1. |
- de Jong, S, et al.
(författare)
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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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2. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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5. |
- Degerman, Sofie, et al.
(författare)
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Maintained memory in aging is associated with young epigenetic age
- 2017
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 55, s. 167-171
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic alterations during aging have been proposed to contribute to decline in physical and cognitive functions, and accelerated epigenetic aging has been associated with disease and all-cause mortality later in life. In this study, we estimated epigenetic age dynamics in groups with different memory trajectories (maintained high performance, average decline, and accelerated decline) over a 15-year period. Epigenetic (DNA-methylation [DNAm]) age was assessed, and delta age (DNAm age - chronological age) was calculated in blood samples at baseline (age: 55-65 years) and 15 years later in 52 age- and gender-matched individuals from the Betula study in Sweden. A lower delta DNAm age was observed for those with maintained memory functions compared with those with average (p = 0.035) or accelerated decline (p = 0.037). Moreover, separate analyses revealed that DNAm age at follow-up, but not chronologic age, was a significant predictor of dementia (p = 0.019). Our findings suggest that young epigenetic age contributes to maintained memory in aging.
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6. |
- Ekström, Ingrid, et al.
(författare)
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Smell Loss Predicts Mortality Risk Regardless of Dementia Conversion
- 2017
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Ingår i: Journal of The American Geriatrics Society. - : Wiley. - 0002-8614 .- 1532-5415. ; 65:6, s. 1238-1243
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesTo determine whether dementia could explain the association between poor olfactory performance and mortality risk within a decade-long follow-up period.DesignProspective cohort study.SettingBetula Study, Umeå, Sweden.ParticipantsA population-based sample of adult participants without dementia at baseline aged 40 to 90 (N = 1,774).MeasurementsOlfactory performance using the Scandinavian Odor-Identification Test (SOIT) and self-reported olfactory function; several social, cognitive, and medical risk factors at baseline; and incident dementia during the following decade.ResultsWithin the 10-year follow-up, 411 of 1,774 (23.2%) participants had died. In a Cox model, the association between higher SOIT score and lower mortality was significant (hazard ratio (HR) = 0.74 per point interval, 95% confidence interval (CI) = 0.71-0.77, P < .001). The effect was attenuated, but remained significant, after controlling for age, sex, education, and health-related and cognitive variables (HR = 0.92, 95% CI = 0.87-0.97, P = .001). The association between SOIT score and mortality was retained after controlling for dementia conversion before death (HR = 0.92, 95% CI = 0.87-0.97, P = .001). Similar results were obtained for self-reported olfactory dysfunction.ConclusionPoor odor identification and poor self-reported olfactory function are associated with greater likelihood of future mortality. Dementia does not attenuate the association between olfactory loss and mortality, suggesting that olfactory loss might mark deteriorating health, irrespective of dementia.
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7. |
- Figueira, Joao, et al.
(författare)
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NMR analysis of the human saliva metabolome distinguishes dementia patients from matched controls
- 2016
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 12:8, s. 2562-2571
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Tidskriftsartikel (refereegranskat)abstract
- Saliva is a biofluid that is sensitive to metabolic changes and is straightforward to collect in a non-invasive manner, but it is seldom used for metabolite analysis when studying neurodegenerative disorders. We present a procedure for both an untargeted and targeted analysis of the saliva metabolome in which nuclear magnetic resonance (NMR) spectroscopy is used in combination with multivariate data analysis. The applicability of this approach is demonstrated on saliva samples selected from the 25 year prospective Betula study, including samples from dementia subjects with either Alzheimer's disease (AD) or vascular dementia at the time of sampling or who developed it by the next sampling/assessment occasion five years later, and age-, gender-, and education-matched control individuals without dementia. Statistically significant multivariate models were obtained that separated patients with dementia from controls and revealed seven discriminatory metabolites. Dementia patients showed significantly increased concentrations of acetic acid (fold change (fc) = 1.25, p = 2 x 10(-5)), histamine (fc = 1.26, p = 0.019), and propionate (fc = 1.35, p = 0.002), while significantly decreased levels were observed for dimethyl sulfone (fc = 0.81, p = 0.005), glycerol (fc = 0.79, p = 0.04), taurine (fc = 0.70, p = 0.007), and succinate (fc = 0.62, p = 0.008). Histamine, succinate, and taurine are known to be important in AD, and acetic acid and glycerol are involved in related pathways. Dimethyl sulfone and propionate originate from the diet and bacterial flora and might reflect poorer periodontal status in the dementia patients. For these seven metabolites, a weak but statistically significant pre-diagnostic value was observed. Taken together, we present a robust and general NMR analysis approach for studying the saliva metabolome that has potential use for screening and early detection of dementia.
