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Abstract Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction—driven by genes different from APOE—which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

Abstract Introduction It is unclear how rates of white matter microstructural decline differ between normal aging and abnormal aging. Methods Diffusion MRI data from several well‐established longitudinal cohorts of aging (Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], Vanderbilt Memory & Aging Project [VMAP]) were free‐water corrected and harmonized. This dataset included 1723 participants (age at baseline: 72.8 ± 8.87 years, 49.5% male) and 4605 imaging sessions (follow‐up time: 2.97 ± 2.09 years, follow‐up range: 1–13 years, mean number of visits: 4.42 ± 1.98). Differences in white matter microstructural decline in normal and abnormal agers was assessed. Results While we found a global decline in white matter in normal/abnormal aging, we found that several white matter tracts (e.g., cingulum bundle) were vulnerable to abnormal aging. Conclusions There is a prevalent role of white matter microstructural decline in aging, and future large‐scale studies in this area may further refine our understanding of the underlying neurodegenerative processes. HIGHLIGHTS Longitudinal data were free‐water corrected and harmonized. Global effects of white matter decline were seen in normal and abnormal aging. The free‐water metric was most vulnerable to abnormal aging. Cingulum free‐water was the most vulnerable to abnormal aging.

Abstract INTRODUCTION It is necessary to accurately account for systematic differences due to variability in scanners, radiotracers, and acquisition protocols in multisite studies combining amyloid imaging data. METHODS We propose Probabilistic Estimation for Across‐batch Compatibility Enhancement (PEACE), a fully Bayesian multimodal extension of the widely used ComBat harmonization model, and we apply it to harmonize regional amyloid positron emission tomography data from two scanners. RESULTS Simulations show that PEACE recovers true harmonized values better than ComBat, even for unimodal data. PEACE harmonization of multiscanner regional amyloid imaging data yields results that agree better with longitudinal data compared to ComBat, without removing the known biological effects of age or apolipoprotein E genotype. DISCUSSION PEACE outperforms ComBat in both unimodal and bimodal contexts, is applicable to multisite amyloid imaging data, and holds promise for the harmonization of other neuroimaging data over ComBat. HIGHLIGHTS We introduce PEACE, a fully Bayesian multimodal extension of ComBat harmonization. Simulations show that PEACE recovers true harmonized values better than ComBat. PEACE accurately harmonizes multiscanner regional amyloid imaging data.

Abstract Introduction Beta‐amyloid (Aβ) plaque deposition is a biomarker of preclinical Alzheimer's disease (AD). Impairments in sensory function are associated with cognitive decline. We sought to investigate the relationship between PET‐indicated Aβ deposition and sensory impairment. Methods Using data from 174 participants ≥55 years in the Baltimore Longitudinal Study of Aging, we analyzed associations between sensory impairments and Aβ deposition measured by PET and Pittsburgh Compound B (PiB) mean cortical distribution volume ratio (cDVR). Results The combinations of hearing and proprioceptive impairment and hearing, vision, and proprioceptive impairment, were positively correlated with cDVR (β = 0.087 and p = 0.036, β = 0.110 and p = 0.018, respectively). In stratified analyses of PiB+ participants, combinations of two, three, and four sensory impairments (all involving proprioception) were associated with higher cDVR. Discussion Our findings suggest a relationship between multi‐sensory impairment (notably proprioceptive impairment) and Aβ deposition, which could reflect sensory impairment as an indicator or potentially a risk factor for Aβ deposition.

