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Alzheimer’s disease (AD) is a common and increasing societal problem due to the extending human lifespan. In males, loss of Y (LOY) in leukocytes is more prevalent in AD patients. We studied DNA methylation, gene expression and other epigenetic changes in monocytes and granulocytes with and without LOY from male AD patients and controls. New candidate genes were identified and numerous genes already implicated in AD pathogenesis were confirmed. We show that multi-omics of leukocytes can define AD candidate genes and we strengthen the role of LOY in disease development. The LOY-associated differences in DNA methylation levels were predominantly observed in regulatory regions, and supported by expression analysis showing down-regulation of immune genes. The single-cell transcriptomics highlighted that the AD patient-specific immune activation dominates over LOY-specific activation. Our findings agree with the hypothesis that age-related dysfunction of immune cells contribute to AD and that LOY is reflected by higher-level epigenetic changes with an AD-specific pattern.

Background: There are more than 300 presenilin-1 (PSEN1) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed. Objective: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer’s disease (sAD). Methods: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations. Results: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations. Conclusion: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness.

Background: Open-angle glaucoma (OAG) and Alzheimer’s disease (AD) are two age-related neurodegenerative diseases of significant public health importance. Epidemiological studies have indicated that there might be an association between the disorders. Methods: Predictors of AD, including mixed and unspecified dementia, were analysed in a cohort of 712 residents aged 65–74 years, examined in a population survey in the rural district of Tierp, Sweden, from 1984 to 1986. To expand the sample size, 821 people were recruited by means of glaucoma case records established at the Eye Department in Tierp from 1978 to 2007. In this way, the cohort comprised 1,533 people, representing more than 21,000 person-years at risk. Medical records were reviewed to identify subjects diagnosed with dementia. Those with a follow-up duration shorter than 2 years were excluded. Results: By the conclusion of the study, in August 2020, 307 subjects had received a diagnosis of AD, including mixed and unspecified dementia. Of these cases, 55 were affected with definite OAG at baseline. Higher age and ischemic heart disease were the only predictors of AD identified. In multivariate analysis, adjusting for age, participation in the population survey and competing events, no association was found between OAG and AD (hazard ratio 1.08; 95% confidence interval: 0.80–1.47). Conclusion: In this long-term follow-up study of subjects aged 65–74 years old in Sweden, OAG was not associated with AD.

A lower day-to-night systolic blood pressure (BP) dip has previously been associated with poor brain health and cognitive functions. Here, we sought to examine whether reduced (nighttime/daytime ratio of systolic BP >0.9 and ≤1) and reverse (nighttime/daytime ratio of systolic BP >1) dipping of systolic BP is associated with the prospective risk of being diagnosed with any dementia in Swedish older men. Twenty-four-hour ambulatory BP monitoring was used to estimate the nocturnal systolic BP dipping status of men at mean age 71 (n=997; 35% on antihypertensive medication) and 77.6 (n=611; 41% on antihypertensive medication). Dementia incidence during the observational period up to 24 years (n=286 cases) was determined by reviewing participants’ medical history and independently confirmed by at least 2 experienced geriatricians. Using time-updated Cox regression (ie, time-updated information on covariates and exposure), we found that reverse systolic BP dipping was associated with a higher risk of being diagnosed with any dementia (adjusted HR, 1.64 [95% CI, 1.14–2.34], P =0.007) and Alzheimer’s disease (1.67 [1.01–2.76], P =0.047) but not vascular dementia (1.29 [0.55–3.06], P =0.559). In contrast, reduced dipping of nocturnal systolic BP was not associated with a higher risk of being diagnosed with dementia. Our findings suggest that reverse systolic BP dipping may represent an independent risk factor for dementia and Alzheimer’s disease in older men. Future studies should decipher whether therapies lowering nocturnal systolic BP below daytime levels, such as bedtime dosing of antihypertensive medication, can meaningfully curb the development of dementia.

