Introduction Despite the association of vitamin D deficiency with incident dementia, the role of supplementation is unclear. We prospectively explored associations between vitamin D supplementation and incident dementia in 12,388 dementia‐free persons from the National Alzheimer's Coordinating Center. Methods Baseline exposure to vitamin D was considered D+; no exposure prior to dementia onset was considered D−. Kaplan–Meier curves compared dementia‐free survival between groups. Cox models assessed dementia incidence rates across groups, adjusted for age, sex, education, race, cognitive diagnosis, depression, and apolipoprotein E ( APOE ) ε4. Sensitivity analyses examined incidence rates for each vitamin D formulation. Potential interactions between exposure and model covariates were explored. Results Across all formulations, vitamin D exposure was associated with significantly longer dementia‐free survival and lower dementia incidence rate than no exposure (hazard ratio = 0.60, 95% confidence interval: 0.55–0.65). The effect of vitamin D on incidence rate differed significantly across the strata of sex, cognitive status, and APOE ε4 status. Discussion Vitamin D may be a potential agent for dementia prevention. Highlights In a prospective cohort study, we assessed effects of Vitamin D on dementia incidence in 12,388 participants from the National Alzheimer's Coordinating Center dataset. Vitamin D exposure was associated with 40% lower dementia incidence versus no exposure. Vitamin D effects were significantly greater in females versus males and in normal cognition versus mild cognitive impairment. Vitamin D effects were significantly greater in apolipoprotein E ε4 non‐carriers versus carriers. Vitamin D has potential for dementia prevention, especially in the high‐risk strata.

BackgroundMild behavioral impairment (MBI) is a validated neurobehavioral syndrome describing emergent and persistent neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. In cognitively normal older adults MBI is associated with positron emission tomography and cerebrospinal fluid measured amyloid‐β and tau, the characteristic hallmarks of Alzheimer’s disease (AD). Plasma p‐tau181 is a blood‐based biomarker recently identified as an accessible alternative for in‐vivo detection of AD pathologies. So far, no study has explored plasma p‐tau181 in MBI. Here, we investigated the cross‐sectional and longitudinal associations of MBI with plasma p‐tau181 in dementia‐free older adults, and the associations of MBI with risk of AD.MethodThe sample included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who were cognitively unimpaired (CU) or had mild cognitive impairment (MCI). MBI status was determined using NPS total score at baseline and year‐one. NPS scores were derived from the Neuropsychiatric Inventory and categorized as persistent NPS (i.e., MBI, score>0 at both visits); transient/impersistent NPS (score>0 at only one visit); and no NPS (score = 0 at both visits). Cross‐sectionally, linear regression models were fitted with p‐tau181 as dependent variable and NPS profile as independent variable. Longitudinally, Cox proportional hazards models examined associations between NPS profile and incident dementia. Multilevel linear mixed effect (MLME) models assessed the associations between NPS status, categorized as within‐person NPS variability (impersistent NPS, not consistent with MBI) and between‐person NPS burden (persistent NPS, consistent with MBI), and p‐tau181 across four years.ResultThe final sample consisted of 571 dementia‐free participants (age 72.2, 46.8% females). Compared to no NPS, participants with persistent NPS but not transient NPS had higher baseline plasma ptau‐181 levels. Longitudinally, persistent NPS were associated with 3.42 times greater risk for dementia compared to no NPS. MLME analyses on annual measures of NPS and p‐tau181 over four years demonstrated that only the between‐person NPS measure was associated with higher p‐tau181 levels.ConclusionThese findings extend the evidence base that MBI is a clinically relevant syndrome associated with the AD pathophysiological process. Incorporating MBI into clinical screening may help to identify those with preclinical or prodromal AD.

Background: In the absence of clear disease-modifying drugs for dementia, modifiable risk factors have been explored to slow disease progression. Vitamin D deficiency is a risk factor, associated with higher risk of dementia. However, the role of vitamin D supplementation has been a subject of debate. Here we explored longitudinal associations between vitamin D supplementation and incident dementia in dementia-free older adults from the National Alzheimer's Coordinating Center (NACC).Method: All participants had normal cognition (NC) or mild cognitive impairment (MCI) at baseline. Exposure to vitamin D supplementation was based on the NACC A4 medication form. Three vitamin D formulations were considered: calcium-vitamin D, cholecalciferol, and ergocalciferol. For the primary analysis, participants with baseline exposure to any supplement were considered D+, while those without any exposure in advance of dementia diagnosis were considered D-. Kaplan-Meier curves were generated to compare ten-year dementia-free survival between D+ and D-groups. Cox proportional hazards models were implemented to assess the risk of dementia across vitamin D exposure groups, adjusted for baseline age, sex, years of education, race, APOE-e4 status, cognitive diagnosis, and depression. To distinguish the associations of various vitamin D formulations with risk of dementia, sensitivity analyses were conducted to independently examine the effect of each formulation (calcium-vitamin D, cholecalciferol, ergocalciferol). Result:The final sample consisted of 2836 D+ (mean age = 72.1; 68.4% female) and 5075 D-participants (mean age = 72; 45.1% female). MCI was more prevalent in D-vs D+ participants (35.7% vs 26.8%; p<0.001). Similarly, depression was more prevalent in D-vs D+ participants (6.9% vs. 4.3%, p<0.001). Across all three vitamin D formulations, exposure was associated with longer dementia-free survival (p<0.001) and lower adjusted hazard ratio (HR) for incident dementia compared to no exposure (calcium-

