Abstract: Background: Cerebrovascular pathologies are common in the elderly and are associated with dementia. Cardiovascular risk factors are thought to contribute to their development, but this evidence mainly comes from imaging studies or autopsy studies in younger individuals. We performed a systematic review to investigate associations of cardiovascular risk factors with cerebrovascular pathologies in the oldest‐old (age >80) vs. the younger‐old (ages 65‐80). Methods: Figure 1 describes how studies were identified. Cardiovascular risk factors were hypertension (HTN), hyperlipidemia (HLD), and diabetes (DM). Cerebrovascular pathologies were arteriolosclerosis, atherosclerosis, CAA, and MVLs. PubMed, Scopus, and Web of Science databases were searched for articles in English that investigated associations between self‐reported cardiovascular risk factors and presence of cerebrovascular pathologies on autopsy with a mean age >65 years, which reported odds ratios (OR), or information to calculate OR, for the individual associations of cardiovascular risk factors and cerebrovascular pathologies. Initial searching involved all combinations of cardiovascular MeSH terms by cerebrovascular pathology MeSH terms (n = 1038). JW and RR screened titles and abstracts to identify potential studies (n = 45), which reduced to 10 after applying the restrictions above. We used meta‐analytic methods to estimate OR when multiple studies reported on the same associations. Results: We reviewed 10 studies (Table 1) from 6 unique cohorts (n = 1,815, ages 65‐80 and n = 7,995, age >80). HTN was positively associated with cerebrovascular pathologies for all the instances except arteriolosclerosis‐oldest‐old [OR = 1.20, n = 2,089], (arteriolosclerosis‐younger‐old [OR = 1.30 n = 1,599], atherosclerosis‐oldest‐old [OR = 1.29, n = 2,620], CAA‐oldest‐old [OR = 1.23, n = 2,198], and MVLs‐oldest‐old [OR = 1.54, n = 1,710]) (Figure 2). HLD was associated with arteriolosclerosis in the younger‐old ([OR = 1.27 n = 922]), but not the oldest‐old ([OR = 0.98, n = 1,255]), and not associated with CAA in the oldest‐old ([OR = 1.13, n = 3,508]). DM was not associated in any situation in which it was investigated (Figure 2). Conclusions: Cardiovascular risk factors were more associated with cerebrovascular pathologies in the younger‐old than oldest‐old. HTN was consistently associated with cerebrovascular pathologies in both age groups while DM was consistently not associated. Cardiovascular risk factors were understudied in the younger‐old. These findings highlight the importance of further clinicopathologic studies to clarify age‐dependent associations of cardiovascular risk factors and cerebrovascular pathologies.

Abstract: Background: SuperAgers are individuals who maintain superior cognitive performance despite advanced age. Most studies define SuperAgers as superior performers only in episodic memory. Our aim was to assess in a diverse oldest‐old cohort if superior performance in one domain indicates superior performance in other domains and explore demographic characteristics. Methods: The LifeAfter90 study is a multi‐ethnic cohort of members of Kaiser Permanente Northern California aged 90 or older. Baseline verbal episodic memory (VEM), semantic memory (SM), and executive function (EF) were evaluated using the Spanish and English Neuropsychological Assessment Scale (SENAS). SuperAgers were individuals who scored above the mean of domain and race‐specific SENAS scores from a reference cohort aged 65‐70 years. The reference group were similar participants from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study. To assess the association between age, sex, education, and being a SuperAger, odds ratios (OR) and 95% confidence interval (CI) were calculated using multiple logistic regression. Results: The 617 study participants (236 men and 381 women) had a mean age of 92.9 years (Table1). 53.6% of individuals were SuperAgers in one domain, 22.8% in any two domains, and 7.7% in all three domains. 7.0% of individuals were SuperAgers in SM and EF, 4.5% in VEM and EF, and 3.5% in VEM and SM (Figure1). SuperAgers were younger than non‐SuperAgers. Women were more likely to be SuperAgers in VEM (OR = 2.13; 95%CI: 1.43,3.18) and EF (OR = 2.18; 95%CI: 1.44,3.30) and less likely in SM (OR = 0.49; 95%CI: 0.34,0.71) compared to men. Higher education was related to being a SuperAger in SM (OR = 1.85; 95%CI: 1.28,2.67) and EF (OR = 2.56; 95%CI: 1.74,3.78) but not VEM (Table2). Conclusion: In this diverse cohort of oldest‐old SuperAgers we found that exceptional episodic memory performance does not indicate exceptional performance in other cognitive domains. Education was not a predictor of exceptional performance in all domains. Future work should investigate predictors of exceptional cognitive aging after age 90.

