Diffusion MRI relates to plasma Aß42/40 in PET negative participants without dementia.

INTRODUCTION: Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid-ß (Aß42/40) positivity in Aß positron emission tomography (PET) negative individuals. METHODS: Diffusion free-water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aß plasma-/PET- (NC = 22, MCI = 60), plasma+/PET- (NC = 5, MCI = 20), and plasma+/PET+ (AD dementia = 21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross-sectionally and the relationships between imaging, plasma and PET biomarkers were assessed. RESULTS: Plasma+/PET- demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma-/PET-. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET-. Composite brain FW correlated with plasma Aß42/40 and p-tau181. DISCUSSION: FW imaging changes distinguish plasma Aß42/40 positive and negative groups, independent of group differences in cognitive status, Aß PET status, and other plasma biomarkers (i.e., t-tau, p-tau181, glial fibrillary acidic protein, neurofilament light). HIGHLIGHTS: Plasma Aß42/40 positivity is associated with brain microstructure decline. Plasma+/PET- demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET- demonstrated decreased FAt in 66 total GM and WM regions. Whole-brain FW correlated with plasma Aß42/40 and p-tau181 measures. Plasma+/PET- demonstrated decreased cortical volume and thickness.

Plasma Alzheimer's biomarkers and brain amyloid in Hispanic and non-Hispanic older adults.

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p-tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non-amnestic MCI/dementia), and Aß-PET in Hispanic and non-Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three-hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aß-PET. P-tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aß-PET[+] and Aß-PET[-] (AUC = 0.86). P-tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p-tau181 than non-Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p-tau181 informs etiological diagnosis of cognitively impaired Hispanic and non-Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non-Alzheimer's contributions to memory loss. HIGHLIGHTS: Alzheimer's biomarkers were measured in Hispanic and non-Hispanic older adults. Plasma p-tau181 related to amnestic cognitive decline and brain amyloid burden. AD biomarker associations did not differ between Hispanic and non-Hispanic ethnicity. Hispanic individuals may be more likely to have non-Alzheimer causes of memory loss.

Declarative Learning, Priming, and Procedural Learning Performances comparing Individuals with Amnestic Mild Cognitive Impairment, and Cognitively Unimpaired Older Adults.

OBJECTIVE: While declarative learning is dependent on the hippocampus, procedural learning and repetition priming can operate independently from the hippocampus, making them potential targets for behavioral interventions that utilize non-declarative memory systems to compensate for the declarative learning deficits associated with hippocampal insult. Few studies have assessed procedural learning and repetition priming in individuals with amnestic mild cognitive impairment (aMCI). METHOD: This study offers an overview across declarative, conceptual repetition priming, and procedural learning tasks by providing between-group effect sizes and Bayes Factors (BFs) comparing individuals with aMCI and controls. Seventy-six individuals with aMCI and 83 cognitively unimpaired controls were assessed. We hypothesized to see the largest differences between individuals with aMCI and controls on declarative learning, followed by conceptual repetition priming, with the smallest differences on procedural learning. RESULTS: Consistent with our hypotheses, we found large differences between groups with supporting BFs on declarative learning. For conceptual repetition priming, we found a small-to-moderate between-group effect size and a non-conclusive BF somewhat in favor of a difference between groups. We found more variable but overall trivial differences on procedural learning tasks, with inconclusive BFs, in line with expectations. CONCLUSIONS: The current results suggest that conceptual repetition priming does not remain intact in individuals with aMCI while procedural learning may remain intact. While additional studies are needed, our results contribute to the evidence-base that suggests that procedural learning may remain spared in aMCI and helps inform behavioral interventions that aim to utilize procedural learning in this population.

Procedural learning, declarative learning, and working memory as predictors of learning the use of a memory compensation tool in persons with amnestic mild cognitive impairment.

Persons with amnestic Mild Cognitive Impairment (aMCI) are at risk for experiencing changes in their daily functioning due to their memory impairment. The Memory Support System (MSS), a compensatory calendaring system, was developed to support functional independence in persons with aMCI (pwaMCI). This cross-sectional study examined procedural learning, declarative learning, and working memory as predictors of MSS learning efficiency in pwaMCI. Sixty pwaMCI participated in MSS training. The Serial Reaction Time Test and Mirror Tracing Test were used to assess procedural learning. The Rey Auditory Verbal Learning Test and CogState One Card Learning were used to assess declarative learning and the CogState One Back task was used to assess working memory. Multiple regression analyses were conducted to assess if procedural learning, declarative learning, and working memory predicted MSS learning efficiency. This study showed that declarative learning predicted MSS learning efficiency in pwaMCI, with less consistent results for procedural learning and non-significant results for working memory. Findings suggest that success in teaching compensatory tools is greater when training is offered in early aMCI before declarative learning skill is fully lost. Future studies should assess additional strategies to facilitate MSS learning in advanced aMCI.

Health concerns and attitudes towards research participation in a community of rural Black Americans.

OBJECTIVES: Describe health concerns of Black Americans as they age and what influences their participation in aging and clinical research. METHODS: Fifty participants attended focus groups and completed questionnaires to identify barriers to research participation and attitudes toward dementia screening. Bivariate correlations explored associations between barriers to research participation and attitudes toward dementia screening. RESULTS: Cancer, hereditary conditions, vascular conditions, memory disorders, and psychological disorders were the greatest health concerns. Time demands, mistrust, lack of knowledge about potential research, and stigma were identified as barriers for research participation. Incentives, better understanding of how proposed research will benefit the community, lifestyle modification studies, active presence of principal researchers/clinicians, and community investment were identified as factors to improve participation. Questionnaires revealed mistrust and religious beliefs to be among the primary barriers. Attitudes toward dementia screening reflected perceived stigma, suffering, and subsequent loss of independence. Higher barriers to participation were associated with perceived stigma and loss of independence related to dementia screening. CONCLUSIONS: Successfully recruiting Black Americans for aging and clinical research remains a challenge. This study identifies barriers to participation and offers suggestions for planning and recruitment.

The impact of patient and partner personality traits on learning success for a cognitive rehabilitation intervention for patients with MCI.

The Memory Support System (MSS) is the memory compensation tool used in the HABIT Healthy Action to Benefit Independence and Thinking® Program. People diagnosed with mild cognitive impairment (pwMCI; n = 153) participated in this cognitive rehabilitative programme with a partner. We first aimed to determine if prior research on the positive impact of higher baseline cognitive status on successful MSS learning would be replicated in a new sample. We further evaluated the impact of the pwMCI's and partner's personality traits, as measured by the Ten Item Personality Inventory, on successful learning. Better global cognitive status was again shown to increase the odds for MSS learning success. In terms of personality, the highest odds of learning success occurred when the pwMCI was high in Openness to Experience (OR = 5.43), followed by high partner Openness (OR = 2.53) or high Openness in both the pwMCI and partner (OR = 2.31). In sum, when the pwMCI possessed both better cognitive status and openness to new experience they were better able to master a cognitive rehabilitation tool for MCI.

Procedural Learning in Individuals with Amnestic Mild Cognitive Impairment and Alzheimer's Dementia: a Systematic Review and Meta-analysis.

The notion that procedural learning and memory is spared in Alzheimer's disease (AD) has important implications for interventions aiming to build on intact cognitive functions. However, despite these clinical implications, there are mixed findings in the literature about whether or not procedural learning remains intact. This meta-analysis examines the standard mean difference of all published studies regarding procedural learning in AD dementia or amnestic Mild Cognitive Impairment (aMCI) compared to cognitively healthy older adults. Additionally, we conducted statistical equivalence analyses. Our systematic review showed that only a limited number of studies (k = 17) have compared procedural learning between individuals with aMCI or AD dementia and healthy controls. Our meta-analysis, which synthesized these studies, demonstrated that while procedural learning performance was not statistically equivalent between individuals with aMCI or AD dementia, and healthy older adults, the difference was clinically and statistically trivial. Although larger studies are needed, the present findings suggest that procedural learning does appear to remain spared in aMCI and AD dementia.

