Racial and Ethnic Differences in the Population-Attributable Fractions of Alzheimer Disease and Related Dementias.

BACKGROUND AND OBJECTIVES: Previous studies estimated that modifiable risk factors explain up to 40% of the dementia cases in the United States and that this population-attributable fraction (PAF) differs by race and ethnicity-estimates of future impact based on the risk factor prevalence in contemporary surveys. The aim of this study was to determine the race-specific and ethnicity-specific PAF of late-onset Alzheimer disease and related dementias (ADRDs) based on the risk factor prevalence and associations observed on the same individuals within a prospective cohort. METHODS: Data were from Multiethnic Cohort Study participants (African American, Japanese American, Latino, Native Hawaiian, and White) enrolled in Medicare Fee-for-Service. We estimated the PAF based on the prevalence of risk factors at cohort baseline and their mutually adjusted association with subsequent ADRD incidence. Risk factors included low educational attainment and midlife exposures to low neighborhood socioeconomic status, unmarried status, history of hypertension, stroke, diabetes or heart disease, smoking, physical inactivity, short or long sleep duration, obesity, and low-quality diet, as well as APOE ε4 for a subset. RESULTS: Among 91,881 participants (mean age 59.3 at baseline, 55.0% female participants), 16,507 incident ADRD cases were identified from Medicare claims (1999-2016, mean follow-up 9.3 years). The PAF for nongenetic factors combined was similar in men (24.0% [95% CI 21.3-26.6]) and women (22.8% [20.3-25.2]) but varied across Japanese American (14.2% [11.1-17.2]), White (21.9% [19.0-24.7]), African American (27.8% [22.3-33.0]), Native Hawaiian (29.3% [21.0-36.7]), and Latino (33.3% [27.5-38.5]) groups. The combined PAF was attenuated when accounting for competing risk of death, in both men (10.4%) and women (13.9%) and across racial and ethnic groups (4.7%-25.5%). The combined PAF was also different by age at diagnosis and ADRD subtypes, higher for younger (65-74 years: 43.2%) than older (75-84 years: 32.4%; ≥85 years: 11.3%) diagnoses and higher for vascular or unspecified ADRD than for AD or Lewy body dementia. An additional PAF of 11.8% (9.9-13.6) was associated with APOE ε4, which together with nongenetic risk factors accounted for 30.6% (25.8-35.1) of ADRD. DISCUSSION: Known risk factors explained about a third of the ADRD cases but with unequal distributions across racial and ethnic groups.

Quantitative estimate of cognitive resilience and its medical and genetic associations.

BACKGROUND: We have proposed that cognitive resilience (CR) counteracts brain damage from Alzheimer's disease (AD) or AD-related dementias such that older individuals who harbor neurodegenerative disease burden sufficient to cause dementia remain cognitively normal. However, CR traditionally is considered a binary trait, capturing only the most extreme examples, and is often inconsistently defined. METHODS: This study addressed existing discrepancies and shortcomings of the current CR definition by proposing a framework for defining CR as a continuous variable for each neuropsychological test. The linear equations clarified CR's relationship to closely related terms, including cognitive function, reserve, compensation, and damage. Primarily, resilience is defined as a function of cognitive performance and damage from neuropathologic damage. As such, the study utilized data from 844 individuals (age = 79 ± 12, 44% female) in the National Alzheimer's Coordinating Center cohort that met our inclusion criteria of comprehensive lesion rankings for 17 neuropathologic features and complete neuropsychological test results. Machine learning models and GWAS then were used to identify medical and genetic factors that are associated with CR. RESULTS: CR varied across five cognitive assessments and was greater in female participants, associated with longer survival, and weakly associated with educational attainment or APOE ε4 allele. In contrast, damage was strongly associated with APOE ε4 allele (P value < 0.0001). Major predictors of CR were cardiovascular health and social interactions, as well as the absence of behavioral symptoms. CONCLUSIONS: Our framework explicitly decoupled the effects of CR from neuropathologic damage. Characterizations and genetic association study of these two components suggest that the underlying CR mechanism has minimal overlap with the disease mechanism. Moreover, the identified medical features associated with CR suggest modifiable features to counteract clinical expression of damage and maintain cognitive function in older individuals.

Paradigm Shift: Multiple Potential Pathways to Neurodegenerative Dementia.