Abstract: Background: In the oldest‐old (those >90 years) cerebrovascular diseases are highly prevalent and independently associated with dementia. Although cardiovascular risk factors like hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM) are thought to be major contributors to the development of cerebrovascular diseases, autopsy studies in the oldest‐old show weak associations with HTN, no association with DM, and HLD remains understudied. We expanded upon existing studies by investigating the associations of cardiovascular risk factors, conditions, interventions, and APOE genotype with the presence of cerebrovascular diseases in participants >90‐years‐old. Methods: Participants are from The 90+ study, a population‐based epidemiology study of dementia and aging whose participants were survivors of the Leisure World cohort (n = 267). The self‐reported cardiovascular risk factors were DM, HLD, and HTN. Cardiovascular conditions were arrhythmia, coronary artery disease, congestive heart failure (CHF), heart valve disease, myocardial infarction, stroke, and transient ischemic attack. Cardiovascular interventions were coronary artery bypass, pacemaker placement, and statin use. Cerebrovascular diseases were arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy (CAA), and microvascular lesions (MVLs) on autopsy. Neuropathologic evaluation followed NIA‐AA guidelines. We investigated the association between individual cardiovascular risk factors, conditions, interventions, and APOE genotype with individual cerebrovascular pathologies using logistic regressions adjusted for age of death, sex, and education. Results: Participants were on average 98.1 years at death and 75% were female (Table 1). None of the cardiovascular features were associated with arteriolosclerosis or atherosclerosis (Figure 1). APOE‐ε4 was positively associated with CAA [OR = 3.62] while DM [OR = 0.23] and statin use [OR = 0.57] were negatively associated (Figure 2). CHF was negatively associated with the likelihood of MVLs [OR = 0.39] (figure 2). Conclusions: Cardiovascular risk factors were not associated with cerebrovascular pathologies in our age group, leading to three potential interpretations: 1) they are not risk factors for cerebrovascular pathologies, 2) they have been mitigated through treatment, or 3) they are not associated due to survival bias, as these conditions reduce life expectancy. Associations of APOE‐ε4, DM, and statin use with CAA may relate to β‐amyloid metabolism while CHF’s negative association with MVLs may relate to decreased blood pressure variability. These initial findings on the limited associations warrant further exploration.

Abstract: Background: The oldest‐old are the fastest growing segment of the elderly population but very little is known about cognition in this age group; particularly in diverse populations. Our goal was to evaluate if domain specific cognitive change was different across different ethnoracial groups in those aged 90+. Method: LifeAfter90 (LA90) is an ongoing cohort of participants aged 90+ who are long‐term members of Kaiser Permanente Northern California participants. Participants (n = 984) were interviewed every 6 months for up to 3.5 years (1‐7 visits). Executive Function (EF) and Verbal Episodic Memory (VEM) were measured every six months using z‐standardized Spanish English Neuropsychological Assessment Scale. Racial/ethnic identify (Asian, Black, Latino, or White participants) was used in linear mixed models with random slopes and intercepts adjusting for baseline age, gender, education, interview mode, and practice effects. Result: Participants were 20% Latino, 23% Black, 24% Asian, 27% White, and 7% other individuals with a mean age of 92.4 (SD = 2.3) and a mean follow up time 1.1 years (Table 1). 39% of the cohort were men, 35% were college educated, and 29% were high school or less educated. Average annual change in EF was ‐0.06 (95% CI: ‐0.12, ‐0.00). Stratified models with Latino as the reference group showed White participants had significantly greater decline in EF (β = ‐0.13; 95%CI:‐0.20,‐0.06), followed by Asian participants (β = ‐0.09; 95%CI:‐0.17,‐0.01). EF scores among Black participants and participants who identified as other declined at a similar rate as Latino participants (β = ‐0.03; 95%CI:‐0.11,‐0.05; β = 0.00; 95%CI:‐0.10, 0.11; respectively) (Table 2: model 2). VEM had an annual change of ‐0.26 (95%CI: ‐0.40, ‐0.13), but there were no significant differences across ethnoracial groups in rate of decline. Conclusion: In this population of individuals aged 90+, decline in EF over the study period varied across ethnoracial group with White participants experiencing the fastest decline and Black, Latino, and other participants experiencing the slowest decline. Continued follow up will identify if there are differences in risk of cognitive impairment in this diverse population of oldest‐old. The results suggest the disparities in cognitive aging for those aged 90+ don’t mirror disparities seen in younger‐elderly ages.

Abstract: Background: Neuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life. Most studies, however, have limited ethnoracial diversity with almost exclusively White decedents. Our goal was to characterize neuropathology in a cohort of ethnically and racially diverse oldest‐old decedents. Method: The LifeAfter90 study is an ongoing cohort study of Kaiser Permanente Northern California members, aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Interviews and cognitive assessments occur approximately every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer’s Coordinating Center Neuropathology form v.10 and used NIA‐AA guidelines for Alzheimer’s diagnoses. As of January 2023, 304 participants (40%) were enrolled in autopsy (20% Asian, 18% African American, 17% Latino, 9% Multiracial/Other, and 36% White). Result: Of the 304 participants, 59 had died and neuropathological evaluations were completed. The median age of death was 93 years (range 90‐105), 33 (56%) were female, 8 Asian, 5 Black, 10 Latino, 31 White, and 5 Multiracial/Other. At final clinical exam, 17 participants had dementia (29%), 25 questionable/mild cognitive impairment (42%), and 16 were cognitively normal (27%). Alzheimer disease (AD) and vascular pathologies were the most frequent findings (Figure). Twenty two percent of participants did not have AD, one lacked neurofibrillary tangles (NFT). The most severe distributions/densities of NFTs and plaques were infrequent, with high likelihood of AD in two participants. For vascular pathologies, 98% had some level of arteriolosclerosis, 97% had atherosclerosis, 70% had amyloid angiopathy, and 26% had at least one old microinfarct. Other pathologies were less common: 27% had Lewy bodies, 18% had TDP‐43 deposits, and only one had Hippocampal sclerosis. Although data is sparse to test for associations, the proportion of individuals with dementia tended to increase with increasing pathology severity especially for AD pathologies. Conclusion: This diverse cohort of oldest‐old individuals reveal numerous brain pathologies are present with advanced age, with AD and select vascular pathologies being the most common. Future analyses will investigate their role with cognitive impairment.

Abstract: Background: Whether subjective evaluations of cognition can accurately predict cognitive decline is not well understood in ethnically diverse populations nor oldest‐old. In a multi‐ethnic cohort of adults aged 90+, we aim to investigate the association between self‐perceived memory concerns and objectively measured cognitive change. Method: LifeAfter90 is an active longitudinal cohort study of Kaiser Permanente Northern California members ages 90+ with no prior dementia diagnosis. Verbal episodic memory (VEM) and executive function (EF) were assessed every 6 months between July 2018 and March 2022 using the Spanish and English Neuropsychological Assessment Scales (SENAS). At baseline, participants answered the question “Are you concerned that you have a memory or other thinking problem?” We evaluated associations between memory concerns and domain‐specific cognition at baseline and over time using linear mixed models with random intercepts and slopes, adjusted for baseline age, sex, race/ethnicity, education, interview mode (in‐person or phone), and practice effects. Sensitivity analyses stratified by 1) gender and 2) age (+/‐ 95 years). Result: At baseline, participants (n = 975) had a mean age of 92.4 (SD = 2.3) years, 61% were women, 73% were racial/ethnic minorities, and 36% reported memory concerns (Table 1). Memory concerns were associated with worse baseline VEM (b = ‐0.17, 95% CI ‐0.27,‐0.07; Table 2) and EF (b = ‐0.08, 95% CI ‐0.15,‐0.01; Table 3), but not associated with rate of change for either domain. When stratified by gender, both men and women with memory concerns had worse baseline VEM (b = ‐0.21, 95% CI ‐0.36,‐0.06 and b = ‐0.15, 95% CI ‐0.27,‐0.02, respectively; Table 2). Additionally, men with memory concerns had worse baseline EF (b = ‐0.19; 95% CI ‐0.30,‐0.08; Table 3). Among participants younger than 95 years, memory concerns were associated with worse baseline VEM (b = ‐0.15, 95% CI ‐0.25,‐0.04; Table 2) and EF (b = ‐0.10, 95% CI ‐0.17,‐0.02; Table 3). Conclusion: In this diverse cohort of oldest‐old, those with subjective memory concerns had worse baseline VEM and EF. Although memory concern may suggest objective cognitive impairment, it is not associated with decline over the short term; (an average follow up time of 1.05 years). Additional follow up will identify how changes in memory concerns may be associated with cognitive change.