides, Agent Orange) and metal dust has been associated with increased risk of developing cancer, cardiovascular disease, and other diseases that contribute to shorter life expectancy. Associations with brain health in relation to these exposures are less well studied. We examined the relationship between brain health and prolonged exposure to different harmful substances in 498 male participants average age 68 (range 61 to 73) from the Vietnam Era Twin Study of Aging (VETSA). For self-reported tobacco smoke, herbicides/pesticides, and metal dust we created three groups reflecting recency of exposure (current/former/never). For Agent Orange we examined two exposure groups (ever/never). Brain health, defined as predicted brain age (PBAD), was evaluated by applying Brain-Age Regression Analysis and Computation Utility software (BARACUS) to magnetic resonance images collected at age 68. Tobacco smoking (r=-0.15, p=0.0004 ) was significantly correlated with PBAD and remained significant (F=5.56, p=0.005) in multivariate analyses adjusted for age, socioeconomic status (SES), age 20 general cognitive ability, and non-independence of twins within pairs. Never smokers had significantly younger brains than current or former smokers. PBAD did not differ for current versus former smokers. In other analyses, more advanced PBAD was associated with non-amnestic MCI. In this sample, tobacco smoking had the strongest relationship with overall brain health in late midlife compared with other types of environmental exposures, reinforcing its role in pathological aging and its importance as a public health priority.

Pathological changes in Alzheimer’s disease (AD) begin decades before dementia onset. Because locus coeruleus tau pathology is the earliest occurring AD pathology, targeting indicators of locus coeruleus (dys)function may improve midlife screening for earlier identification of AD risk. Pupillary responses during cognitive tasks are driven by the locus coeruleus and index cognitive effort. Several findings suggest task-associated pupillary response as an early marker of AD risk. Requiring greater effort suggests being closer to one’s compensatory capacity, and adults with mild cognitive impairment (MCI) have greater pupil dilation during digit span tasks than cognitively normal individuals, despite equivalent task performance. Higher AD polygenic risk scores (AD-PRSs) are associated with increased odds of MCI and tau positivity. We hypothesized that AD-PRSs would be associated with pupillary responses in cognitively normal middle-aged adults. We demonstrated that pupillary responses during digit span tasks were heritable (h2=.30-.36) in 1119 men ages 56-66. We then examined associations between AD-PRSs and pupillary responses in a cognitively normal subset who all had comparable span capacities (n=539). Higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit recall) cognitive load condition; Cohen’s d=.36 for the upper versus lower quartile of the AD-PRS distribution. Results held up after controlling for APOE genotype. The results support pupillary response—and by inference, locus coeruleus dysfunction—as a genetically-mediated biomarker of early MCI/AD risk. In some studies, cognition predicted disease progression earlier than biomarkers. Pupillary responses might improve screening and early identification of genetically at-risk individuals even before cognitive performance declines.