Truly Cross-fit: The Association of Exercise and Clinical Outcomes: Introduction to a JINS Special Section.

We introduce a JINS special section inspired by a symposium presented at INS 2020 in Denver. The symposium was entitled Truly Cross-fit: The Association of Exercise and Cognitive Reserve. The collection of papers herein spans diverse methods, a range of developmental and clinical conditions, and a variety of outcomes all reflecting on the association of exercise and cognition-related outcomes. Taken together, the studies in this Special Section direct us to the variety of dimensions to be considered in understanding this association including what mode, intensity, duration, and timing of physical activity and aspects of age, sex, genetics, baseline characteristics, and disease status moderate these findings. We hope this Special Section will not only provide a framing for important future research on exercise and clinical outcomes but also inspiration to pursue them.

Comparative Effects of Physical Exercise and Other Behavioral Interventions on Functional Status Outcomes in Mild Cognitive Impairment.

OBJECTIVES: Lifestyle modifications for those with mild cognitive impairment (MCI) may promote functional stability, lesson disease severity, and improve well-being outcomes such as quality of life. The current analysis of our larger comparative effectiveness study evaluated which specific combinations of lifestyle modifications offered as part of the Mayo Clinic Healthy Action to Benefit Independence in Thinking (HABIT) program contributed to the least functional decline in people with MCI (pwMCI) over 18 months. METHODS: We undertook to compare evidence-based interventions with one another rather than to a no-treatment control group. The interventions were five behavioral treatments: computerized cognitive training (CCT), yoga, Memory Support System (MSS) training, peer support group (SG), and wellness education (WE), each delivered to both pwMCI and care partners, in a group-based program. To compare interventions, we randomly withheld one of the five HABIT® interventions in each of the group sessions. We conducted 24 group sessions with between 8 and 20 pwMCI-partner dyads in a session. RESULTS: Withholding yoga led to the greatest declines in functional ability as measured by the Functional Activities Questionnaire and Clinical Dementia Rating. In addition, memory compensation (calendar) training and cognitive exercise appeared to have associations (moderate effect sizes) with better functional outcomes. Withholding SG or WE appeared to have little effect on functioning at 18 months. CONCLUSIONS: Overall, these results add to the growing literature that physical exercise can play a significant and lasting role in modifying outcomes in a host of medical conditions, including neurodegenerative diseases.

Clinical Care and Unmet Needs of Individuals With Dementia With Lewy Bodies and Caregivers: An Interview Study.

BACKGROUND: Patient-centered care requires understanding patient preferences and needs, but research on the clinical care preferences of individuals living with dementia and caregivers is sparse, particularly in dementia with Lewy bodies (DLB). METHODS: Investigators conducted telephone interviews with individuals living with DLB and caregivers from a Lewy body dementia specialty center. Interviews employed a semistructured questionnaire querying helpful aspects of care and unmet needs. Investigators used a qualitative descriptive approach to analyze transcripts and identify themes. RESULTS: Twenty individuals with DLB and 25 caregivers participated. Twenty-three of the caregivers were spouses, 2 were daughters. Aspects of clinical care valued by individuals with DLB and caregivers included clinician time, diagnosis, education, symptom management, communication, and caring staff. Unmet needs or challenges included patient/caregiver education, education of nonspecialist clinicians and community care providers, scheduling difficulties, caregiver support, financial concerns, assistance with advance care planning and finding local resources, and effective treatments for DLB symptoms. CONCLUSION AND RELEVANCE: Improving care for individuals with DLB and their families will require a multipronged strategy including education for nonspecialist care providers, increasing specialty care access, improved clinical care services, research to support disease prognosis and treatment decisions, and local and national strategies for enhanced caregiver support.

Memory Support System training in mild cognitive impairment: Predictors of learning and adherence.