The role of milk and fermented milk consumption in stroke risk is unclear. We investigated associations of time-updated information on milk and fermented milk consumption (1997 and 2009) with total stroke, cerebral infarction, and hemorrhagic stroke risk among 79,618 Swedish women and men (mean age 61.3 years). During a mean follow-up of 17.7 years, we identified 9735 incident cases of total stroke, of which 7573 were cerebral infarctions, 1470 hemorrhagic strokes, and 692 unspecified strokes. Compared with an intake of 100 g/day of milk, the multivariable-adjusted hazard ratios (95% confidence interval) of cerebral infarction were 1.05 (1.02–1.08) for 0 g/day, 0.97 (0.95–0.99) for 200 g/day, 0.96 (0.92–1.00) for 400 g/day, 0.98 (0.94–1.03) for 600 g/day, and 1.01 (0.94–1.07) for 800 g/day. Corresponding estimates for hemorrhagic stroke were 0.98 (0.91–1.05) for 0 g/day, 1.02 (0.97–1.07) for 200 g/day, 1.07 (0.98–1.17) for 400 g/day, 1.13 (1.02–1.25) for 600 g/day, and 1.19 (1.03–1.36) for 800 g/day. No associations were observed between milk consumption and total stroke or for fermented milk consumption and any of the stroke outcomes. Higher long-term milk consumption based on repeated measures of intake was weakly and non-linearly associated with cerebral infarction, and was directly associated with hemorrhagic stroke.

Background: There is substantial evidence that midlife hypertension is a risk factor for late life dementia. Our aim was to investigate if even high blood pressure at a single timepoint in midlife can predict an increased risk for all-cause dementia, Alzheimer’s disease (AD), or vascular dementia (VaD) later in life. Methods: The community-based study population comprised 30,102 dementia-free individuals from the Westmannia Cardiovascular Risk Factors Study. The participants were aged 40 or 50 years when the health examination took place in 1990–2000. Diagnose registers from both hospitals and primary healthcare centers were used to identify individuals who after inclusion to the study developed dementia. The association between midlife high blood pressure (defined as systolic blood pressure >140 and/or diastolic blood pressure >90 mmHg) at a single timepoint and dementia was adjusted for age, gender, body mass index (BMI), fasting blood glucose, education, smoking, and physical activity level. Multivariate binary cox regression analyses were used. Results: After a mean follow-up time of 24 years resulting in 662,244 person/years, 761 (2.5%) individuals had been diagnosed with dementia. Midlife high blood pressure at a single timepoint predicted all-cause dementia (hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.02–1.45) and VaD (HR: 2.10, 95% CI: 1.47–3.00) but not AD (HR: 1.06, 95% CI: 0.81–1.38). Conclusion: This study suggests that even midlife high blood pressure at a single timepoint predicts all-cause dementia and more than doubles the risk for VaD later in life independently of established confounders. Even though there was no such association with AD, this strengthens the importance of midlife health examinations in order to identify individuals with hypertension and initiate treatment.

Mosaic loss of chromosome Y (LOY) in immune cells is a male-specific mutation associated with increased risk for morbidity and mortality. TheCD99gene, positioned in the pseudoautosomal regions of chromosomes X and Y, encodes a cell surface protein essential for several key properties of leukocytes and immune system functions. Here we used CITE-seq for simultaneous quantification ofCD99derived mRNA and cell surface CD99 protein abundance in relation to LOY in single cells. The abundance of CD99 molecules was lower on the surfaces of LOY cells compared with cells without this aneuploidy in all six types of leukocytes studied, while the abundance of CD proteins encoded by genes located on autosomal chromosomes were independent from LOY. These results connect LOY in single cells with immune related cellular properties at the protein level, providing mechanistic insight regarding disease vulnerability in men affected with mosaic chromosome Y loss in blood leukocytes.

Background Vascular dementia (VaD) and atypical parkinsonism often present with symptoms that can resemble idiopathic normal pressure hydrocephalus (iNPH) and enlarged cerebral ventricles, and can be challenging differential diagnoses. The aim was to investigate frequencies of imaging features usually associated with iNPH and their radiological diagnostic accuracy in a sample containing the relevant differential diagnoses VaD, progressive supranuclear palsy (PSP), multiple system atrophy parkinsonian type (MSA-P), and healthy controls. Methods Nine morphological imaging features usually associated with iNPH were retrospectively investigated in MR images of 55 patients with shunt-responsive iNPH, 32 patients with VaD, 30 patients with PSP, 27 patients with MSA-P, and 39 age-matched healthy controls. Logistic regression and receiver operating characteristic curves were used to assess diagnostic accuracy, sensitivity, and specificity for each imaging finding. Results In a logistic regression model using iNPH diagnosis as a dependent variable, the following imaging features contributed significantly to the model: callosal angle (OR = 0.95 (0.92–0.99), p = 0.012), Evans’ index * 100 (OR = 1.51 (1.23–1.86), p Conclusions There is a notable overlap between some of the commonly used imaging markers regarding iNPH, VaD and atypical parkinsonism, such as PSP. However, this study shows that the specificity of imaging markers usually associated with iNPH was high even when comparing with these challenging differential diagnoses. The callosal angle was the single imaging feature with highest diagnostic accuracy to discriminate iNPH from its mimics. A simplified rating scale using only a few selected features could be used with retained specificity.