Neurodegenerative dementia can result from multiple underlying abnormalities, including neurotransmitter imbalances, protein aggregation, and other neurotoxic events. A major complication in identifying effective treatment targets is the frequent co-occurrence of multiple neurodegenerative processes, occurring either in parallel or sequentially. The path towards developing effective treatments for Alzheimer's disease (AD) and other dementias has been relatively slow and until recently has focused on disease symptoms. Aducanumab and lecanemab, recently approved by the FDA, are meant to target disease structures but have only modest benefit on symptom progression and remain unproven in reversing or preventing dementia. A third, donanemab, appears more promising but awaits FDA approval. Ongoing trials include potential cognition enhancers, new combinations of known drugs for synergistic effects, prodrugs with less toxicity, and increasing interest in drugs targeting neuroinflammation or microbiome. Scientific and technological advances offer the opportunity to move in new therapy directions, such as modifying microglia to prevent or suppress underlying disease. A major challenge, however, is that underlying comorbidities likely influence the effectiveness of therapies. Indeed, the full range of comorbidity, today only definitively identified postmortem, likely contributes to failed clinical trials and overmedication of older adults, since it is difficult to exclude (during life) people unlikely to respond. Our current knowledge thus signals that a paradigm shift towards individualized and multimodal treatments is necessary to effectively advance the field of dementia therapeutics.

Neuropathologic Changes of Alzheimer's Disease and Related Dementias: Relevance to Future Prevention.

BACKGROUND: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer's disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia. OBJECTIVE: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC. METHODS: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC). RESULTS: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels. CONCLUSION: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.

If Midlife Brain Injury Is a Risk Factor for Alzheimer's Disease and Related Dementias, What Is the Neuropathologic Mechanism?

While we know that brain injuries related to sport and military activities sometimes lead to cognitive impairment or early onset dementia, it is unclear if and how they might influence the development of Alzheimer's Disease and Related Dementias (ADRD). Published analytic conclusions have been mixed. Two reports in the Journal of Alzheimer's Disease reach the same answer: a history of brain injury appears to be a risk factor for generalized brain atrophy, which would likely increase vulnerability to the subsequent development of any variety of ADRD, or to dementia directly attributable to reduced brain mass.

The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia.

BACKGROUND: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. METHODS: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. FINDINGS: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]). INTERPRETATION: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. FUNDING: Gates Ventures.

Prediction of neuropathologic lesions from clinical data.

INTRODUCTION: Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life. METHODS: This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities. RESULTS: Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased. DISCUSSION: Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.

Mid- and later-life risk factors for predicting neuropathological brain changes associated with Alzheimer's and vascular dementia: The Honolulu Asia Aging Study and the Age, Gene/Environment Susceptibility-Reykjavik Study.

INTRODUCTION: Dementia prediction models are necessary to inform the development of dementia risk reduction strategies. Here, we examine the utility of neuropathological-based risk scores to predict clinical dementia. METHODS: Models were developed for predicting Alzheimer's disease (AD) and non-AD neuropathologies using the Honolulu Asia Aging neuropathological sub-study (HAAS; n = 852). Model accuracy for predicting clinical dementia, over 30 years, was tested in the non-autopsied HAAS sample (n = 2960) and the Age, Gene/Environment Susceptibility-Reykjavik Study (n = 4614). RESULTS: Different models were identified for predicting neurodegenerative and vascular neuropathology (c-statistic range: 0.62 to 0.72). These typically included age, APOE, and a blood pressure-related measure. The neurofibrillary tangle and micro-vascular lesion models showed good accuracy for predicting clinical vascular dementia. DISCUSSION: There may be shared risk factors across dementia-related lesions, suggesting common pathways. Strategies targeting these models may reduce risk or postpone clinical symptoms of dementia as well as reduce neuropathological burden associated with AD and vascular lesions.

Modifying effects of race and ethnicity and APOE on the association of physical activity with risk of Alzheimer's disease and related dementias.

INTRODUCTION: We investigated whether the protective association of physical activity with risk of Alzheimer's disease and related dementias (ADRD) has genetic or behavioral variations. METHODS: In the Multiethnic Cohort, we analyzed moderate or vigorous physical activity (MVPA) reported at ages 45 to 75 among 88,047 participants in relation to 13,039 incident diagnoses of late-onset ADRD identified in Medicare claims (1999 to 2014), by five racial and ethnic groups, hours sitting, and in a subset (16%), apolipoprotein E (APOE) genotype. RESULTS: MVPA was inversely associated with ADRD (hazard ratio for ≥14 vs <2.5 hours/week: 0.83, 95% confidence interval [CI]: 0.76 to 0.90 in men; 0.88, 5% CI: 0.81 to 0.95 in women). The association was inverse in all racial and ethnic groups except Black participants (P-heterogeneity = 0.52), but stronger in individuals with lower levels of sitting duration or those who do not carry the APOE e4 risk allele. DISCUSSION: The different effects of physical activity by sitting duration and APOE genotype warrant further research.