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8. |
- Figueira, Joao, et al.
(författare)
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Serum Metabolite Markers of Dementia Through Quantitative NMR Analysis : The Importance of Threonine-Linked Metabolic Pathways
- 2019
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 69:3, s. 763-774
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Tidskriftsartikel (refereegranskat)abstract
- There is a great need for diagnostic biomarkers of impending dementia. Metabolite markers in blood have been investigated in several studies, but inconclusive findings encourage further investigation, particularly in the pre-diagnostic phase. In the present study, the serum metabolomes of 110 dementia or pre-diagnostic dementia individuals and 201 healthy individuals matched for age, gender, and education were analyzed by nuclear magnetic resonance spectroscopy in combination with multivariate data analysis. 58 metabolites were quantified in each of the 311 samples. Individuals with dementia were discriminated from controls using a panel of seven metabolites, while the pre-diagnostic dementia subjects were distinguished from controls using a separate set of seven metabolites, where threonine was a common significant metabolite in both panels. Metabolite and pathway alterations specific for dementia and pre-diagnostic dementia were identified, in particular a disturbed threonine catabolism at the pre-diagnostic stage that extends to several threonine-linked pathways at the dementia stage.
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9. |
- Hagg, S, et al.
(författare)
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Short telomere length is associated with impaired cognitive performance in European ancestry cohorts
- 2017
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:4, s. e1100-
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Tidskriftsartikel (refereegranskat)abstract
- The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=−0.053; 95% CI: −0.087, −0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10−5), whereas carriers performed better in STROOP (β=−0.074; 95% CI: −0.140, −0.009; P=0.03). Causal associations were found for STROOP only (β=−0.598 per s.d.-increase of TL; 95% CI: −1.125, −0.072; P=0.026), with a larger effect in ɛ4-carriers (β=−0.699; 95% CI: −1.330, −0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.
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10. |
- Josefsson, Maria, 1979-, et al.
(författare)
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Memory profiles predict dementia over 23–28 years in normal but not successful aging
- 2023
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Ingår i: International psychogeriatrics. - : Cambridge University Press. - 1041-6102 .- 1741-203X. ; 35:7, s. 351-359
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Prospective studies suggest that memory deficits are detectable decades before clinical symptoms of dementia emerge. However, individual differences in long-term memory trajectories prior to diagnosis need to be further elucidated. The aim of the current study was to investigate long-term dementia and mortality risk for individuals with different memory trajectory profiles in a well-characterized population-based sample.Methods: 1062 adults (aged 45–80 years) who were non-demented at baseline were followed over 23–28 years. Dementia and mortality risk were studied for three previously classified episodic memory trajectory groups: maintained high performance (Maintainers; 26%), average decline (Averages; 64%), and accelerated decline (Decliners; 12%), using multistate modeling to characterize individuals’ transitions from an initial non-demented state, possibly to a state of dementia and/or death.Results: The memory groups showed considerable intergroup variability in memory profiles, starting 10–15 years prior to dementia diagnosis, and prior to death. A strong relationship between memory trajectory group and dementia risk was found. Specifically, Decliners had more than a fourfold risk of developing dementia compared to Averages. In contrast, Maintainers had a 2.6 times decreased dementia risk compared to Averages, and in addition showed no detectable memory decline prior to dementia diagnosis. A similar pattern of association was found for the memory groups and mortality risk, although only among non-demented.Conclusion: There was a strong relationship between accelerated memory decline and dementia, further supporting the prognostic value of memory decline. The intergroup differences, however, suggest that mechanisms involved in successful memory aging may delay symptom onset.
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11. |
- Kauppi, Karolina, et al.