Altres ajuts: Swedish Alzheimer Foundation (AF-930343); Swedish Brain Foundation (FO2018-0118); Gun and Bertil Stohne's Foundation; Geriatriska Fonden; Stiftelsen för Gamla Tjänarinnor; Fondo de Investigaciones Sanitario (FIS); CIBERNED program (Program 1, Alzheimer Disease); Fondo Europeo de Desarrollo Regional (FEDER); German Federal Ministry of Education and Research (grant # FTLDc01GI1007A, Genfi-Prox 01ED2008). Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: Fold change [FC]=1.32, 95% confidence interval [CI] 1.14-1.53, q=0.018; MCI/AD: FC=1.53, 95% CI 1.20-1.94, q=0.045; and FTD: FC=1.42, 95% CI 1.10-1.83, q=0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q

International audience; Objective: Decreased amyloid beta (Aβ) 42 together with increased tau and phospho-tau in cerebrospinal fluid (CSF) is indicative of Alzheimer’s disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages.Methods: We utilized an antibody-based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETIONOMY consortium. Two additional cohorts from Sweden were used for biological verification.Results: Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP-regulated phosphoprotein 21 (ARPP21), growth-associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of Aβ42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations.Interpretation: In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.

Funder: Kjell och Märta Beijers Stiftelse (SE), Funder: Hjärnfonden; doi: http://dx.doi.org/10.13039/501100003792, Funder: Cancerfonden; doi: http://dx.doi.org/10.13039/501100002794, Funder: Vetenskapsrådet; doi: http://dx.doi.org/10.13039/501100004359, Funder: Alzheimerfonden; doi: http://dx.doi.org/10.13039/501100008599, Funder: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse (SE), Funder: Science for Life Laboratory (SE), Funder: Fundacja na rzecz Nauki Polskiej (PL), Funder: Uppsala University, Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.

Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer’s disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the Uppsala APP mutation (Δ690–695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of sporadic AD, except that these three patients had high cerebrospinal fluid (CSF) Aβ42 and only modest brain pathology as detected by amyloid-positron emission tomography. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing β-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aβ, AβUpp1–42Δ19–24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.

Point mutations in the amyloid precursor protein gene (

BackgroundThe clinical presentations of frontotemporal dementia (FTD) are diverse and overlap with other neurological disorders. There are, as of today, no biomarkers in clinical practice for diagnosing the disorders. Here, we aimed to find protein markers in cerebrospinal fluid (CSF) from patients with FTD, presymptomatic mutation carriers and non-carriers.MethodsAntibody suspension bead arrays were used to analyse 328 proteins in CSF from patients with behavioural variant FTD (bvFTD,n = 16) and progressive primary aphasia (PPA,n = 13), as well as presymptomatic mutation carriers (PMC,n = 16) and non-carriers (NC,n = 8). A total of 492 antibodies were used to measure protein levels by direct labelling of the CSF samples. The findings were further examined in an independent cohort including 13 FTD patients, 79 patients with Alzheimer’s disease and 18 healthy controls.ResultsWe found significantly altered protein levels in CSF from FTD patients compared to unaffected individuals (PMC and NC) for 26 proteins. The analysis show patterns of separation between unaffected individuals and FTD patients, especially for those with a clinical diagnosis of bvFTD. The most statistically significant differences in protein levels were found for VGF, TN-R, NPTXR, TMEM132D, PDYN and NF-M. Patients with FTD were found to have higher levels of TN-R and NF-M, and lower levels of VGF, NPTXR, TMEM132D and PDYN, compared to unaffected individuals. The main findings were reproduced in the independent cohort.ConclusionIn this pilot study, we show a separation of FTD patients from unaffected individuals based on protein levels in CSF. Further investigation is required to explore the CSF profiles in larger cohorts, but the results presented here has the potential to enable future clinical utilization of these potential biomarkers within FTD.

