Jason R. Smith

Plasma biomarkers of Alzheimer disease (AD) neuropathology (amyloid-β42 to amyloid β40 [Aβ42/40] ratio, phosphorylated tau at threonine [p-tau181]), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (glial fibrillary acidic protein [GFAP]) in late-life are associated with cognitive decline. Whether these biomarkers in midlife are predictive of subsequent cognitive decline, and whether they are associated with different cognitive domains, is uncertain. In this study, we investigated associations of midlife and late-life plasma Aβ42/40, p-tau181, NfL, and GFAP with late-life change in domain-specific (memory, language, and executive function) and global cognitive function. We performed a prospective cohort analysis of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Outcome follow-up was from ARIC visit 5 (2011-2013) to visit 9 (2021-2022). We included all individuals from ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Washington County, Maryland; and Minneapolis suburbs, Minnesota) with biomarkers measured from stored specimens in midlife (visit 3, 1993-1995, mean age 59.0 years) and late-life (visit 5, 2011-2013, mean age 76.8 years). Aβ42/40, p-tau181, NfL, and GFAP were measured with the Quanterix Simoa platform and standardized to visit 3 to facilitate cross-biomarker comparisons of their rate of change from midlife to late-life. We estimated change in memory, language, executive function, and global cognition factor scores from visit 5 to visit 9 with linear mixed-effect models. In 1,515 included participants, 60.7% (n = 920) were female and 25.5% (n = 387) were Black. Each SD increase in p-tau181 in midlife was significantly associated with faster late-life memory decline (β = -0.030 [95% CI -0.059 to -0.001] SD. Midlife Aβ42/40, NfL, and GFAP were not associated with subsequent decline in any cognitive domain. In late-life, p-tau181, NfL, and GFAP were significantly associated with faster decline in different cognitive domains, with the strongest associations seen with memory (β = -0.091 [95% CI -0.123 to -0.058] SD; β = -0.064 [95% CI -0.106 to -0.023] SD; and β = -0.048 [95% CI -0.082 to -0.013] SD, respectively). Midlife p-tau181 was associated with faster 11-year memory decline beginning 20 years later in the ARIC cohort, which underscores a potentially long prodromal phase of cognitive decline that could precede dementia onset. In late-life, biomarkers for AD, neurodegeneration, and neuroinflammation were associated with faster decline across different cognitive domains, but associations remained strongest for p-tau181 and memory.

Background and ObjectivesMidlife vascular risk factors are associated with both dementia and premature death; however, their combined association with dementia-free survival years remains unclear. ...

Genetics represent a nonmodifiable risk factor for Alzheimer disease (AD), with 60%-80% heritability. Midlife hypertension is a modifiable risk factor for both dementia and death. Our primary objective was to determine how genetic risk for AD modifies the association between hypertension and dementia. The Atherosclerosis Risk in Communities Study is an ongoing community-based prospective cohort study of 4 US centers. We analyzed White and Black participants free of dementia at age 55 years with genotypes and blood pressure measured at visit 1 (1987-1989). Three genetic risk groups (low, medium, high) were defined based on tertiles of a race-specific AD polygenic risk score. Dementia was ascertained through cognitive testing, informant interviews, hospitalization, codes and death records. Death was ascertained through the National Death Index. We examined the association of midlife hypertension with incident dementia within 3 genetic risk groups using Cox proportional-hazards and cumulative incidence function estimations. We used age 55 years as the time origin, with left truncation to allow entry at ages older than 55 years; age on December 31, 2022, was the administrative censoring date. Among 8,931 White and 2,666 Black participants, the median follow up time was 26.6 and 23.8 years, the mean age was 54.0/53.5 years, and 53.0%/62.5% were female, respectively. After adjusting for demographics, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants (low risk hazard ratio [HR] 1.29; 95% CI 1.07-1.55, medium risk HR 1.34; 95% CI 1.13-1.58, high risk HR 1.19; 95% CI 1.03-1.38) and among Black participants at high genetic risk (HR 1.31; 95% CI 1.04-1.66). Associations for low and medium genetic risk Black participants were consistent but not statistically significant. There were no significant differences in association of hypertension with dementia by AD genetic risk group. Individuals with hypertension had a 0%-2% higher probability of developing dementia by age 80 and a 6%-13% lower probability of dementia-free survival to age 80 years vs those without hypertension, across race and genetic risk groups. Genetic risk for AD does not modify the association between hypertension and dementia. These data support the fact that all individuals with hypertension are likely to benefit from antihypertensive treatment.

