Improving risk indexes for Alzheimer's disease and related dementias for use in midlife

Abstract

Knowledge of a person's risk for Alzheimer's disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (β's from 0.16 to 0.22), white matter hyperintensities volume (β's from 0.16 to 0.19), hippocampal volume (β's from -0.08 to -0.11), tested cognitive deficits (β's from -0.36 to -0.49), everyday cognitive problems (β's from 0.14 to 0.38), and longitudinal cognitive decline (β's from -0.18 to -0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Keywords: Alzheimer’s disease; dementia; modifiable risk factors; preventive medicine; risk index.

Graphical abstract

Figure 1

Schematic of the DunedinARB. The comprehensive DunedinARB is comprised of 48 risk indicators grouped into 10 conceptually distinct domains. Genetic risk includes family history of dementia and APOE ε4 allele status. Lifestyle risk includes physical activity, diet, tobacco smoking, alcohol consumption, folic acid supplementation, and regular prophylactic NSAID use. Socioeconomic risk includes occupational and educational attainment. Psycho-somatic Function risk includes chronic pain, history of migraine, history of depression, social isolation, sleep quality, neuroticism and conscientiousness. Physical and Sensory Function risk includes balance, gait, hearing acuity and subjective hearing function, objective and subjective vision function, and sense of smell. Cardio-Metabolic Status risk includes hypertension, obesity, and diabetes status, total cholesterol, triglycerides, and retinal vascular health. Inflammatory risk includes CRP, Interleukin 6, and soluble urokinase Plasminogen Activator Receptor levels and history of rheumatoid arthritis. Epigenetic Cellular Aging risk includes four separate DNA methylation ‘aging’ clocks (Horvath, Hannum, PhenoAge and GrimAge). Harmful Events and Exposures risk includes childhood lead exposure, occupational exposure to neurotoxicants and history of TBI. Subjective Overall Health risk includes self, informant and research-worker ratings of Study member overall health. Details on the individual risk factors and indicators are provided in Supplementary Table 1.

Figure 2

Overlap (correlation, Pearson’s r) among the 10 domains of risk comprising the DunedinARB. *P-values < 0.05, **P-values < 0.01, ***P-values < 0.001. Shading reflects association size for significant associations (P < 0.05), with darker colours highlighting larger associations. Risk domains are as follows: (i) genetic risk; (ii) lifestyle risk, (iii) socioeconomic risk; (iv) psycho-somatic function risk; (v) physical and sensory function risk; (vi) cardio-metabolic status risk; (vii) inflammatory risk; (viii) epigenetic cellular aging risk; (ix) harmful events and exposures risk; and (x) subjective overall health risk. Individual risk indicators contributing to each of the 10 risk domains are detailed in Supplementary Table 1; risk domains included between 2 and 7 indicators each.

Figure 3

Performance characteristics of the DunedinARB. (A) Presents the distribution of DunedinARB scores in the cohort. (B) Presents the association of the DunedinARB with the midlife measures of brain structural (MRI) and functional (cognitive) integrity. β's coefficients in (B) are derived from OLS regression of the brain integrity outcomes onto the DunedinARB, with adjustment for sex. Analytic sample sizes vary by outcome, from N = 852 (white matter hyperintensities volume) to N = 921 (subjective midlife cognitive problems).

Figure 4

Composition of the four published ADRD risk indexes. The DunedinARB includes direct or proxy measures of all risks listed here with the exception of air pollution exposure and cognitive engagement. Age and sex did not contribute to the DunedinARB score as the cohort is of equal age and sex was retained for use in analyses as a covariate to account for known sex-differences in brain structure.

Figure 5

Distribution and correlation (overlap) of ADRD risk among Dunedin Study members as measured by the four published risk indexes and the DunedinARB. Cells below the diagonal present pairwise Pearson’s r correlation coefficients (95% confidence intervals). All correlations are statistically significant, P < 0.001. Cells on the diagonal present histograms showing the distribution of each risk index in the Dunedin Study cohort and the DunedinARB benchmark.