This study aimed to identify predictors of learning and adherence to a previously validated compensatory calendar and note-taking system (Memory Support System; MSS) in persons with amnestic mild cognitive impairment (aMCI). Age, education, global cognition, depression, and memory-related self-efficacy were studied as predictors of individuals' ability to learn the use of the MSS during the two-week training and of their adherence to the MSS 6, 12, and 18 months after training. How well an individual was able to learn the use of the MSS was itself examined as a predictor of adherence. Two-hundred-and-fifteen older adults with aMCI and their study partners (e.g., spouse, adult child) received MSS training one-hour daily for 10 days. Ordinal logistic regression analyses indicated that (1) global cognition predicted MSS learning at end of training, and (2) MSS learning at end of trainng predicted MSS adherence at 6, 12, and 18 months post-training. The current study suggests that offering compensatory strategies as early as possible for those with MCI might be of most benefit, and might have implications for long-term adherence.

Doctor, Should I Use Computer Games to Prevent Dementia?

Commercial advertising of computerized "brain games" may result in clinicians being asked whether brain games prevent dementia. To address this question, we conducted a review of computerized cognitive training (CCT) interventions in older adults with Mild Cognitive Impairment (MCI). Studies were identified using a PubMed and PSYCinfo search for review articles. Within 11 review articles we identified 15 unique studies. Nine of these studies used commercially available "brain games" as their primary CCT intervention. Nine of 12 studies that examined the effect of CCT on episodic memory performance showed significant improvements in this domain. Furthermore, four of six studies that examined mood and or anxiety showed improvements in these domains following a CCT intervention. While more than double the amount of time was spent on the training that used commercially available "brain games" versus those designed by investigators, there were no differences in outcomes. Overall, it appears that "brain games" may modestly benefit aspects of cognition and aspects of mood in patients presenting with MCI. However, there is no direct evidence from the studies presented here that "brain games"/CCT can prevent dementia. We present recommendations to consider when discussing "brain games" with persons with MCI.

Development and Testing of a Neuropsychiatric Symptoms Model in Mild Cognitive Impairment.

Neuropsychiatric symptoms are prevalent in individuals with mild cognitive impairment (MCI) and have a significant detrimental effect on health and quality of life. Identifying factors that contribute to their occurrence may enable prompt treatment and intervention. The current study entails the development and testing of a biopsychosocially based model to assist nurses in the identification of individuals with MCI who are most likely to experience symptoms of depression, apathy, and/or anxiety. Factors within the biological and sociodemographic domains of the Neuropsychiatric Symptoms in MCI (NPSMCI) model were tested using multivariate logistic regression analyses. Findings suggest that age, presence of an e4 allele of the apolipoprotein E gene, living situation, and degree of comorbid illness were associated with the occurrence of symptoms of depression and apathy. Further testing and refinement are necessary, but the findings provide guidance to nurses and alert them to assess individuals most likely to experience these symptoms. [Journal of Gerontological Nursing, 44(1), 21-30.].

A pilot randomized trial of two cognitive rehabilitation interventions for mild cognitive impairment: caregiver outcomes.

OBJECTIVE: This study aims to provide effect size estimates of the impact of two cognitive rehabilitation interventions provided to patients with mild cognitive impairment: computerized brain fitness exercise and memory support system on support partners' outcomes of depression, anxiety, quality of life, and partner burden. METHODS: A randomized controlled pilot trial was performed. RESULTS: At 6 months, the partners from both treatment groups showed stable to improved depression scores, while partners in an untreated control group showed worsening depression over 6 months. There were no statistically significant differences on anxiety, quality of life, or burden outcomes in this small pilot trial; however, effect sizes were moderate, suggesting that the sample sizes in this pilot study were not adequate to detect statistical significance. CONCLUSION: Either form of cognitive rehabilitation may help partners' mood, compared with providing no treatment. However, effect size estimates related to other partner outcomes (i.e., burden, quality of life, and anxiety) suggest that follow-up efficacy trials will need sample sizes of at least 30-100 people per group to accurately determine significance. Copyright © 2017 John Wiley & Sons, Ltd.

MAPT haplotype H1G is associated with increased risk of dementia with Lewy bodies.