(författare)
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Effects of polygenic risk for Alzheimer's disease on rate of cognitive decline in normal aging
- 2020
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Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Most people's cognitive abilities decline with age, with significant and partly genetically driven, individual differences in rate of change. Although APOE 4 and genetic scores for late-onset Alzheimer's disease (LOAD) have been related to cognitive decline during preclinical stages of dementia, there is limited knowledge concerning genetic factors implied in normal cognitive aging. In the present study, we examined three potential genetic predictors of age-related cognitive decline as follows: (1) the APOE 4 allele, (2) a polygenic score for general cognitive ability (PGS-cog), and (3) a polygenic risk score for late-onset AD (PRS-LOAD). We examined up to six time points of cognitive measurements in the longitudinal population-based Betula study, covering a 25-year follow-up period. Only participants that remained alive and non-demented until the most recent dementia screening (1-3 years after the last test occasion) were included (n=1087). Individual differences in rate of cognitive change (composite score) were predicted by the PRS-LOAD and APOE 4, but not by PGS-cog. To control for the possibility that the results reflected a preclinical state of Alzheimer's disease in some participants, we re-ran the analyses excluding cognitive data from the last test occasion to model cognitive change up-until a minimum of 6 years before potential onset of clinical Alzheimers. Strikingly, the association of PRS-LOAD, but not APOE 4, with cognitive change remained. The results indicate that PRS-LOAD predicts individual difference in rate of cognitive decline in normal aging, but it remains to be determined to what extent this reflects preclinical Alzheimer's disease brain pathophysiology and subsequent risk to develop the disease.
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12. |
- Larsson, Maria, et al.
(författare)
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Loss of Olfactory Function Predicts Mortality Irrespective of Dementia Conversion : 10-year follow-up of an age-varied sample
- 2016
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Ingår i: Chemical Senses. - : Oxford University Press (OUP). - 0379-864X .- 1464-3553. ; 41:9, s. e111-e288
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to examine the association between performance in odor identification and future mortality in a community cohort of adults aged between 40 and 90 years. We assessed olfactory performance with a 13-item-version of the Scandinavian Odor Identification Test (SOIT). The results showed that during follow-up (mean=9.4 years, standard deviation=2.23), 411 of 1774 (23.2%) participants died. In a Cox model, the association between higher SOIT score and mortality was highly significant (hazard ratio [HR]=0.74, per point interval, 95% confidence interval [CI]=0.71–0.77, p<0.001). The effect was attenuated, but remained significant after controlling for age, sex, education, and health and cognitive variables that were also associated with an increased risk of mortality (HR=0.92, 95% CI=0.87–0.97, p=0.001). Controlling for dementia conversion prior to death did not attenuate the association between SOIT score and mortality (HR=0.92, 95% CI=0.87–0.97, p=0.001). Similar results were obtained for olfactory sensitivity as assessed by self-report. Overall, the present findings show that poor odor identification performance is associated with an increased likelihood of future mortality in middle-aged and older adults, after controlling for social, cognitive, and medical risk factors. Most importantly, controlling for the development of dementia did not attenuate the association between odor identification and mortality, suggesting that olfactory decline might mark deteriorating health also irrespective of dementia.
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15. |
- Nyberg, Lars, 1966-, et al.
(författare)
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Biological and environmental predictors of heterogeneity in neurocognitive ageing : Evidence from Betula and other longitudinal studies
- 2020
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Ingår i: Ageing Research Reviews. - : Elsevier. - 1568-1637 .- 1872-9649. ; 64
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Forskningsöversikt (refereegranskat)abstract
- Individual differences in cognitive performance increase with advancing age, reflecting marked cognitive changes in some individuals along with little or no change in others. Genetic and lifestyle factors are assumed to influence cognitive performance in aging by affecting the magnitude and extent of age-related brain changes (i.e., brain maintenance or atrophy), as well as the ability to recruit compensatory processes. The purpose of this review is to present findings from the Betula study and other longitudinal studies, with a focus on clarifying the role of key biological and environmental factors assumed to underlie individual differences in brain and cognitive aging. We discuss the vital importance of sampling, analytic methods, consideration of non-ignorable dropout, and related issues for valid conclusions on factors that influence healthy neurocognitive aging.
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16. |
- Nyberg, Lars, 1966-, et al.
(författare)
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Elevated plasma neurofilament light in aging reflects brain white-matter alterations but does not predict cognitive decline or Alzheimer's disease
- 2020
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionWe investigated neurofilament light (NFL) accumulation in normal aging as well as in preclinical and clinical Alzheimer's disease (AD) and assessed individual differences in NFL load in relation to cognition and brain white-matter integrity. MethodsWe analyzed longitudinal data covering 30 years (1988-2017). Cognitive testing was done up to six times. Plasma NFL was quantified for controls and 142 cases who developed AD over time, and longitudinal changes in NFL were quantified for 100 individuals with three brain-imaging sessions. ResultsLongitudinal analyses revealed age-related NFL increases with marked variability. AD cases had elevated NFL levels, while no significant group differences were seen in the preclinical phase. Variability in NFL levels showed non-significant correlations with cognition but was associated with brain white matter. DiscussionOur findings suggest that elevated blood NFL, likely reflecting brain white-matter alterations, characterizes clinical AD, while NFL levels do not predict age-related cognitive impairment or impending AD.