Background: Mild behavioural impairment (MBI) is a neurobehavioural syndrome characterized by the onset and persistence of neuropsychiatric symptoms (NPS) in later life. While the ATN framework provides a robust overview of Alzheimer's pathology, it does not fully capture the impact of small-vessel cerebrovascular disease in the pathogenesis of dementia. White matter hyperintensities (WMH) may independently contribute to the development of Alzheimer's dementia and predict risk of incident dementia in mild cognitive impairment (MCI). Few studies have established the link between NPS and WMH in MCI populations. Method:We included 760 participants from the French MEMENTO study with MCI and WMH data. WMH volumetry on T 2 -weighted fluid attenuated inversion recovery images was identified using WHASA software, visually verified with the Fazekas and Schmidt scale, and expressed in cm 3 . Mean age was 72.7 (SD 8.0) and 57.9% of participants were female. Neuropsychiatric Inventory items were transformed to MBI domains using a published algorithm. MBI status was based on symptom persistence: NPS at both baseline and 6-months was considered MBI+ (n = 227), whereas nonpersistent NPS (i.e., NPS at either time point but not both) or no NPS at either baseline or 6-months was considered MBI-(n=549). We investigated the association between MBI status and the outcome variable, WMH, using a linear regression model adjusted for age, sex, education, Mini-Mental Status Exam (MMSE) score, and total intracranial volume.Result: MBI was present in 29.9% of participants (n = 227). MBI+ (i.e., persistent NPS) was significantly associated with lower MMSE score (p < 0.001) and male sex (p = 0.025). Compared to MBI-, MBI+ was associated with 9.9% higher WMH volume [p = 0.006 (95% CI 2.8% to 18%), Table 1]. Conclusion:In a memory clinic sample of older adults with MCI, MBI+, operationalized as persistent NPS, is associated with higher WMH. These findings extend the evidence base linking MBI with known dementia biomarkers and raise the possibility that some forms of MBI can be caused by vascular brain injury.

Background Hearing loss and mild behavioral impairment (MBI) are both early warning signs of cognitive decline and dementia in older adults and have been recommended for use as non‐cognitive markers of dementia. To date, few studies have directly investigated the relationship between these two markers. Method Baseline data from 219 non‐demented participants (10 cognitively normal; CN, 48 subjective cognitive decline; SCD, 161 mild cognitive impairment; MCI) in the COMPASS‐ND study (February 2020 release) were analyzed. Hearing impairment was measured in three ways: with a 10‐item self‐report measure using the Hearing Handicap Inventory for the Elderly – Screening Version (HHIE‐S), with a speech and noise test using the Canadian Digit Triplet Test (CDTT), and with screening audiometry using 2 discrete input levels at 2000 Hz to generate 6 hearing loss categories. Global and domain‐specific MBI burden was approximated using the Neuropsychiatric Inventory Questionnaire (NPI‐Q) with a published algorithm. Multivariable linear regressions were conducted to examine the association between the three hearing impairment measures and global MBI burden, adjusting for sex, age, education, hearing aid use, and Montreal Cognitive Assessment (MoCA) score or diagnosis. Multivariable logistic regressions were used to investigate whether the hearing variables could predict MBI domains. Result Half of all participants showed MBI symptoms (Figure 1). Greater self‐reported hearing impairment measured by the HHIE‐S was significantly associated with greater global MBI burden and the presence of apathy and affective dysregulation when controlling for global cognition or diagnosis (Table 1). These associations remained significant in analyses restricted to MCI alone. Performance on CDTT and screening audiometry, were not associated with global or domain‐specific MBI burden. Conclusion The HHIE‐S, which was designed to capture the emotional and social aspects of hearing loss, was positively related to global MBI burden and more specifically to apathy and affect. Unlike audiometry and speech and noise measures, self‐reported measures of hearing impairment can be influenced by age, sex, other comorbidities, and social factors. Our findings underscore that value of self‐report measures of hearing impairment as distinct from audiometry and speech and noise measures in their association with behavioral impairment and as non‐cognitive markers of dementia.