INTRODUCTION: The MAPT H1 haplotype has been associated with several neurodegenerative diseases. We were interested in exploring the role of MAPT haplotypic variation in risk of dementia with Lewy bodies (DLB). METHOD: We genotyped six MAPT haplotype tagging SNPs and screened 431 clinical DLB cases, 347 pathologically defined high-likelihood DLB cases, and 1049 controls. RESULT: We performed haplotypic association tests and detected an association with the protective H2 haplotype in our combined series (odds ratio [OR] = 0.75). We fine-mapped the locus and identified a relatively rare haplotype, H1G, that is associated with an increased risk of DLB (OR = 3.30, P = .0017). This association was replicated in our pathologically defined series (OR = 2.26, P = .035). DISCUSSION: These results support a role for H1 and specifically H1G in susceptibility to DLB. However, the exact functional variant at the locus is still unknown, and additional studies are warranted to fully explain genetic risk of DLB at the MAPT locus.

TDP-43 is a key player in the clinical features associated with Alzheimer's disease.

The aim of this study was to determine whether the TAR DNA-binding protein of 43 kDa (TDP-43) has any independent effect on the clinical and neuroimaging features typically ascribed to Alzheimer's disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred and forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred and ninety-five (57%) cases were TDP-positive. After accounting for age, apolipoprotein ε4 and other pathologies, TDP-43 had a strong effect on cognition, memory loss and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.

Mild cognitive impairment: a concept and diagnostic entity in need of input from neuropsychology.

This virtual issue consists of studies previously published in the Journal of the International Neuropsychological Society and selected on the basis of their content related to one of the most highly researched concepts in behavioral neurology and neuropsychology over the past decade: mild cognitive impairment (MCI). The reliance on cognitive screening measures, staging-based rating scales, and limited neuropsychological testing in diagnosing MCI across most research studies may miss individuals with subtle cognitive declines or mis-diagnose MCI in those who are otherwise cognitively normal on a broader neuropsychological battery of tests. The assembled articles highlight the perils of relying on these conventional criteria for MCI diagnosis and reveal how the reliability of diagnosis is improved when sound neuropsychological approaches are adopted. When these requirements are met, we illustrate with a second series of articles that neuropsychological measures associate strongly with biomarkers and often reflect pathology beyond or instead of typical AD distributions. The final set of articles reveal that people with MCI demonstrate mild but identifiable functional difficulties, and a challenge for neuropsychology is how to incorporate this information to better define MCI and distinguish it from early dementia. Neuropsychology is uniquely positioned to improve upon the state of the science in MCI research and practice by providing critically important empirical information on the specific cognitive domains affected by the predominant neurodegenerative disorders of late life as well as on the diagnostic decision-making strategies used in studies. When such efforts to more comprehensively assess neuropsychological functions are undertaken, better characterizations of spared and impaired cognitive and functional abilities result and lead to more convincing associations with other biomarkers as well as to prediction of clinical outcomes.

Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects.

BACKGROUND: Genetic variants at the CLU, CR1, and PICALM loci associate with risk for late-onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects. METHODS: We pursued an association study between single nucleotide polymorphism genotypes at the CLU, CR1, and PICALM loci and memory endophenotypes. We assessed black subjects (AA series: 44 with LOAD and 224 control subjects) recruited at Mayo Clinic Florida and whites recruited at Mayo Clinic Minnesota (RS series: 372 with LOAD and 1690 control subjects) and Florida (JS series: 60 with LOAD and 529 control subjects). Single nucleotide polymorphisms at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361), and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall, Logical Memory delayed recall, Logical Memory percent retention, Visual Reproduction immediate recall, Visual Reproduction delayed recall, and Visual Reproduction percent retention scores from the Wechsler Memory Scale-Revised using multivariable linear regression analysis, adjusting for age at exam, sex, education, and apolipoprotein E ε4 dosage. RESULTS: We identified nominally significant or suggestive associations between the LOAD-risky CR1 variants and worse Logical Memory immediate recall scores in blacks (P = .068-.046, ß = -2.7 to -1.2). The LOAD-protective CLU variant is associated with better logical memory endophenotypes in white subjects (P = .099-.027, ß = 0.31-0.93). The CR1 associations persisted when the control subjects from the AA series were assessed separately. The CLU associations appeared to be driven by one of the white series (RS) and were also observed when the control subset from RS was analyzed. CONCLUSION: These results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in blacks. In addition, the CLU LOAD-protective variant may confer enhanced memory in whites. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD.

Multimodal cognitive and behavioral interventions for patients with MCI: a systematic review and meta-analysis on cognition and mood.

Background: Research has increasingly suggested a benefit to combining multiple cognitive or behavioral strategies in a single treatment program for cognitively impaired older adults. Therefore, this systematic review and meta-analysis aimed to summarize results on the effects of multimodal cognitive and behavioral interventions versus control conditions on changes in cognition and mood in patients with mild cognitive impairment (pwMCI). Methods: The review followed a general PRISMA guideline for systematic literature review with a format consisting of participants, interventions, comparators, and outcomes (PICO). Multilevel meta-analyses of aggregated efficacy were performed to assess the pooled effect sizes for cognitive and mood outcomes. Risk-of-bias, heterogeneity across studies, and publication bias were assessed for each outcome. Results: After primary and reference searches, 18 studies with low or some concerns of risk of bias were included. Low heterogeneity was found for mood and cognition. Funnel plots did not indicate publication bias. All the studies assessed changes in cognition (n = 1,555) while seven studies with mood outcomes (n = 343) were included. Multilevel meta-analyses demonstrated moderate effect (Hedge's g = 0.44, 95% CI = [0.21-0.67]) in cognitive outcomes and large effect in mood (g = 0.65, 95% CI = [0.37-0.93]). Subdomain analyses found low-moderate effects in global cognition, verbal and non-verbal memory, executive function, visuospatial abilities, and semantic fluency (0.20 < g < 0.50). Conclusion: These findings showed comparable to larger effects of multimodal cognitive and behavioral interventions on cognition than pharmacological treatment. Future studies should focus on the longitudinal effects of multimodal interventions in delaying dementia.Systematic review registration: PROSEPRO, CRD42022349297.

Association of education attainment, smoking status, and alcohol use disorder with dementia risk in older adults: a longitudinal observational study.

BACKGROUND: Previous research on the risk of dementia associated with education attainment, smoking status, and alcohol use disorder (AUD) has yielded inconsistent results, indicating potential heterogeneous treatment effects (HTEs) of these factors on dementia risk. Thus, this study aimed to identify the important variables that may contribute to HTEs of these factors in older adults. METHODS: Using 2005-2021 data from the National Alzheimer's Coordinating Center (NACC), we included older adults (≥ 65 years) with normal cognition at the first visit. The exposure of interest included college education or above, current smoking, and AUD and the outcome was all-cause dementia. We applied doubly robust learning to estimate risk differences (RD) and 95% confidence intervals (CI) between exposed and unexposed groups in the overall cohort and subgroups identified through a decision tree model. RESULTS: Of 10,062 participants included, 929 developed all-cause dementia over a median 4.4-year follow-up. College education or above was associated with a lower risk of all-cause dementia in the overall population (RD, -1.5%; 95%CI, -2.8 to -0.3), especially among the subpopulations without hypertension, regardless of the APOE4 status. Current smoking was not related to increased dementia risk overall (2.8%; -1.5 to 7.2) but was significantly associated with increased dementia risk among men with (21.1%, 3.1 to 39.1) and without (8.4%, 0.9 to 15.8) cerebrovascular disease. AUD was not related to increased dementia risk overall (2.0%; -7.7 to 11.7) but was significantly associated with increased dementia risk among men with neuropsychiatric disorders (31.5%; 7.4 to 55.7). CONCLUSIONS: Our studies identified important factors contributing to HTEs of education, smoking, and AUD on risk of all-cause dementia, suggesting an individualized approach is needed to address dementia disparities.