Association of Cognition and Dementia With Neuropathologic Changes of Alzheimer Disease and Other Conditions in the Oldest-Old.

BACKGROUND AND OBJECTIVES: Age is the largest risk factor for dementia. However, dementia is not universal, even among the oldest-old age groups. Following contemporary neuropathologic guidelines, our objectives were to describe the key neuropathologic lesions and their associations with antemortem cognition in oldest-old individuals. METHODS: Participants were those enrolled in The 90+ Study, a longitudinal, population-based study of aging/dementia in the oldest-old, who agreed to postmortem brain examination. All autopsied brains as of December 2020 were evaluated for prevalence of Alzheimer's disease neuropathologic change (ADNC) and non-ADNC neuropathologic comorbidities. Associations between neuropathologic lesions or total neuropathologic burden score (sum of the individual scores) and cognition were assessed using multinomial logistic regression and multiple linear regression. Separate regression analyses evaluated relationships between limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and hippocampal sclerosis (HS) or ADNC/primary age-related tauopathy (PART). Resistance, or failure to develop ADNC/PART, and resilience, inferred from higher than expected cognitive functioning, were evaluated in the presence or absence of non-ADNC neuropathologic features. RESULTS: The most common neuropathologic features in the sample (n=367) were ADNC/PART-related. Increased dementia odds were associated with elevated total neuropathologic burden (OR=1.5 [95% CI 1.3-1.7] p<0.0001), beta amyloid (OR=1.6 [95% CI 1.2-2.0] p<0.0001), neurofibrillary tangles (OR=2.6 [95% CI 1.7-4.1] p<0.0001), and LATE-NC (OR=2.3 [95% CI 1.7-3.1] p<0.0001), correcting for multiple comparisons. LATE-NC was associated with dementia with (OR=6.1 [95% CI 2.0-18.7] p=0.002) and without (OR=5.0 [95% CI 2.6-9.7] p<0.0001) co-occurring HS, and increased the odds of dementia among participants with ADNC (OR=5.0 [95% CI 2.7-9.2] p<0.0001). Resistance to moderate/severe ADNC/PART was rare (3%), but resilience to ADNC/PART was not (55%). Resilience was rarer in the presence of non-ADNC comorbid lesions, particularly LATE-NC. Among those with moderate/severe ADNC/PART, dementia odds increased with each non-ADNC comorbid lesion (e.g., 1 lesion: OR=2.4 [95% CI 1.3-4.5] p<0.005; 2 lesions: OR=5.9 [95% CI 2.8-12.3] p<0.0001). CONCLUSION: These results highlight the importance of non-ADNC neuropathologic comorbidity, predominantly LATE-NC, to cognition in the oldest-old. Given the cumulative effects of non-ADNC comorbid neuropathologic abnormalities, reducing their prevalence, especially LATE-NC, will be vital to the ultimate goal of reducing dementia burden in the oldest-old individuals.

Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aß phase = 0 (lacking detectable Aß plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Midlife alcohol consumption and later life cognitive impairment: Light drinking is not protective and APOE genotype does not change this relationship.

INTRODUCTION: Much debate exists about the role of light to moderate alcohol intake and subsequent cognitive function. The apolipoprotein E genotype may modify the relationship. METHODS: Using data from the Honolulu-Asia Aging Study, a longitudinal population-based cohort (n = 2,416), Cox proportional hazards regression analyses were performed to measure midlife alcohol intake (average age = 52 years) and later life cognitive function (average age = 87 years) and to explore the role of apolipoprotein E genotype. RESULTS: No protective effect of light drinking (>1 drink/month- 1 drink/day) or moderate drinking (>1-2 drinks/day) was observed in the cohort in adjusted models (HR = 1.013, CI:0.88-1.16; HR = 1.104, CI:0.91-1.34, respectively). Heavy drinking (>2-4 drinks/day) and very heavy drinking (>4 drinks/day) increased the risk for incident moderate cognitive impairment (HR = 1.355, CI:1.09-1.68; HR = 1.462, CI:1.04-2.05, respectively). When examining the relationship by apolipoprotein E ε4 carrier status, a similar dose-response pattern was observed in both groups with higher hazard ratios for those carrying at least one copy of the apolipoprotein E ℇ4 allele. As alcohol level increased, the age at incident moderate cognitive impairment decreased, especially among those with at least one apolipoprotein E ℇ4 allele. DISCUSSION: We did not observe a significant protective effect for light to moderate drinking in midlife and subsequent cognitive impairment in this cohort. Heavy drinking increased the risk for moderate cognitive impairment and decreased the age at incidence, as did carrying at least one allele of the apolipoprotein E ℇ4 gene.