The contribution of late-life vascular risk factors to dementia risk remains controversial. Because low blood pressure (BP) has been associated with worse clinical outcomes in frail individuals, we hypothesized hypertension, but not diabetes or smoking, is associated with higher dementia risk in robust than in frail older adults. We performed a prospective cohort analysis of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) over 11 years (2011-2022). We included all community-living White and Black participants aged 67-89 years without dementia at baseline visit 5 (2011-2013) from ARIC-NCS field centers (Jackson, Mississippi; Forsyth County, North Carolina; Washington County, Maryland; Minneapolis suburbs, Minnesota). The primary vascular risk factors measured at baseline included elevated BP (systolic BP 120-129 mm Hg and diastolic BP < 80 mm Hg), hypertension (systolic BP ≥ 130 mm Hg, diastolic BP ≥ 80 mm Hg, or use of medication for BP), diabetes (fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, self-reported physician's diagnosis, or use of diabetes medication), and former and current smoking (self-reported). We defined frailty status using the Fried criteria (5 components that include low energy, low physical activity, slowness, weakness, and weight loss). We estimated cause-specific hazard ratios (HRs) of incident dementia (ascertained from in-person neuropsychological assessments, semiannual participant or informant report, or surveillance of claims from hospitalizations and death certificates) with Cox proportional hazards models including a multiplicative interaction between vascular factors and frailty. HRs of dementia were then stratified by frailty (robust [no frailty components present] vs prefrail/frail [at least 1 frailty component present]). There were 377 (15.8%) dementia cases in robust participants (n = 2,383; mean age, 74.2 years; 55.4% female) and 812 (30.0%) in prefrail/frail participants (n = 2,710; mean age 76.4 years; 61.3% female). There was a significant interaction between BP and frailty on dementia risk (p = 0.026). For robust participants, HRs were 1.03 (95% CI 0.65-1.64) for elevated BP and 1.39 (95% CI 1.00-1.94) for hypertension relative to normal BP. For prefrail/frail participants, HRs were 0.68 (95% CI 0.49-0.95) and 0.82 (95% CI 0.66-1.01), respectively. Diabetes and current smoking were associated with higher dementia risk in both robust and prefrail/frail individuals. Late-life hypertension was associated with a lower relative risk of dementia in prefrail/frail participants, but the association was positive in robust participants. BP interpretation and management to support brain health in older adults could consider age-related functional status.

Background: Hearing and vision loss can be treatable sensory risk factors for dementia. Nationally-representative estimates of the proportion of dementia prevalence associated with sensory risk factors in late-life are needed for dementia prevention strategies. Objective: To estimate the fraction of dementia prevalence associated with treatable sensory risk factors (hearing and vision loss) and to evaluate differences by age, race/ethnicity, income, and sex. Methods: This was a cross-sectional analysis of Round 12 (2022) of the National Health and Aging Trends Study, a population-based study nationally representative of US Medicare beneficiaries. Among community-living adults aged ≥65 years eligible for cognitive, hearing, and vision assessments (n = 4623), the summary population attributable fraction (PAF) of dementia from at least one objectively-measured sensory risk factor was estimated. Results: The prevalence of at least one sensory risk factor was 66% and dementia was 9%. The PAF of dementia from at least one sensory risk factor was 57% (95% CI: 8%–61%). PAFs were larger for individuals who were aged <80 years compared to ≥80 years (59% [95% CI: 42%–74%] versus 33% [95% CI: −6%–68%), non-Hispanic White compared to Hispanic and non-Hispanic Black (63% [95% CI: 41%–80%] versus 50% [95% CI: 16%–80%] and 32% [95% CI: −1%–64%]), and had higher income versus lower income (57% [95% CI: 36%–74%] versus 47% [95% CI: 7%–81%]). PAFs were consistent by sex. Conclusions: Up to 57% of dementia prevalence in the US was associated with clinically-significant sensory risk factors. Addressing sensory impairments could play an important role in national dementia risk reduction strategies.