Abstract Introduction White matter microstructure may be abnormal along the Alzheimer's disease (AD) continuum. Methods Diffusion magnetic resonance imaging (dMRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 627), Baltimore Longitudinal Study of Aging (BLSA, n = 684), and Vanderbilt Memory & Aging Project (VMAP, n = 296) cohorts were free‐water (FW) corrected and conventional, and FW‐corrected microstructural metrics were quantified within 48 white matter tracts. Microstructural values were subsequently harmonized using the Longitudinal ComBat technique and inputted as independent variables to predict diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI], AD). Models were adjusted for age, sex, race/ethnicity, education, apolipoprotein E (APOE) ε4 carrier status, and APOE ε2 carrier status. Results Conventional dMRI metrics were associated globally with diagnostic status; following FW correction, the FW metric itself exhibited global associations with diagnostic status, but intracellular metric associations were diminished. Discussion White matter microstructure is altered along the AD continuum. FW correction may provide further understanding of the white matter neurodegenerative process in AD. Highlights Longitudinal ComBat successfully harmonized large‐scale diffusion magnetic resonance imaging (dMRI) metrics. Conventional dMRI metrics were globally sensitive to diagnostic status. Free‐water (FW) correction mitigated intracellular associations with diagnostic status. The FW metric itself was globally sensitive to diagnostic status. Multivariate conventional and FW‐corrected models may provide complementary information.

Abstract Introduction Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years. Methods Using 18F‐AV‐1451 (18F‐flortaucipir) positron emission tomography, we evaluated tau pathology in 54 cognitively normal participants (mean age: 77.5 years, SD: 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between positron emission tomography signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status. Results Greater age, male sex, black race, and amyloid positivity were associated with higher 18F‐AV‐1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume (β = −1.124, SE = 0.485, P = .025) and a steeper decline in memory performance (β = −0.086, SE = 0.039, P = .029). Discussion Assessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimer's disease.

Abstract Introduction Characterization of longitudinal trajectories of biomarkers implicated in sporadic Alzheimer's disease (AD) in decades before clinical diagnosis is important for disease prevention and monitoring. Methods We used a multivariate Bayesian model to temporally align 1369 Alzheimer's disease Neuroimaging Initiative participants based on the similarity of their longitudinal biomarker measures and estimated a quantitative template of the temporal evolution of cerebrospinal fluid Aβ1−42, p‐tau181p, and t‐tau and hippocampal volume, brain glucose metabolism, and cognitive measurements. We computed biomarker trajectories as a function of time to AD dementia and predicted AD dementia onset age in a disjoint sample. Results Quantitative template showed early changes in verbal memory, cerebrospinal fluid Aβ1–42 and p‐tau181p, and hippocampal volume. Mean error in predicted AD dementia onset age was

Cardiovascular disease (CVD) is associated with a higher risk of developing dementia. Studies have found that vascular risk factors are associated with greater amyloid-β (Aβ) and tau burden, which are hallmark neuropathologies of Alzheimer's disease (AD). Evidence for these associations during the preclinical stages of AD, when Aβ and tau pathologies first become detectable, is mixed. Quantifying the effect of vascular risk among cognitively normal individuals can help focus the efforts to develop therapeutic approaches aimed at modifying the course of preclinical AD.Using Bayesian analysis, we examined the relationship of Aβ and tau pathology with concurrent vascular risk among 87 cognitively normal individuals (median age 77, interquartile range 70–83) in the Baltimore Longitudinal Study of Aging. We quantified vascular risk as the probability of developing CVD within 10 years using published equations from the Framingham Heart Study. Aβ and tau pathologies were measured using positron emission tomography.As expected, Aβ positive participants had greater tau in the entorhinal cortex (EC) and inferior temporal gyrus (ITG) (difference in means = 0.09, p

BackgroundWhile Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.Methods and findingsWe used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = 4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.ConclusionsWe combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.

Abstract Introduction Higher energetic costs for mobility predict gait speed decline. Slow gait is linked to cognitive decline and Alzheimer's disease (AD). Whether the energetic cost of walking is linked to AD pathology is unknown. We investigated the cross‐sectional association between the energetic cost of walking, gait speed, and amyloid beta (Aβ) status (+/−) in older adults. Methods One hundred forty‐nine cognitively normal adults (56% women, mean age 77.5 ± 8.4 years) completed customary‐paced walking assessments with indirect calorimetry and 11C‐Pittsburgh compound B positron emission tomography. Logistic regression models examined associations adjusted for demographics, body composition, comorbid conditions, and apolipoprotein E ε4. Results Each 0.01 mL/kg/m greater energy cost was associated with 18% higher odds of being Aβ+ (odds ratio [OR] = 1.18; 95% confidence interval [CI]: 1.04 to 1.34; P = .011). These findings were not observed when investigating gait speed (OR = 0.99; 95% CI: 0.97 to 1.01; P = .321). Discussion High energetic cost of walking is linked to AD pathology and may be a potential target for therapeutic intervention.

Studies suggest that concussions may be related to increased risk of neurodegenerative diseases, such as Chronic Traumatic Encephalopathy and Alzheimer's Disease. Most neuroimaging studies show effects of concussions in frontal and temporal lobes of the brain, yet the long-term impacts of concussions on the aging brain have not been well studied. We examined neuroimaging data from 51 participants (mean age at first imaging visit=65.1 ± 11.23) in the Baltimore Longitudinal Study of Aging (BLSA) who reported a concussion in their medical history an average of 23 years prior to the first imaging visit, and compared them to 150 participants (mean age at first imaging visit=66.6 ± 10.97) with no history of concussion. Participants underwent serial structural MRI over a mean of 5.17±6.14 years and DTI over a mean of 2.92±2.22 years to measure brain structure, as well as 15O-water PET over a mean of 5.33±2.19 years to measure brain function. A battery of neuropsychological tests was also administered over a mean of 11.62±7.41 years. Analyses of frontal and temporal lobe regions were performed to examine differences in these measures between the concussion and control groups at first imaging visit and in change over time. Compared to those without concussion, participants with a prior concussion had greater brain atrophy in temporal lobe white matter and hippocampus at first imaging visit, which remained stable throughout the follow-up visits. Those with prior concussion also showed differences in white matter microstructure using DTI, including increased radial and axial diffusivity in the fornix/stria terminalis, anterior corona radiata, and superior longitudinal fasciculus at first imaging visit. In 15O-water PET, higher resting cerebral blood flow was seen at first imaging visit in orbitofrontal and lateral temporal regions, and both increases and decreases were seen in prefrontal, cingulate, insular, hippocampal, and ventral temporal regions with longitudinal follow-up. There were no significant differences in neuropsychological performance between groups. Most of the differences observed between the concussed and non-concussed groups were seen at the first imaging visit, suggesting that concussions can produce long-lasting structural and functional alterations in temporal and frontal regions of the brain in older individuals. These results also suggest that many of the reported short-term effects of concussion may still be apparent later in life.

Abstract Objective To test the hypothesis that among cognitively healthy individuals, distinct groups exist in terms of amyloid and phosphorylated‐tau accumulation rates; that if rapid accumulator groups exist, their membership can be predicted by Alzheimer's disease (AD) risk factors, and that time points of significant increase in AD protein accumulation will be evident. Methods The analysis reports data from 263 individuals from the BIOCARD and 184 individuals from the Baltimore Longitudinal Study of Aging with repeated cerebrospinal fluid (CSF) and positron emission tomography (PET) sampling, respectively. We used latent class mixed‐effect models to identify distinct classes of amyloid (CSF and PET) and p‐Tau (CSF) accumulation rates and generalized additive modeling to investigate non‐linear changes to AD biomarkers. Results For both amyloid and p‐Tau latent class models we confirmed the existence of two separate classes: accumulators and non‐accumulators. The accumulator and non‐accumulator groups differed significantly in terms of baseline AD protein levels and slope of change. APOE ε4 carrier status and episodic memory predicted amyloid class membership. Non‐linear models revealed time points of significant increase in the rate of amyloid and p‐Tau accumulation whereby APOE ε4 carrier status associated with earlier age at onset of rapid accumulation. Conclusions The current analysis demonstrates the existence of distinct classes of amyloid and p‐Tau accumulators. Predictors of class membership were identified but the overall accuracy of the models was modest, highlighting the need for additional biomarkers that are sensitive to early disease phenotypes.

Abstract Introduction Affective changes precede cognitive decline in mild Alzheimer's disease and may relate to increased connectivity in a “salience network” attuned to emotionally significant stimuli. The trajectory of affective changes in preclinical Alzheimer's disease, and its relationship to this network, is unknown. Methods One hundred one cognitively normal older adults received longitudinal assessments of affective symptoms, then amyloid‐PET. We hypothesized amyloid‐positive individuals would show enhanced emotional reactivity associated with salience network connectivity. We tested whether increased global connectivity in key regions significantly related to affective changes. Results In participants later found to be amyloid positive, emotional reactivity increased with age, and interpersonal warmth declined in women. These individuals showed higher global connectivity within the right insula and superior temporal sulcus; higher superior temporal sulcus connectivity predicted increasing emotional reactivity and decreasing interpersonal warmth. Conclusions Affective changes should be considered an early preclinical feature of Alzheimer's disease. These changes may relate to higher functional connectivity in regions critical for social‐emotional processing.

Background: An anatomical covariance analysis (ACA) enables to elucidate inter-regional connections on a group basis, but little is known about the connections among white matter structures or among gray and white matter structures. Effect of including multiple magnetic resonance imaging (MRI) modalities into ACA framework in detecting white-to-white or gray-to-white connections is yet to be investigated. New method: Proposed extended anatomical covariance analysis (eACA), analyzes correlations among gray and white matter structures (multi-structural) in various types of imaging modalities (T1-weighted images, T2 maps obtained from dual-echo sequences, and diffusion tensor images (DTI)). To demonstrate the capability to detect a disruption of the correlation network affected by pathology, we applied the eACA to two groups of cognitively-normal elderly individuals, one with (PiB+) and one without (PiB-) amyloid deposition in their brains. Results: The volume of each anatomical structure was symmetric and functionally related structures formed a cluster. The pseudo-T2 value was highly homogeneous across the entire cortex in the PiB- group, while a number of physiological correlations were altered in the PiB + group. The DTI demonstrated unique correlation network among structures within the same phylogenetic portions of the brain that were altered in the PiB + group. Comparison with Existing Method: The proposed eACA expands the concept of existing ACA to the connections among the white matter structures. The extension to other image modalities expands the way in which connectivity may be detected. Conclusion: The eACA has potential to evaluate alterations of the anatomical network related to pathological processes.

Objective: Amyloid positivity is a biomarker of AD pathology, yet the associations between amyloid positivity and brain volumetric changes, especially in the hippocampus, are inconsistent. We hypothesize that sex differences in associations may contribute to inconsistent findings among cognitively normal older adults. Methods: Using linear mixed effects models, we examined the association of amyloid positivity with prospective volumetric changes (mean = 3.3 visits) of parahippocampal gyrus (phg), hippocampus, entorhinal cortex (erc), precuneus, and fusiform gyrus among 171 Baltimore Longitudinal Study of Aging participants aged ≥55 years. Amyloid positivity was defined by a mean 11C-Pittsburgh Compound B (PiB) distribution volume ratio (DVR) cut-off of 1.062. All analyses included age, race, sex, education, APOE e4 carrier status, and two-way interactions of these covariates with time. Two-way interaction between sex and PiB+/− status and three-way interaction of sex and PiB+/− status with time were added to assess whether sex modified associations. Results: PiB+ status was associated with greater volumetric declines in the phg (β = −0.036, SE = 0.011, p = 0.001) and erc (β = −0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (β = −0.117, SE = 0.049, p = 0.019). PiB+ males had steeper rates of volumetric declines in phg (β = −0.051, SE = 0.013, p

Beta-amyloid (Aβ) plaque deposition is a key feature of Alzheimer’s disease (AD), and occurs years before the onset of symptoms. Aβ plaque deposition has been shown to be present in ~30% of cognitively normal older adults using amyloid C-11 labeled Pittsburgh Compound B (11C-PiB) Positron Emission Tomography (PET) imaging. Prior studies have reported a link between reduced vestibular function and poorer cognition in healthy older adults. It is unknown whether vestibular impairment occurs in association with AD pathology among individuals in the preclinical phase of AD, which could contribute to the observed association between vestibular and cognitive function in healthy older adults. Using the Baltimore Longitudinal Study of Aging (BLSA), we analyzed the association between a comprehensive set of vestibular function measures and PiB status in 98 healthy participants with a mean age of 77.3 (±8.26). We did not observe a significant relationship between any vestibular function measure and PiB status in cognitively-intact older adults in the BLSA. This finding suggests that Aβ deposition does not explain the observed association between reduced vestibular function and poorer cognition in healthy older adults.

Longitudinal analysis of magnetic resonance images of the human brain provides knowledge of brain changes during both normal aging as well as the progression of many diseases. Previous longitudinal segmentation methods have either ignored temporal information or have incorporated temporal consistency constraints within the algorithm. In this work, we assume that some anatomical brain changes can be explained by temporal transitions in image intensities. Once the images are aligned in the same space, the intensities of each scan at the same voxel constitute a temporal (or 4D) intensity trend at that voxel. Temporal intensity variations due to noise or other artifacts are corrected by a 4D intensity-based filter that smooths the intensity values where appropriate, while preserving real anatomical changes such as atrophy. Here smoothing refers to removal of sudden changes or discontinuities in intensities. Images processed with the 4D filter can be used as a pre-processing step to any segmentation method. We show that such a longitudinal pre-processing step produces robust and consistent longitudinal segmentation results, even when applying 3D segmentation algorithms. We compare with state-of-the-art 4D segmentation algorithms. Specifically, we experimented on three longitudinal datasets containing 4–12 time-points, and showed that the 4D temporal filter is more robust and has more power in distinguishing between healthy subjects and those with dementia, mild cognitive impairment, as well as different phenotypes of multiple sclerosis.

Purpose: Previously, we have shown that the SNP rs10932201 genotype of the cyclic AMP responsive element binding protein 1 gene (CREB1) contributes to individual differences in executive and memory function at the neural system and behavioral levels in healthy, young adults. However, longitudinal effects of CREB1 genotypes on cognition have not yet been addressed. Furthermore we were interested in replicating associations between CREB1 genotypes and human cognition in previous cross-sectional studies and explore whether APOE𝜀4 status might modify these relations.Materials and Methods: We investigated whether common, independent tag SNPs within CREB1 (rs2253206, rs10932201, rs6785) influence individual differences in age-related longitudinal change and level of executive function and memory performance independent of baseline age, sex, APOE𝜀4 status, and education. Our analysis included data from cognitively unimpaired older adults participating in the Baltimore Longitudinal Study of Aging. Eleven measures from six cognitive tests (sample sizes range 617–786) were analyzed using linear mixed effects and generalized estimating equations models. Mean baseline age ranged from 50 to 69 years and mean time of follow-up (interval) ranged from 8 to 22 years.Results: We found significant effects of all three CREB1 SNPs on performance level and/or longitudinal change in performance based on eight measures assessing semantic memory, episodic memory, or both executive function and semantic memory. SNP rs10932201 showed the most significant and largest effect (Cohen’s d = -0.70, p < 0.01) on age-related longitudinal decline of semantic memory. Additionally, we show interactions between all three CREB1 SNPs and APOE𝜀4 status on age-related longitudinal declines and levels of memory and executive function.Conclusion: Our results suggest that CREB1 genotypes independently and by interactions with APOE𝜀4 status contribute to individual differences in cognitive aging.