The aim of this study was to investigate whether Timed Up-and-Go (TUG) dual-task (TUGdt) tests predict dementia incidence among patients with subjective or mild cognitive impairment (SCI, MCI). Other study objectives were to determine whether TUGdt improves dementia prediction compared to a) demographic characteristics and standard cognitive tests alone, and b) TUG and Verbal Fluency performed separately. Patients (n = 172, age range 39&ndash, 91 years, 78 women) with SCI or MCI performed TUGdt tests, including 1) naming animals and 2) reciting months backwards, and clinical cognitive tests at baseline. Diagnoses were identified at follow-up after 2.5 years. Logistic regression was used to predict dementia incidence, receiver operating characteristic (ROC) curves and c-statistics for predictive capacity. Analyses were stratified by age and gender. At follow-up, 51 patients had developed dementia. The TUGdt result &ldquo, animals/10 s&rdquo, was associated with dementia incidence (standardized odds ratio (OR) = 4.06, 95% confidence interval (CI) 2.28&ndash, 7.23, p &lt, 0.001), more so among patients under the median age of 72 years (standardized OR = 19.4, 95% CI 3.53&ndash, 106.17, p &lt, 0.001). TUGdt &ldquo, improved dementia prediction compared to demographic characteristics and standard tests alone (c-statistics 0.88 to 0.94) and single-task tests (c-statistics 0.86 to 0.89), but only in the younger patient group. TUGdt has the potential to become a useful tool for dementia prediction.

Background Discrimination between early-stage dementia and other cognitive impairment diagnoses is central to enable appropriate interventions. Previous studies indicate that dual-task testing may be useful in such differentiation. The objective of this study was to investigate whether dual-task test outcomes discriminate between groups of individuals with dementia disorder, mild cognitive impairment, subjective cognitive impairment, and healthy controls. Methods A total of 464 individuals (mean age 71 years, 47% women) were included in the study, of which 298 were patients undergoing memory assessment and 166 were cognitively healthy controls. Patients were grouped according to the diagnosis received: dementia disorder, mild cognitive impairment, or subjective cognitive impairment. Data collection included participants’ demographic characteristics. The patients’ cognitive test results and diagnoses were collected from their medical records. Healthy controls underwent the same cognitive tests as the patients. The mobility test Timed Up-and-Go (TUG single-task) and two dual-task tests including TUG (TUGdt) were carried out: TUGdt naming animals and TUGdt months backwards. The outcomes registered were: time scores for TUG single-task and both TUGdt tests, TUGdt costs (relative time difference between TUG single-task and TUGdt), number of different animals named, number of months recited in correct order, number of animals per 10 s, and number of months per 10 s. Logistic regression models examined associations between TUG outcomes pairwise between groups. Results The TUGdt outcomes “animals/10 s” and “months/10 s” discriminated significantly (p Conclusions The novel TUGdt outcomes “words per time unit”, i.e. “animals/10 s” and “months/10 s”, demonstrate high levels of discrimination between all investigated groups. Thus, the TUGdt tests in the current study could be useful as complementary tools in diagnostic assessments. Future studies will be focused on the predictive value of TUGdt outcomes concerning dementia risk for individuals with mild cognitive impairment or subjective cognitive impairment.

Introduction The e4 allele of the apolipoprotein E ( APOE ) gene is a prominent risk factor for Alzheimer's disease (AD), but its implication in other dementias is less well studied. Methods We used a data set on 2858 subjects (1098 AD, 260 vascular dementia [VaD], 145 mixed AD and VaD, 90 other dementia diagnoses, and 1265 controls) to examine the association of APOE polymorphisms with clinical dementia diagnoses, biomarker profiles, and longevity. Results The e4 allele was associated with reduced longevity as e4 versus e3 homozygotes lived on average 2.6 years shorter ( P = .006). In AD, e4 carriers lived 1.0 years shorter than noncarriers ( P = .028). The e4 allele was more prevalent in AD, mixed AD and VaD, and VaD patients compared to controls, but not in other dementia disorders. Discussion The APOE e4 allele is influential in AD but might also be of importance in VaD and in mixed AD and VaD, diseases in which concomitant AD pathology is common.