Risk of Alzheimer's disease and related dementia by sex and race/ethnicity: The Multiethnic Cohort Study.

INTRODUCTION: Data are limited for comparison of sex- and race/ethnicity-specific risks of Alzheimer's disease and related dementia (ADRD). METHODS: In the population-based Multiethnic Cohort, we estimated the age-standardized diagnostic incidence rate (ASDIR) and relative risk of late-onset ADRD (n = 16,410) among 105,796 participants based on Medicare claims (1999-2014) by sex and race/ethnicity. RESULTS: The ASDIR for ADRD was higher for women (17.0 per 1000 person-years) than for men (15.3) and varied across African Americans (22.9 in women, 21.5 in men), Native Hawaiians (19.3, 19.4), Latinos (16.8, 14.7), Whites (16.4, 15.5), Japanese Americans (14.8, 13.8), and Filipinos (12.5, 9.7). Similar risk patterns were observed for AD. Adjustment for education and cardiometabolic diseases attenuated the differences. Accounting for deaths from competing causes increased the sex difference, while reducing the racial/ethnic differences. Less racial/ethnic disparity was detected among apolipoprotein E (APOE) e4 carriers. DISCUSSION: More research is needed to understand the sex and racial/ethnic differences in ADRD.

Cognitive Impairment in Older Adults and Therapeutic Strategies.

Cognitive impairment and its severe form dementia are increasingly prevalent in older adults and loom as a public health disaster unless effective interventions are developed. Cognitive impairment is a convergent trait caused by damage from an idiosyncratic mix of four prevalent diseases (Alzheimer disease; vascular brain injury; Lewy body diseases, such as Parkinson disease and dementia with Lewy bodies; and limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy) that is counterbalanced by individually varying resilience, which is comprised of reserve and compensation. Brain regional damage from each of these four prevalent diseases is generated by the net effect of injury and (mal)adaptive response and is accompanied by characteristic lesions. Existing therapeutics enhance resilience, whereas most agents under development target mechanisms of damage with only suppression of vascular brain injury yet to show therapeutic promise. We hope to anticipate future tailored interventions that target mechanisms of damage and thereby avert the oncoming surge of cognitive impairment and dementia in older adults. SIGNIFICANCE STATEMENT: Brain regional damage is generated by the net effect of injury and (mal)adaptive response. The extent to which signs and symptoms of such damage occur is influenced by an underlying resilience comprising reserve and compensation. Finding tailored interventions that target specific mechanisms of damage likely yields the most effective therapies.

Incident prolonged QT interval in midlife and late-life cognitive performance.

BACKGROUND: Measures of cardiac ventricular electrophysiology have been associated with cognitive performance in cross-sectional studies. We sought to evaluate the association of worsening ventricular repolarization in midlife, as measured by incident prolonged QT interval, with cognitive decline in late life. METHODS: Midlife QT interval was assessed by electrocardiography during three study visits from 1965/68 to 1971/74 in a cohort of Japanese American men aged 46-68 at Exam 1 from the Honolulu Heart Study. We defined incident prolonged QT as the QT interval in the upper quartile at Exam 2 or 3 after QT interval in lower three quartiles at Exam 1. Cognitive performance was assessed at least once using the Cognitive Abilities Screening Instrument (CASI), scored using item response theory (CASI-IRT), during four subsequent visits from 1991/93 to 1999/2000 among 2,511 of the 4,737 men in the Honolulu-Asia Aging Study otherwise eligible for inclusion in analyses. We used marginal structural modeling to determine the association of incident prolonged QT with cognitive decline, using weighting to account for confounding and attrition. RESULTS: Incident prolonged QT interval in midlife was not associated with late-life CASI-IRT at cognitive baseline (estimated difference in CASI-IRT: 0.04; 95% CI: -0.28, 0.35; p = 0.81), or change in CASI-IRT over time (estimated difference in annual change in CASI-IRT: -0.002; 95%CI: -0.013, 0.010; p = 0.79). Findings were consistent across sensitivity analyses. CONCLUSIONS: Although many midlife cardiovascular risk factors and cardiac structure and function measures are associated with late-life cognitive decline, incident prolonged QT interval in midlife was not associated with late-life cognitive performance or cognitive decline.

Military-related experiences and late-life depressive symptomatology among Japanese-American world war II veterans.