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18. |
- Olofsson, Jonas K., et al.
(författare)
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Long-term episodic memory decline is associated with olfactory deficits only in carriers of ApoE-є4
- 2016
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Ingår i: Neuropsychologia. - : Elsevier BV. - 0028-3932 .- 1873-3514. ; 85, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- The ɛ4 allele of the Apolipoprotein E gene is a genetic risk factor for late-onset dementia of the Alzheimers' type (DAT), which is characterized by loss of both episodic memoryand olfactory functions. Little is known about the possible role of ɛ4 in the association between ongoing episodic memory decline and olfactory deficits in the general population, but such information is relevant in determining the relevance of olfaction as a marker of DAT risk. The present study was based on a large, population-based sample (n=1087, aged 45–90 years, of which 324 were ɛ4-carriers). Episodic memory change rates were established using data collected every 5 years for a 10–20 year interval leading up to an olfactory assessment using the Scandinavian Odor Identification Test at the last wave of data collection. Participants were classified according to whether or not their episodic memory ability declined more rapidly than the age-typical norm (by >1SD). Our main result is that only in ɛ4-carriers was episodic memory decline associated with odor identification impairment. In individuals without ɛ4, odor identification was unrelated to episodic memory decline status. Follow-up analyses indicated that this moderation by ɛ4 was due to the olfactory nature of the identification test, and that the effect was not caused by 63 individuals with dementia. Our results suggest that the ɛ4 determines the functional association between ongoing episodic memory decline and olfaction. These findings are consistent with the notion that ɛ4-carriers with DAT, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions. Olfactory and memory assessments might provide complementary information on mediotemporal atrophy prior to clinical dementia onset, but the ɛ4 should be considered when using olfactory assessment as an early-stage indicator.
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19. |
- Oudin, Anna, et al.
(författare)
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Traffic-Related Air Pollution and Dementia Incidence in Northern Sweden : A Longitudinal Study
- 2016
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 124:3, s. 306-312
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Exposure to ambient air pollution is suspected to cause cognitive effects, but a prospective cohort is needed to study exposure to air pollution at the home address and the incidence of dementia.OBJECTIVES: We aimed to assess the association between long-term exposure to traffic-related air pollution and dementia incidence in a major city in northern Sweden.METHODS: Data on dementia incidence over a 15-year period were obtained from the longitudinal Betula study. Traffic air pollution exposure was assessed with a Land Use Regression Model with a spatial resolution of 50 m x 50 m. Annual mean nitrogen oxide levels at the residential address of the participants at baseline (the start of follow-up) was used as a marker for long-term exposure to air pollution.RESULTS: Out of 1806 participants at baseline, 191 were diagnosed with Alzheimer's disease during follow-up, and 111 were diagnosed with vascular dementia. Participants in the highest exposure group were more likely to be diagnosed with dementia (Alzheimer's disease or vascular dementia), with a Hazard Ratio (HR) of 1.43 (95% Confidence Interval (CI): 0.998, 2.05 for the highest versus lowest quartile). The estimates were similar for Alzheimer's disease (HR 1.38) and vascular dementia (HR 1.47). The HR for dementia associated for the third quartile versus the lowest quartile was 1.48 (95% CI: 1.03, 2.11). A sub-analysis that excluded a younger sample that had been re-tested after only 5 years of follow-up suggested stronger associations with exposure than in the full cohort (HR = 1.71; 95% CI: 1.08, 2.73 for the highest versus lowest quartile).CONCLUSIONS: If the associations we observed are causal, then air pollution from traffic might be an important risk factor for vascular dementia and Alzheimer's disease.
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20. |
- Oudin, Anna, et al.
(författare)
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Traffic-Related Air Pollution as a Risk Factor for Dementia : No Clear Modifying Effects of APOEɛ4 in the Betula Cohort
- 2019
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 71:3, s. 733-740
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Tidskriftsartikel (refereegranskat)abstract
- It is widely known that the apolipoprotein E (APOE) ɛ4 allele imposes a higher risk for Alzheimer’s disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOE ɛ4 carriers than in non-carriers. Air pollution and interaction with APOE ɛ4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOE ɛ4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOE ɛ4 on the association (p-value for interaction > 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOE ɛ4 carriers than in the total population.