OBJECTIVES: To investigate associations between time updated information of milk and fermented milk consumption and risk of total stroke. METHODS: We included 79,613 Swedish adults (35,892 women and 43,721 men), 45–83 years of age, without stroke at baseline in 1997 (SIMPLER, simpler4health.se). The participants completed a validated 96-item food frequency questionnaire including questions about milk and soured milk and yogurt consumption at baseline and in 2009. Incident and previous stroke cases were identified by linkage with the Swedish National Patient and Cause of Death Registers. Associations between milk and fermented milk intake and incident total stroke were assessed by restricted cubic spline Cox regression. We included the baseline covariates sex and educational level, and time updated exposures and covariates (age, smoking, total energy intake, body mass index, physical activity, living alone, coffee, vitamin- and mineral supplements, alcohol consumption, hypertension, hypercholesterolemia, diabetes mellitus, coronary heart disease, weighted Charlson Comorbidity Index, and intakes of fermented milk (in analyses of milk), milk (in analyses of fermented milk), fruits and vegetables, processed meat, soft drink, juice, total fat, and saturated fat) from 2009. RESULTS: The average intake in 1997 was 260 grams (g)/day (d) for milk and 160 g/d for fermented milk (200 g corresponds to 1 glass). During a mean follow-up of 17.7 years (maximum follow-up of 22 years), 9736 total stroke cases were identified. P-values for non-linearity were 0.010 for milk and 0.721 for fermented milk. Compared with zero intake the Hazard ratio (HR) for milk intake was 0.95 (95% Confidence Interval (CI) 0.91, 0.99) for 200 g/d, 0.94 (95% CI 0.89, 1.00) for 400 g/d, and 0.97 (95% CI (0.91, 1.02) for 600 g/d. For fermented milk intake the HR was 0.99 (95% CI 0.95, 1.04) for 200 g/day, 1.00 (0.95% CI 0.95, 1.05) for 400 g/d, and 1.01 (95% CI 0.95, 1.07) for 600 g/d compared with zero intake. CONCLUSIONS: A low to moderate, but not higher, milk consumption (1–2 glasses/d) seem to have a protective effect on total stroke, compared to zero intake. Consumption of fermented milk was not associated with total stroke. FUNDING SOURCES: SIMPLER is funded by Vetenskapsrådet. The current work is funded by Forte.

OBJECTIVES: To find cut-off values for different medial temporal lobe atrophy (MTA) measures (right, left, average, and highest), accounting for gender and education, investigate the association with cognitive performance, and to compare with decline of cognitive function over 5 years in a large population-based cohort. METHODS: Three hundred and ninety 75-year-old individuals were examined with magnetic resonance imaging of the brain and cognitive testing. The Scheltens's scale was used to assess visually MTA scores (0-4) in all subjects. Cognitive tests were repeated in 278 of them after 5 years. Normal MTA cut-off values were calculated based on the 10th percentile. RESULTS: Most 75-year-old individuals had MTA score ≤2. Men had significantly higher MTA scores than women. Scores for left and average MTA were significantly higher in highly educated individuals. Abnormal MTA was associated with worse results in cognitive test and individuals with abnormal right MTA had faster cognitive decline. CONCLUSION: At age 75, gender and education are confounders for MTA grading. A score of ≥2 is abnormal for low-educated women and a score of ≥2.5 is abnormal for men and high-educated women. Subjects with abnormal right MTA, but normal MMSE scores had developed worse MMSE scores 5 years later. KEY POINTS: • Gender and education are confounders for MTA grading. • We suggest cut-off values for 75-year-olds, taking gender and education into account. • Males have higher MTA scores than women. • Higher MTA scores are associated with worse cognitive performance.

Background Many people with Alzheimer's disease (AD) live alone in their own homes. There is a lack of knowledge about whether these individuals receive the same quality of diagnostics and treatment for AD as patients who are cohabiting. Objectives To investigate the diagnostic work-up and treatment of community-dwelling AD patients who live alone. Methods We performed a cross-sectional cohort study based on data from the Swedish Dementia Registry (SveDem). We studied patients diagnosed with AD between 2007 and 2015 (n = 26,163). Information about drugs and comorbidities was acquired from the Swedish Prescribed Drug Register and the Swedish Patient Register. Results 11,878 (46%) patients lived alone, primarily older women. After adjusting for confounders, living alone was inversely associated with receiving computed tomography (OR 0.90; 95% CI 0.82-0.99), magnetic resonance imaging (OR 0.91; 95% CI 0.83-0.99), and lumbar puncture (OR 0.86; 95% CI 0.80-0.92). Living alone was also negatively associated with the use of cholinesterase inhibitors (OR 0.81; 95% CI 0.76; 0.87), memantine (OR 0.77; 95% CI 0.72; 0.83), and cardiovascular medication (OR 0.92; 0.86; 0.99). On the other hand, living alone was positively associated with the use of antidepressants (OR 1.15; 95% CI 1.08; 1.22), antipsychotics (OR 1.41; 95% CI 1.25; 1.58), and hypnotics and sedatives (OR 1.09; 95% CI 1.02; 1.17). Conclusions Solitary living AD patients do not receive the same extent of care as those who are cohabiting.