Importance: Midlife vascular risk factors are associated with an elevated risk of dementia. However, the total contribution of vascular risk factors in midlife and late life with incident dementia is uncertain.Objective: To quantify the proportion of incident dementia attributable to modifiable vascular risk factors measured in midlife and late life and to examine differences by apolipoprotein ε4 genotype, self-reported race, and sex.Design, Setting, and Participants: This was a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study using 33 years of follow-up (1987-2020). The setting included ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Minneapolis suburbs, Minnesota; Washington County, Maryland). Study baseline in Black and White participants with complete exposure and covariate data was set by age at risk factor measurement (45-54 years, 55-64 years, and 65-74 years). Data were analyzed from August 2023 to December 2024.Exposures: Hypertension (systolic blood pressure [BP] ≥130 mm Hg, diastolic BP ≥80 mm Hg, or use of medication for BP), diabetes (fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, self-reported physician’s diagnosis, or use of any diabetes medication), and current smoking (self-reported).Main Outcomes and Measures: Incident dementia. Population attributable fractions were estimated by age 80 years, and separately after 80 years, from having at least 1 vascular risk factor by age at risk factor measurement.Results: A total of 7731 participants were included in analysis of risk factors measured at age 45 to 54 years (4494 female [58%]; 2207 Black [29%]; 5524 White [71%]), 12 274 contributed to analysis of risk factors measured at age 55 to 64 years (6698 female [55%]; 2886 Black [24%]; 9388 White [76%]), and 6787 contributed to analysis of risk factors measured at age 65 to 74 years (3764 female [56%], 1375 Black [20%]; 5412 White [80%]). There were 801, 995, and 422 dementia cases by 80 years, respectively. The fraction of dementia by 80 years attributable to at least 1 vascular factor at age 45 to 54 years was 21.8% (95% CI, 14.3%-29.3%), at 55 to 64 years was 26.4% (95% CI, 19.1%-33.6%), and at 65 to 74 years was 44.0% (95% CI, 30.9%-57.2%). Attributable fractions for these factors were higher in apolipoprotein ε4 noncarriers at age 55 years and older (range, 33.3%-61.4%), Black individuals at age 45 years and older (range, 25.5%-52.9%), and female individuals at age 55 years and older (range, 29.2%-51.3%). Only 2% to 8% of dementia cases after 80 years were attributable to these factors.Conclusions and Relevance: Results of this cohort study suggest that between 22% and 44% of incident dementia cases by 80 years in the ARIC study were attributed to midlife and late-life vascular risk factors. Assuming causal relationships, maintaining optimal vascular health across the life course could mitigate a sizeable proportion of dementia risk by 80 years.

Importance: Hearing loss treatment delays cognitive decline in high-risk older adults. The preventive potential of addressing hearing loss on incident dementia in a community-based population of older adults, and whether it varies by method of hearing loss measurement, is unknown.Objective: To calculate the population attributable fraction of incident dementia associated with hearing loss in older adults and to investigate differences by age, sex, self-reported race, and method of hearing loss measurement.Design, Setting, and Participants: This prospective cohort study was part of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) and had up to 8 years of follow-up (2011-2019). The 4 ARIC field centers in the study included Jackson, Mississippi; Forsyth County, North Carolina; the Minneapolis suburbs, Minnesota; and Washington County, Maryland. Community-dwelling older adults aged 66 to 90 years without dementia at baseline who underwent a hearing assessment at ARIC-NCS visit 6 (2016-2017) were included in the analysis. Data analysis took place between June 2022 and July 2024.Exposures: Hearing loss measured objectively (audiometric) and subjectively (self-reported).Main Outcomes and Measures: The main outcome was incident dementia (standardized algorithmic diagnosis with expert panel review). The population attributable fractions of dementia from both audiometric and self-reported hearing loss were calculated in the same participants, which quantified the maximum proportion of dementia risk in the population that can be attributed to hearing loss.Results: Among 2946 participants (mean [SD] age, 74.9 [4.6] years; 1751 [59.4] female; 637 Black [21.6%] and 2309 White [78.4%] individuals), 1947 participants (66.1%) had audiometric hearing loss, and 1097 (37.2%) had self-reported hearing loss. The population attributable fraction of dementia from any audiometric hearing loss was 32.0% (95% CI, 11.0%-46.5%). Population attributable fractions were similar by hearing loss severity (mild HL: 16.2% [95% CI, 4.2%-24.2%]; moderate or greater HL: 16.6% [95% CI, 3.9%-24.3%]). Self-reported hearing loss was not associated with an increased risk for dementia, so the population attributable fraction was not quantifiable. Population attributable fractions from audiometric hearing loss were larger among those who were 75 years and older (30.5% [95% CI, −5.8% to 53.1%]), female (30.8% [95% CI, 5.9%-47.1%]), and White (27.8% [95% CI, −6.0% to 49.8%]), relative to those who were younger than 75 years, male, and Black.Conclusions and Relevance: This cohort study suggests that treating hearing loss might delay dementia for a large number of older adults. Public health interventions targeting clinically significant audiometric hearing loss might have broad benefits for dementia prevention. Future research quantifying population attributable fractions should carefully consider which measures are used to define hearing loss, as self-reporting may underestimate hearing-associated dementia risk.

Background: Midlife vascular risk factors are associated with an increased risk of dementia. However, the overall contribution of modifiable vascular risk factors in midlife and late‐life to dementia remains unclear. In this study, we quantified population attributable fractions, which account for risk factor prevalence and strength of relative risks, of incident dementia from vascular risk factors measured in midlife and early late‐life.Method: We used 33 years of prospective cohort data in the Atherosclerosis Risk in Communities Study. Incident dementia (community surveillance and algorithmic diagnosis with expert clinical adjudication) was ascertained from baseline (1987‐1989) through December 31, 2020. We quantified population attributable fractions of incident dementia by age 80 from the combination of hypertension (systolic blood pressure ≥130, diastolic blood pressure ≥80, or use of medication), diabetes (fasting glucose ≥126, non‐fasting glucose ≥200, self‐reported physician diagnosis of diabetes, or use of medication for diabetes/insulin), and self‐reported current cigarette smoking (at least one risk factor versus none) measured at different ages (45‐54 [n = 7,731], 55‐64 [n = 12,273]; 65‐74 [n = 6,660]). We also computed attributable fractions stratified by sex, apolipoprotein ε4 genotype, and self‐reported race.Result: The prevalence of having one or more of the vascular risk factors was 61.6% (95% CI: 60.5, 62.7%) at age 45‐54 and increased to 77.5% (95% CI: 76.5, 78.5%) by age 65‐74. Population attributable fractions of dementia increased from 22.7% (95% CI: 15.3, 30.1%) for vascular risk factors measured at age 45‐54 to 45.4% (95% CI: 32.5, 58.3%) for vascular risk factors assessed at age 65‐74 (see Figure). Attributable fractions were larger in females, participants without apolipoprotein ε4 alleles, and Black participants (Figure).Conclusion: Between 23% to 45% of incident dementia cases by age 80 were attributed to a combination of hypertension, diabetes, or current smoking up through age 74. Attributable fractions for the combined impact of vascular risk varied by key demographics. Public health strategies targeting modifiable vascular risk factors could reduce dementia risk and increase healthy lifespan.

Cognitive training intervention implementation and efficacy should be evaluated among representative samples, including those at highest risk of cognitive decline. Hearing and vision impairments are prevalent among older adults and confer an increased risk of cognitive decline/dementia. Whether cognitive training interventions enroll and are designed to include this important subgroup is unknown. A scoping review of PubMed and PsycINFO was conducted to examine the inclusion of older adults with hearing and/or vision impairment in cognitive training interventions. Eligible articles included English-language cognitive training randomized controlled trials and a study population that was cognitively unimpaired, aged ≥55-years, and community-dwelling. Among the 130 articles in the review, 103(79%) were cognitive training and 27(21%) were multimodal interventions that included cognitive training. Over half the trials systematically excluded participants with hearing and/or vision impairment (n=60, 58%). Few studies measured and reported participant hearing and/or vision impairment (cognitive: n=16, 16%; multimodal: n=3, 11%) or reported incorporating low hearing/vision accessibility features into intervention design (cognitive: n=7, 7%; multimodal: n=0, 0%). Greater representation of older adults with hearing and/or vision impairment in cognitive training interventions is needed and can be achieved by strengthening measurement and reporting of participant hearing and vision, minimizing barriers to participation by increasing accessibility in recruitment and intervention design, and intentional inclusion of older adults with hearing and/or vision impairment. With greater representation of older adults with hearing and/or vision impairment, studies can better evaluate group-specific differences in training effect and begin to tailor interventions to potentially maximize benefit.