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21. |
- Oudin, Anna, et al.
(författare)
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Traffic-Related air pollution as a risk factor for dementia : no clear modifying effects of apoe ɛ4 in the betula cohort
- 2021
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Ingår i: Alzheimer's disease and air pollution. - Amsterdam : IOS Press. - 2210-5727. - 9781643681597 - 9781643681580 ; , s. 357-364
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Bokkapitel (refereegranskat)abstract
- It is widely known that the apolipoprotein E (APOE) ε4 allele imposes a higher risk for Alzheimer's disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOE ε4 carriers than in non-carriers. Air pollution and interaction with APOE ε4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOE ε4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOE ε4 on the association (p-value for interaction > 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOE ε4 carriers than in the total population.
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22. |
- Pudas, Sara, Fil. Dr. 1983-, et al.
(författare)
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Short leukocyte telomeres, but not telomere attrition rates, predict memory decline in the 20-year longitudinal Betula study
- 2021
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Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press. - 1079-5006 .- 1758-535X. ; 76:6, s. 955-963
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Tidskriftsartikel (refereegranskat)abstract
- Leukocyte telomere length (LTL) is a proposed biomarker for aging-related disorders, including cognitive decline and dementia. Long-term longitudinal studies measuring intra-individual changes in both LTL and cognitive outcomes are scarce, precluding strong conclusions about a potential aging-related relationship between LTL shortening and cognitive decline. This study investigated associations between baseline levels and longitudinal changes in LTL and memory performance across an up to 20-year follow-up in 880 dementia-free participants from a population-based study (mean baseline age: 56.8 years, range: 40–80; 52% female). Shorter baseline LTL significantly predicted subsequent memory decline (r = .34, 95% confidence interval: 0.06, 0.82), controlling for age, sex, and other relevant covariates. No significant associations were however observed between intra-individual changes in LTL and memory, neither concurrently nor with a 5-year time-lag between LTL shortening and memory decline. These results support the notion of short LTL as a predictive factor for aging-related memory decline, but suggest that LTL dynamics in adulthood and older age may be less informative of cognitive outcomes in aging. Furthermore, the results highlight the importance of long-term longitudinal evaluation of outcomes in biomarker research.
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24. |
- Salami, Alireza, et al.
(författare)
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Association of APOE ɛ4 and Plasma p-tau181 with Preclinical Alzheimer’s Disease and Longitudinal Change in Hippocampus Function
- 2022
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 85:3, s. 1309-1320
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Apolipoprotein E (APOE) ɛ4 allele has been linked to increased tau phosphorylation and tangle formation. APOE ɛ4 carriers with elevated tau might be at the higher risk for Alzheimer’s disease (AD) progression. Previous studies showed that tau pathology begins early in areas of the medial temporal lobe. Similarly, APOE ɛ4 carriers showed altered hippocampal functional integrity. However, it remains unknown whether the influence of elevated tau accumulation on hippocampal functional changes would be more pronounced for APOE ɛ4 carriers.Objective: We related ɛ4 carriage to levels of plasma phosphorylated tau (p-tau181) up to 15 years prior to AD onset. Furthermore, elevated p-tau181 was explored in relation to longitudinal changes in hippocampal function and connectivity.Methods: Plasma p-tau181 was analyzed in 142 clinically defined AD cases and 126 matched controls. The longitudinal analysis involved 87 non-demented individuals (from population-based study) with two waves of plasma samples and three waves of functional magnetic resonance imaging during rest and memory encoding.Results: Increased p-tau181 was observed for both ɛ4 carriers and non-carriers close to AD onset, but exclusively for ɛ4 carriers in the early preclinical groups (7- and 13-years pre-AD). In ɛ4 carriers, longitudinal p-tau181 increase was paralleled by elevated local hippocampal connectivity at rest and subsequent reduction of hippocampus encoding-related activity.Conclusion: Our findings support an association of APOE ɛ4 and p-tau181 with preclinical AD and hippocampus functioning.
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25. |
- Schäfer Hackenhaar, Fernanda, et al.
(författare)
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Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers
- 2021
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Ingår i: Alzheimer's Research & Therapy. - : BioMed Central (BMC). - 1758-9193. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Leukocyte telomere length (LTL) has been shown to predict Alzheimer’s disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.Methods: We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.Results: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1–24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404–7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947–2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.Conclusions: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.
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