OBJECTIVE The aim of this study was to explore whether total atherosclerotic burden is related to future decline in performance on cognitive tests. METHODS The total atherosclerotic burden (TAS) was assessed by whole-body magnetic resonance angiography (WBMRA) in 305 subjects at age 70 in the study Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS). The mini-mental state examination (MMSE) and trail making tests (TMT) A and B were evaluated at ages 75 and 80 in 190 of those subjects. No subject with a diagnosis of dementia was included in the sample. RESULTS MMSE did not change during the 5 years of follow-up, while TMT A and B increased by 4 and 7 s, respectively. TAS at age 70 was significantly related to the individual change in TMT B (P

Background: Vitamin D has been implicated as being important for maintaining cognitive function in old age. Results from longitudinal studies examining the association of vitamin D with incident dementia and cognitive impairment have been inconsistent.Objective: We investigated the relation between vitamin D, assessed in 3 different ways, and the risk of dementia.Design: We measured plasma 25-hydroxyvitamin D [25(OH)D] with the use of high-performance liquid chromatography-mass spectrometry, assessed dietary vitamin D intake with the use of 7-d dietary records, and created a vitamin D-synthesis genetic risk score (GRS) at baseline (1991-1995) in a cohort of 1182 Swedish men (mean age: 71 y). In a maximum of 18 y (median: 12 y) of follow-up, 116 men developed Alzheimer disease, 64 men developed vascular dementia, and 250 men developed all-cause dementia. An additional 80 men declined in cognitive function as assessed with the use of the Mini-Mental State Examination. Adjusted HRs and ORs were calculated with the use of Cox and logistic regressions.Results: The mean ± SD plasma 25(OH)D concentration was 68.7 ± 19.1 nmol/L. Plasma 25(OH)D, dietary vitamin D intake, and vitamin D-synthesis GRS were not associated with any cognitive outcomes (crude and adjusted HRs and ORs were ∼1.0 for all continuous exposures). The adjusted HR for all-cause dementia was 0.88 (95% CI: 0.59, 1.31) in men with plasma 25(OH)D concentrations ≤50 compared with >75 nmol/L. The adjusted HR for all-cause dementia was 0.92 (95% CI: 0.63, 1.32) for the lowest compared with highest tertiles of vitamin D intake. The adjusted HR for the continuous GRS for all-cause dementia was 1.04 (95% CI: 0.91, 1.19).Conclusion: In this cohort study, we show that there is no association between baseline vitamin D status and long-term risk of dementia or cognitive impairment over an 18-y period of time.

Background Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. Objective We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. Methods We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable. Results By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. Conclusions Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

Background Preserved functions of daily life and cognition are cornerstones of independent aging, which is crucial for maintaining a high quality of life. The aim of this study was to examine the impact of sarcopenia, and its underlying components, on independent ageing in a cohort study of very old men. Methods The presence of sarcopenia and independent ageing at a mean age of 87 was investigated in 287 men from the Uppsala Longitudinal Study of Adult Men. Five years later 127 men were re-evaluated for independent ageing. Sarcopenia was defined by two different definitions from the European Working Group on Sarcopenia in Older People. In the first definition sarcopenia was defined as skeletal muscle index 15 s defines probable sarcopenia, which is confirmed by SMI

1 Purpose This study is part of a larger effort aiming to expand the knowledge of brain‐enriched proteins in human cerebrospinal fluid (CSF) and to provide novel insight into the relation between such proteins and different neurodegenerative diseases. 2 Experimental design Here 280 brain‐enriched proteins in CSF from patients with Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are profiled. In total, 441 human samples of ventricular CSF collected post mortem and lumbar CSF collected ante mortem are analyzed using 376 antibodies in a suspension bead array setup, utilizing a direct labelling approach. 3 Results Among several proteins displaying differentiated profiles between sample groups, we focus here on two synaptic proteins, neuromodulin (GAP43) and neurogranin (NRGN). They are both found at elevated levels in CSF from AD patients in two independent cohorts, providing disease‐associated profiles in addition to verifying and strengthening previously observed patterns. Increased levels are also observed for patients for whom the AD diagnosis was not established at the time of sampling. 4 Conclusions and clinical relevance These findings indicate that analyzing the brain‐enriched proteins in CSF is of particular interest to increase the understanding of the CSF proteome and its relation to neurodegenerative disorders. In addition, this study lends support to the notion that measurements of these synaptic proteins could potentially be of great relevance in future diagnostic tests for AD.

Neuroimaging is a central part of diagnostic work-up of patients with suspected neurodegenerative disease. FDG-PET can reveal pathological changes earlier and more reliably than morphological imaging. Diagnostic accuracy can be improved by constructing 3D SSP Z-score maps, showing patterns of significant deficits. During FDG-PET, the subject receives a moderate but not insignificant dose of ionizing radiation, and a dose reduction with retained image quality is desirable. With lower dose, repeated examinations can become a useful tool for monitoring disease progress and potential effects of disease-modifying interventions. The aim of this study was to evaluate Z-maps created from low-dose and normal-dose FDG-PET of the brain, with quantitative and qualitative methods. Nine patients with neurodegenerative disorders were prospectively enrolled and nine age-matched controls were recruited through advertising. All subjects (n=18) underwent two FDG-PET scans on separate occasions; a routine and a low-dose scan. The routine dosage of FDG was 3 MBq/kg, and low dosage was 0.75 MBq/kg. 3D-SSP images showing Z-scores of < -1.96 were created from 10-minute summations. The study was comprised of a quantitative part comparing the Z-scores, and a qualitative part where experienced nuclear medicine specialists visually assessed the images. Regarding the quantitative part, Bland-Altman analysis showed a slight constant bias (0.206). Regarding qualitative discrimination between patients and controls, the performance between normal- and low-dose were equal, both showing 72% sensitivity, 83% specificity and 78% accuracy. In this study, visual assessment of 3D-SSP Z-score maps from low-dose FDG-PET provided diagnostic information highly comparable to normal-dose, with minor quantitative discrepancies.

Background and Purpose: Signs of small vessel disease (SVD) are commonly seen on magnetic resonance imaging (MRI) of the brain in cognitively healthy elderly individuals, and the clinical relevance of these are often unclear. We have previously described three different MRI manifestations of SVD as well as cerebral perfusion in a longitudinal study of non-demented 75-year-old subjects. The purpose of the present study was to evaluate the relationship of these findings to cognition and executive function at age 75 and changes after 5 years. Methods: In all, 406 subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study were examined with MRI of the brain at age 75 years. Two-hundred and fifty of the subjects were re-examined 5 years later. White matter hyperintensities (WMHs) and lacunar infarcts (LIs) were assessed on both occasions, but microbleeds (MBs) and perfusion only at age 75. Cognitive function was screened by the Mini Mental State Examination (MMSE). Trail Making Test A and B (TMT-A and TMT-B) were performed at baseline and at follow-up at age 80. Results: At baseline, 93% performed >27 points in the MMSE. The TMT-B at age 75 was significantly related to WMH visual scoring after adjustment for sex, education and cerebrovascular disease risk factors (+80 s (95% CI 0.3-161 s), P < 0.05 for grade 2-3 vs. grade 0). Neither MMSE nor TMT-A was significantly related to WMH scoring. There was no relation between any test performance and WMH volume, white matter volume, number of MBs or brain perfusion at age 75. Subjects who had sustained a new LI (n = 26) showed a greater increase of the time to perform TMT-A at the 5-year follow-up (+25 s vs. +4 s in LI-free subjects, P = 0.003). Changes in MMSE or TMT-A and -B test performance between ages 75 and 80 were not related to changes in WMH scoring or volume during the 5 years follow-up, or to brain perfusion at age 75. Conclusion: In this cognitively healthy community-based population, moderate-severe WMHs and incident LIs on brain MRI in individuals aged 75-80 years were associated with a mild impairment of processing speed and executive function.