Objectives: To examine military service-related variables and late-life depressive symptomatology among older Japanese-American males.Method: This study is a secondary data analysis of a longitudinal, community-based study. A sample of 2669 participants (771 World War II veterans, 1898 civilians) was drawn from the Honolulu-Asia Aging Study. Depressive symptoms were assessed twice across a 9-year period with the Center for Epidemiologic Studies-Depression scale. Covariates included sociodemographic, physical health, health behavior, and psychosocial variables. Combat exposure and symptomatology were examined among a subset of 426 veterans. Cross-sectional and longitudinal designs were analyzed with linear regression.Results: Veterans and civilians did not differ in depression scores. Baseline depression scores significantly predicted follow-up depression scores. For the full sample, lower ratings of quality of life satisfaction, daily activity control and general health were associated with higher depression scores both cross-sectionally and longitudinally. Among veterans, light combat exposure was marginally associated with lower depression scores and longitudinally, previous depression scores and poorer health ratings were significant predictors of depression scores.Conclusion: Results suggest that military service does not affect late-life depressive symptomatology. However, combat exposure may play a marginal role in increased symptoms. Reasons for results include the possibility that other factors are more relevant to late-life depression, symptomatology naturally decreasing over time, or type of combat exposure measurement. Results expand literature by examination of an ethnoracial group not studied often and longitudinal examination of late-life depressive symptoms within a military-related context. Stakeholders should be knowledgeable of the distinct issues presented when serving aging veterans.

Brain Injury and Later-Life Cognitive Impairment and Neuropathology: The Honolulu-Asia Aging Study.

BACKGROUND: Findings are inconsistent regarding the role of traumatic head injury in the subsequent development of neurologic outcomes. OBJECTIVE: Examine the relationship between head injury and later cognitive impairment. METHODS: A sample of 3,123 Japanese-American men was assessed for history of head injury and evaluated for cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). For a subsample of 676 respondents, neuropathologic results from those with and without head injury were compared. RESULTS: Although the crude model showed an association between history of head injury and later severe cognitive impairment, the relationship lost significance in the adjusted model (OR = 1.320, CI: 0.90-1.93), regardless of time between injury and impairment. Similar to cognitive impairment, hippocampal sclerosis was observed significantly more in the brains of respondents with a history of head injury in the crude model, but the relationship weakened in the adjusted model (OR = 1.462, CI: 0.68-3.12). After adjustment, decedents with a head injury demonstrated marginally higher brain weight (OR = 1.003, CI: 1.00-1.01). CONCLUSION: We did not find a relationship between head injury and subsequent cognitive decline in this cohort. The neuropathology results also displayed no strong association between history of head injury and specific brain lesions and characteristics. These results support other findings in prospective cohorts. However, they could be influenced by the demographic make-up of the sample (male Japanese-Americans) or by the observation that the majority reported only a single head injury.

Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies.

BACKGROUND: Dementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia. METHODS: We did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses. RESULTS: Six prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7-22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), there was no association between AHM use and incident dementia or Alzheimer's disease. INTERPRETATION: Over a long period of observation, no evidence was found that a specific AHM drug class was more effective than others in lowering risk of dementia. Among people with hypertensive levels of blood pressure, use of any AHM with efficacy to lower blood pressure might reduce the risk for dementia. These findings suggest future clinical guidelines for hypertension management should also consider the beneficial effect of AHM on the risk for dementia. FUNDING: The Alzheimer's Drug Discovery Foundation and the National Institute on Aging Intramural Research Program.

How do we validate approaches that aim to harness reserve to improve the aging brain?

An accurate assessment of the impact of reserve on cognitive functioning in older individuals with brain pathology requires careful measurement of each and an assessment of the extent to which each influences the other. Studies to integrate information about molecular biology, neuropathology, behavioral aspects of cognitive decline, and cognitive resilience will be of particular importance. In addition, more work is needed to improve our understanding of the effect of systemic factors on brain health and function. It seems likely that, even in later life, the brain's plasticity may allow for a positive response to stimulation. The ultimate goal of this research is to create a validated set of variables and interventions-and to understand the biology underlying them-that are useful not only in describing an individual's cognitive state but also in identifying promising paths for treatment and prevention of cognitive decline.

Excessive daytime sleepiness and topographic expansion of Lewy pathology.

OBJECTIVE: While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up. METHODS: Identification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72-97 years. RESULTS: Although EDS was more common in the presence vs absence of LP (p = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1-4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP (p = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], p = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], p < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies. CONCLUSIONS: The association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation.