Mapping the gene network landscape of Alzheimer's disease through integrating genomics and transcriptomics.

Integration of multi-omics data with molecular interaction networks enables elucidation of the pathophysiology of Alzheimer's disease (AD). Using the latest genome-wide association studies (GWAS) including proxy cases and the STRING interactome, we identified an AD network of 142 risk genes and 646 network-proximal genes, many of which were linked to synaptic functions annotated by mouse knockout data. The proximal genes were confirmed to be enriched in a replication GWAS of autopsy-documented cases. By integrating the AD gene network with transcriptomic data of AD and healthy temporal cortices, we identified 17 gene clusters of pathways, such as up-regulated complement activation and lipid metabolism, down-regulated cholinergic activity, and dysregulated RNA metabolism and proteostasis. The relationships among these pathways were further organized by a hierarchy of the AD network pinpointing major parent nodes in graph structure including endocytosis and immune reaction. Control analyses were performed using transcriptomics from cerebellum and a brain-specific interactome. Further integration with cell-specific RNA sequencing data demonstrated genes in our clusters of immunoregulation and complement activation were highly expressed in microglia.

Neuroimaging-Derived Predicted Brain Age and Alcohol Use Among Community-Dwelling Older Adults.

OBJECTIVES: Observational studies have suggested that moderate alcohol use is associated with reduced risk of dementia. However, the nature of this association is not understood. We investigated whether light to moderate alcohol use may be associated with slower brain aging, among a cohort of older community-dwelling adults using a biomarker of brain age based on structural neuroimaging measures. DESIGN: Cross-sectional observational study. PARTICIPANTS: Well-characterized members of a longitudinal cohort study who underwent neuroimaging. We categorized the 163 participants (mean age 76.7 ± 7.7, 60% women) into current nondrinkers, light drinkers (1-7 drinks/week) moderate drinkers (>7-14 drinks/week), or heavier drinkers (>14 drinks/week). MEASUREMENTS: We calculated brain-predicted age using structural MRIs processed with the BrainAgeR program, and calculated the difference between brain-predicted age and chronological age (brain-predicted age difference, or brain-PAD). We used analysis of variance to determine if brain-PAD differed across alcohol groups, controlling for potential confounders. RESULTS: Brain-PAD differed across alcohol groups (F[3, 150] = 4.02; p = 0.009) with heavier drinkers showing older brain-PAD than light drinkers (by about 6 years). Brain-PAD did not differ across light, moderate, and nondrinkers. Similar results were obtained after adjusting for potentially mediating health-related measures, and after excluding individuals with a history of heavier drinking. DISCUSSION: Among this sample of healthy older adults, consumption of more than 14 drinks/week was associated with a biomarker of advanced brain aging. Light and moderate drinking was not associated with slower brain aging relative to non-drinking.

Alcohol use and cognitive aging in middle-aged men: The Vietnam Era Twin Study of Aging.

OBJECTIVE: To determine associations of alcohol use with cognitive aging among middle-aged men. METHOD: 1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003-2007 to 2016-2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1-4 drinks in past 14 days), light (5-14 drinks), moderate (15-28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors. RESULTS: Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by -0.21 SD (95% CI -0.35, -0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, -0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association. CONCLUSIONS: Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.

Associations between MRI-assessed locus coeruleus integrity and cortical gray matter microstructure.

The locus coeruleus (LC) is one of the earliest sites of tau pathology, making it a key structure in early Alzheimer's disease (AD) progression. As the primary source of norepinephrine for the brain, reduced LC integrity may have negative consequences for brain health, yet macrostructural brain measures (e.g. cortical thickness) may not be sensitive to early stages of neurodegeneration. We therefore examined whether LC integrity was associated with differences in cortical gray matter microstructure among 435 men (mean age = 67.5; range = 62-71.7). LC structural integrity was indexed by contrast-to-noise ratio (LCCNR) from a neuromelanin-sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi-shell diffusion technique, was used to characterize cortical microstructure, modeling total diffusion in restricted, hindered, and free water compartments. Higher LCCNR (greater integrity) was associated with higher hindered and lower free water diffusion in multiple cortical regions. In contrast, no associations between LCCNR and cortical thickness survived correction. Results suggest lower LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cytoarchitectural barriers due to broader neurodegenerative processes. These findings highlight the potential utility for LC imaging and advanced diffusion measures of cortical microstructure in assessing brain health and early identification of neurodegenerative processes.

Perceived discrimination and nativity status: risk of cognitive impairment among Latin American older adults.

OBJECTIVES: We examined the association between perceived discrimination and the risk of cognitive impairment with no dementia (CIND) and Alzheimer's disease and related dementias (ADRD) while considering the potential effects of nativity status. DESIGN: A prospective analysis of discrimination and nativity status with dementia and cognitive impairment was conducted among Latinx adults aged 51 years and older who participated in the Health and Retirement Study. SETTING: A national representative sample. PARTICIPANTS: A sample of 1,175 Latinx adults aged 51 years and older. MEASUREMENTS: Demographics, cognitive functioning, perceived discrimination, and nativity status (US-born vs. non-US born) were assessed. Traditional survival analysis methods (Fine and gray models) were used to account for the semi-competing risk of death with up to 10 years of follow-up. RESULTS: According to our results, neither everyday discrimination nor nativity status on their own had a statistically significant association with CIND/ADRD; however, non-US-born Latinx adults who reported no discrimination had a 42% lower risk of CIND/ADRD (SHR = 0.58 [0.41, 0.83], p = .003) than US-born adults. CONCLUSIONS: These results highlight the need for healthcare providers to assess for discrimination and provide support and resources for those experiencing discrimination. It also highlights the need for better policies that address discrimination and reduce health disparities.

Improved multimodal prediction of progression from MCI to Alzheimer's disease combining genetics with quantitative brain MRI and cognitive measures.

INTRODUCTION: There is a pressing need for non-invasive, cost-effective tools for early detection of Alzheimer's disease (AD). METHODS: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Cox proportional models were conducted to develop a multimodal hazard score (MHS) combining age, a polygenic hazard score (PHS), brain atrophy, and memory to predict conversion from mild cognitive impairment (MCI) to dementia. Power calculations estimated required clinical trial sample sizes after hypothetical enrichment using the MHS. Cox regression determined predicted age of onset for AD pathology from the PHS. RESULTS: The MHS predicted conversion from MCI to dementia (hazard ratio for 80th versus 20th percentile: 27.03). Models suggest that application of the MHS could reduce clinical trial sample sizes by 67%. The PHS alone predicted age of onset of amyloid and tau. DISCUSSION: The MHS may improve early detection of AD for use in memory clinics or for clinical trial enrichment. HIGHLIGHTS: A multimodal hazard score (MHS) combined age, genetics, brain atrophy, and memory. The MHS predicted time to conversion from mild cognitive impairment to dementia. MHS reduced hypothetical Alzheimer's disease (AD) clinical trial sample sizes by 67%. A polygenic hazard score predicted age of onset of AD neuropathology.

Markers of kidney function, genetic variation related to cognitive function, and cognitive performance in the UK Biobank.

BACKGROUND: Chronic kidney disease has been linked to worse cognition. However, this association may be dependent on the marker of kidney function used, and studies assessing modification by genetics are lacking. This study examined associations between multiple measures of kidney function and assessed effect modification by a polygenic score for general cognitive function. METHODS: In this cross-sectional study of up to 341,208 European ancestry participants from the UK Biobank study, we examined associations between albuminuria and estimated glomerular filtration rate based on creatinine (eGFRcre) or cystatin C (eGFRcys) with cognitive performance on tests of verbal-numeric reasoning, reaction time and visual memory. Adjustment for confounding factors was performed using multivariate regression and propensity-score matching. Interaction between kidney function markers and a polygenic risk score for general cognitive function was also assessed. RESULTS: Albuminuria was associated with worse performance on tasks of verbal-numeric reasoning (ß(points) = -0.09, p < 0.001), reaction time (ß(milliseconds) = 7.06, p < 0.001) and visual memory (ß(log errors) = 0.013, p = 0.01). A polygenic score for cognitive function modified the association between albuminuria and verbal-numeric reasoning with significantly lower scores in those with albuminuria and a lower polygenic score (p = 0.009). Compared to participants with eGFRcre ≥ 60 ml/min, those with eGFRcre < 60 ml/min had lower verbal-numeric reasoning scores and slower mean reaction times (verbal numeric reasoning ß = -0.11, p < 0.001 and reaction time ß = 6.08, p < 0.001 for eGFRcre < 60 vs eGFRcre ≥ 60). Associations were stronger using cystatin C-based eGFR than creatinine-based eGFR (verbal numeric reasoning ß = -0.21, p < 0.001 and reaction time ß = 11.21, p < 0.001 for eGFRcys < 60 vs eGFRcys ≥ 60). CONCLUSIONS: Increased urine albumin is associated with worse cognition, but this may depend on genetic risk. Cystatin C-based eGFR may better predict cognitive performance than creatinine-based estimates.

Alcohol use and cognitive performance: a comparison between Greece and the United States.

OBJECTIVES: To examine associations between alcohol use and cognitive performance among older adults in Greece and the United States, and assess potential differences due to differing drinking practices in the two countries. METHODS: Data came from Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) and National Alzheimer's Coordinating Center Uniform Dataset (NACC). We examined those aged 65-90 years at baseline who had no cognitive impairment and complete data for cognitive and alcohol use variables (N = 1110 from HELIAD; N = 2455 from NACC). We examined associations between current alcohol use and frequency of such use with cognitive performance on various cognitive tasks stratified by gender. RESULTS: In NACC, use of alcohol was associated with better cognitive performance. Men drinkers performed better than non-drinkers on Trail A (standardized mean 0.07 vs. -0.24, p<.001), Trail B (0.06 vs. -0.19, p=.001), and women drinkers performed better on Trail A (0.04 vs. -0.09, p=.016), Trail B (0.04 vs. -0.10, p=.005), verbal fluency (Animals: 0.05 vs. -0.13, p<.001; Vegetables: 0.04 vs. -0.09, p=.027), and MoCA (0.03 vs. -0.08, p=.039). In HELIAD, fewer differences were seen with only women drinkers exhibiting better performance than non-drinkers on the Boston Naming Task (0.11 vs. -0.05, p=.016). In general, more frequent drinkers performed better on cognitive tasks than less frequent drinkers, although this was only statistically significant in the NACC dataset. CONCLUSION: While drinking alcohol may be associated with better cognitive performance across both the US and Greece, more research is needed to assess the cultural factors that may modify this association.

Interaction between Alcohol Consumption and Apolipoprotein E (ApoE) Genotype with Cognition in Middle-Aged Men.

OBJECTIVE: Heavy alcohol consumption is associated with poorer cognitive function in older adults. Although understudied in middle-aged adults, the relationship between alcohol and cognition may also be influenced by genetics such as the apolipoprotein (ApoE) ε4 allele, a risk factor for Alzheimer's disease. We examined the relationship between alcohol consumption, ApoE genotype, and cognition in middle-aged adults and hypothesized that light and/or moderate drinkers (≤2 drinks per day) would show better cognitive performance than heavy drinkers or non-drinkers. Additionally, we hypothesized that the association between alcohol use and cognitive function would differ by ApoE genotype (ε4+ vs. ε4-). METHOD: Participants were 1266 men from the Vietnam Era Twin Study of Aging (VETSA; M age = 56; range 51-60) who completed a neuropsychological battery assessing seven cognitive abilities: general cognitive ability (GCA), episodic memory, processing speed, executive function, abstract reasoning, verbal fluency, and visuospatial ability. Alcohol consumption was categorized into five groups: never, former, light, moderate, and heavy. RESULTS: In fully adjusted models, there was no significant main effect of alcohol consumption on cognitive functions. However, there was a significant interaction between alcohol consumption and ApoE ε4 status for GCA and episodic memory, such that the relationship of alcohol consumption and cognition was stronger in ε4 carriers. The ε4+ heavy drinking subgroup had the poorest GCA and episodic memory. CONCLUSIONS: Presence of the ε4 allele may increase vulnerability to the deleterious effects of heavy alcohol consumption. Beneficial effects of light or moderate alcohol consumption were not observed.

Sex-dependent autosomal effects on clinical progression of Alzheimer's disease.

Sex differences in the manifestations of Alzheimer's disease are under intense investigation. Despite the emerging importance of polygenic predictions for Alzheimer's disease, sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on Alzheimer's disease can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Relative to sex-mismatched scores, sex-matched polygenic hazard scores showed significantly stronger associations with age-at-disease-onset, clinical progression, amyloid deposition, neurofibrillary tangles, and composite neuropathological scores, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores, showed lower predictive power than polygenic hazard scores with no evidence for sex differences. Our results indicate that revealing sex-dependent genetic architecture requires the consideration of temporal processes of Alzheimer's disease. This has strong implications not only for the genetic underpinning of Alzheimer's disease but also for how we estimate sex-dependent polygenic effects for clinical use.

Dual impairments in visual and hearing acuity and age-related cognitive decline in older adults from the Rancho Bernardo Study of Healthy Aging.

BACKGROUND: We examined the associations between dual impairments in visual and hearing acuity and aging-related cognitive decline. METHODS: This was a longitudinal study of adults who had visual and hearing acuity and cognitive function assessed in 1992-1996 and were followed for up to 24 years (mean = 7.3 years), with up to five additional cognitive assessments. Visual impairment was defined as vision worse than 20/40, hearing impairment as pure-tone average thresholds >25 dB. Associations were tested using linear mixed-effects regressions. RESULTS: Of 1,383 participants, 293 had visual impairment, 990 had a hearing impairment and 251 had both deficits. In fully adjusted models, low visual acuity was associated with poorer Mini-Mental State Examination (MMSE; ß = -0.29) and Trail-Making Test Part B (Trails B; ß = 13.22) performance, and with faster declines in MMSE (ß = -0.12) and Trails B (ß = 1.84). The combination of low visual and low hearing acuity was associated with poorer MMSE (ß = -0.44) and Trails B (ß = 11.20) scores, and with faster declines in MMSE (ß = -0.19), Trails B (ß = 3.50), and Verbal Fluency Test (VFT; ß = -0.14) performance. Associations were similar in men and women. CONCLUSION: Impairments in both vision and hearing are associated with a more rapid decline in cognitive function with aging.

Facial pressure injuries and the COVID-19 pandemic: skin protection care to enhance staff safety in an acute hospital setting.

OBJECTIVES: The aim of this study was to determine the impact of a specially designed care bundle on the development of facial pressure injuries (PI) among frontline healthcare workers wearing personal protective equipment (PPE) during the COVID-19 pandemic. The primary outcome of interest was the incidence of facial PIs. The secondary outcomes of interest were facial pain while wearing PPE and ease of use of the care bundle. METHODS: This study used a voluntary survey by questionnaire, supplemented by a qualitative analysis of interviews from a small purposive sample that took place in one large Irish hospital over a two-month period in 2020. The hospital was a city-based public university teaching hospital with 800 inpatient beds. The intervention was a care bundle consisting of skin protection, face mask selection, material use, skin inspection, cleansing and hydration developed in line with international best practice guidelines. All staff working in COVID-19 wards, intensive care units and the emergency department in the hospital were given a kitbag containing the elements of the care bundle plus an information pamphlet. Data were collected via a survey and interviews. RESULTS: A total of 114 staff provided feedback on the use of the care bundle. Before using the care bundle 29% (n=33) of the respondents reported developing a facial PI, whereas after using the care bundle only 8% (n=9) of the respondents reported developing a facial PI. The odds ratio (OR) of skin injury development was 4.75 (95% confidence interval (CI): 2.15-10.49; p=0.0001), suggesting that after the care bundle was issued, those who responded to the survey were almost five times less likely to develop a skin injury. Interviews with 14 staff determined that the bundle was easy to use and safe. CONCLUSION: Among those who responded to the survey, the use of the bundle was associated with a reduction in the incidence of skin injury from 29% to 8%, and respondents found the bundle easy to use, safe and effective. As with evidence from the international literature, this study has identified that when skincare is prioritised, and a systematic preventative care bundle approach is adopted, there are clear benefits for the individuals involved.

MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction.

INTRODUCTION: The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression. METHODS: Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction. RESULTS: Heritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction. DISCUSSION: Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

Polygenic hazard score, amyloid deposition and Alzheimer's neurodegeneration.

Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-ß protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.

Predominantly global genetic influences on individual white matter tract microstructure.

Individual differences in white matter tract microstructure, measured with diffusion tensor imaging (DTI), demonstrate substantial heritability. However, it is unclear to what extent this heritability reflects global genetic influences or tract-specific genetic influences. The goal of the current study was to quantify the proportion of genetic and environmental variance in white matter tracts attributable to global versus tract-specific influences. We assessed fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) across 11 tracts and 22 subdivisions of these tracts in 392 middle-aged male twins from the Vietnam Era Twin Study of Aging (VETSA). In principal component analyses of the 11 white matter tracts, the first component, which represents the global signal, explained 50.1% and 62.5% of the variance in FA and MD, respectively. Similarly, the first principal component of the 22 tract subdivisions explained 38.4% and 47.0% of the variance in FA and MD, respectively. Twin modeling revealed that DTI measures of all tracts and subdivisions were heritable, and that genetic influences on global FA and MD accounted for approximately half of the heritability in the tracts or tract subdivisions. Similar results were observed for the AD and RD diffusion metrics. These findings underscore the importance of controlling for DTI global signals when measuring associations between specific tracts and outcomes such as cognitive ability, neurological and psychiatric disorders, and brain aging.

Genetic architecture of hippocampal subfields on standard resolution MRI: How the parts relate to the whole.

The human hippocampus can be subdivided into subfields with unique functional properties and differential vulnerability to disease or neuropsychiatric conditions. Identifying genes that confer susceptibility to such processes is an important goal in developing treatments. Recent advances in automatic subfield segmentation from magnetic resonance images make it possible to use these measures as phenotypes in large-scale genome-wide association studies. Such analyses are likely to rely largely on standard resolution (~1 mm isotropic) T1 -weighted images acquired on 3.0T scanners. Determining whether the genetic architecture of subfields can be detected from such images is therefore an important step. We used Freesurfer v6.0 to segment hippocampal subfields in two large twin studies, the Vietnam Era Twin Study of Aging and the Human Connectome Project. We estimated heritability of subfields and the genetic overlap with total hippocampal volume. Heritability was similar across samples, but little genetic variance remained after accounting for genetic influences on total hippocampal volume. Importantly, we examined genetic relationships between subfields to determine whether subfields can be grouped based on a smaller number of underlying, genetically independent factors. We identified three genetic factors in both samples, but the high degree of cross loadings precluded formation of genetically distinct groupings of subfields. These results confirm the reliability of Freesurfer v6.0 generated subfields across samples for phenotypic analyses. However, the current results suggest that it will be difficult for large-scale genetic analyses to identify subfield-specific genes that are distinct from both total hippocampal volume and other subfields using segmentations generated from standard resolution T1 -weighted images.

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

Lifetime physical activity and late-life cognitive function: the Rancho Bernardo study.

BACKGROUND: physical activity in older age has been associated with better cognitive function, but the role of earlier life physical activity is less well understood. OBJECTIVE: determine associations between physical activity throughout the lifespan and cognitive function in older age. DESIGN: cross-sectional study. SETTING: the Rancho Bernardo Study of Healthy Aging in southern California. SUBJECTS: A total of 1,826 community-dwelling men and women (60-99 years) who attended a research visit in 1988-92. METHODS: participants underwent cognitive testing at older age, and reported physical activity as a teenager, at age 30 years, 50 years and currently. For each time-point, participants were classified as regularly active (3+ times/week) or inactive. RESULTS: regular physical activity was associated with better cognitive function, with physical activity at older ages showing the strongest associations. Physical activity in older age was associated with better global cognitive function, executive function and episodic memory, regardless of intensity. Intense physical activity in teenage years was associated with better late-life global cognitive function in women. Teenage physical activity interacted with older age physical activity on executive function; those active at both periods performed better than those active at only one period. Similar patterns of associations were observed after excluding individuals with poor health. CONCLUSIONS: regular physical activity in older age, regardless of intensity, is associated with better cognitive function. Physical activity in teenage years may enhance cognitive reserve to protect against age-related decline in executive function. Further research is needed to assess the effect of physical activity across the lifespan on healthy brain ageing.

Polygenic hazard scores in preclinical Alzheimer disease.

Identifying asymptomatic older individuals at elevated risk for developing Alzheimer disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE ɛ4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high Consortium to Establish a Registry for Alzheimer's Disease (amyloid) and Braak (tau) scores at autopsy, even among APOE ɛ4 noncarriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer neurodegeneration. Ann Neurol 2017;82:484-488.

Polygenic hazard score: an enrichment marker for Alzheimer's associated amyloid and tau deposition.

There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer's disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7-90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4-91.4, 98.83% white) individuals from the Alzheimer's Disease Neuroimaging Initiative 1, GO, and 2. We further investigated the association of PHS with post-mortem amyloid load and neurofibrillary tangles in the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 485, age at death range = 71.3-108.3). In CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%; for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. High PHS individuals with amyloid and tau pathology showed the steepest longitudinal cognitive and clinical decline, even among APOE ε4 noncarriers. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression. In the ROSMAP cohort, higher PHS was associated with higher post-mortem amyloid load and neurofibrillary tangles, even in APOE ε4 noncarriers. Together, our results show that even after accounting for APOE ε4 effects, PHS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression.