Faster Rate Of Cognitive Decline Research Articles

Interleukin-6 and C-Reactive Protein Levels and 9-Year Cognitive Decline in Community-Dwelling Older Women: The Women’s Health and Aging Study II

Elevated inflammation is a proposed mechanism relating chronic diseases to cognitive dysfunction. The objective of this study was to test the hypothesis that greater levels of inflammation, as measured by the proinflammatory cytokine interleukin-6 (IL-6) and C-reactive protein, are associated with faster rates of cognitive decline among cognitively intact community-dwelling older women. We analyzed 336 women from the Women's Health and Aging Study II. Cognitive assessments were performed at baseline and every 18-36 months, and included the following domains: immediate and delayed memory (Hopkins Verbal Learning Test), psychomotor speed (Trail Making Test, Part A), and executive function (Trail Making Test, Part B). Aggregate measures of IL-6 and C-reactive protein, based on the average from visits one and two, were analyzed categorically. Random effects models were employed to test the relationship between tertiles of each inflammatory marker and changes in cognitive domain scores over 9 years. Moderate and high levels of IL-6 predicted early declines in psychomotor speed by 1.0 connection/min per year. There were no differences in baseline scores or rates of change across tertiles of IL-6 in memory or executive function. No differences were observed across tertiles of C-reactive protein for all cognitive domains. Higher levels of serum IL-6 were associated with greater declines in psychomotor speed over 9 years. This finding could suggest that elevated IL-6 may result in microvascular changes that may lead to damage of myelin sheaths that line neuronal axons, leading to decreased neuron propagation and impaired processing speed; however, mechanistic studies are needed to evaluate these hypotheses.

Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals.

Human cytomegalovirus (CMV) is prevalent in older adults and has been implicated in many chronic diseases of aging. This study investigated the relation between CMV and the risk of Alzheimer disease (AD). Data come from 3 cohort studies that included 849 participants (mean age [±SD], 78.6 ± 7.2 years; mean education duration [±SD], 15.4 ± 3.3 years; 25% black). A solid-phase enzyme-linked immunosorbent assay was used for detecting type-specific immunoglobulin G antibody responses to CMV and herpes simplex virus type 1 (HSV-1) measured in archived serum samples. Of 849 participants, 73.4% had serologic evidence of exposure to CMV (89.0% black and 68.2% white; P < .001). During an average of 5.0 years of follow-up, 93 persons developed AD. CMV seropositivity was associated with an increased risk of AD (relative risk, 2.15; 95% confidence interval, 1.42-3.27) and a faster rate of decline in global cognition (estimate [±standard error], -0.02 ± 0.01; P = .03) in models that controlled for age, sex, education duration, race, vascular risk factors, vascular diseases, and apolipoprotein ε4 level. Results were similar in black and white individuals for both incident AD and change in cognitive function and were independent of HSV-1 status. These results suggest that CMV infection is associated with an increased risk of AD and a faster rate of cognitive decline in older diverse populations.

Perceived stress and change in cognitive function among adults 65 years and older.

Exposure to acute and chronic stress can affect learning and memory, but most evidence comes from animal studies or clinical observations. Almost no population-based studies have investigated the relation of stress to cognition or changes in cognition over time. We examined whether higher levels of perceived stress were associated with accelerated decline in cognitive function in older blacks and whites from a community-based population sample. Participants included 6207 black and white adults (65.7% black, 63.3% women) from the Chicago Health and Aging Project. Two to five in-home assessments were completed over an average of 6.8 years of follow-up and included sociodemographics, health behaviors, psychosocial measures, cognitive function tests, and health history. Perceived stress was measured by a six-item scale, and a composite measure of four tests of cognition was used to determine cognitive function at each assessment. Mixed-effects regression models showed that increasing levels of perceived stress were related to lower initial cognitive scores (B = -0.0379, standard error = 0.0025, p < .001) and a faster rate of cognitive decline (stress × time interaction: B = -0.0015, standard error = 0.0004, p < .001). Results were similar after adjusting for demographic variables, smoking, systolic blood pressure, body mass index, chronic medical conditions, and psychosocial factors and did not vary by race, sex, age, or education. Increasing levels of stress are independently associated with accelerated declines in cognitive function in black and white adults 65 years and older.

Impact of Offspring Death on Cognitive Health in Late Life: The Cache County Study

Experiencing the death of a child is associated with negative short-term mental health consequences, but less is known about cognitive outcomes and whether such associations extend to late life. We tested the hypothesis that experiencing an offspring death (OD) is associated with an increased rate of cognitive decline in late life. This population-based longitudinal study observed four cognitive statuses spaced 3-4 years apart, linked to an extensive database containing objective genealogic and vital statistics data. Home visits were conducted with 3,174 residents of a rural county in northern Utah, initially without dementia, aged 65-105. Cognitive status was measured with the Modified Mini-Mental State Exam at baseline and at 3-, 7-, and 10-year follow-ups. OD was obtained from the Utah Population Database, which contains statewide birth and death records. In linear mixed models, controlling for age, gender, education, and apolipoprotein E status, subjects who experienced OD while younger than age 31 years experienced a significantly faster rate of cognitive decline in late life, but only if they had an ε4 allele. Reclassifying all OD (regardless of age) according to subsequent birth of another child, OD was only related to faster cognitive decline when there were no subsequent births. Experiencing OD in early adulthood has a long-term association with cognitive functioning in late life, with a gene-environment interaction at the apolipoprotein E locus. Subsequent birth of another child attenuates this association.

Cerebrospinal Fluid PKR Level Predicts Cognitive Decline in Alzheimer’s Disease

The cerebrospinal fluid (CSF) levels of the proapoptotic kinase R (PKR) and its phosphorylated PKR (pPKR) are increased in Alzheimer’s disease (AD), but whether CSF PKR concentrations are associated with cognitive decline in AD patients remain unknown. In this study, 41 consecutive patients with AD and 11 patients with amnestic mild cognitive impairment (aMCI) from our Memory Clinic were included. A lumbar puncture was performed during the following month of the clinical diagnosis and Mini-Mental State Examination (MMSE) evaluations were repeated every 6 months during a mean follow-up of 2 years. In AD patients, linear mixed models adjusted for age and sex were used to assess the cross-sectional and longitudinal associations between MMSE scores and baseline CSF levels of Aβ peptide (Aβ 1-42), Tau, phosphorylated Tau (p-Tau 181), PKR and pPKR. The mean (SD) MMSE at baseline was 20.5 (6.1) and MMSE scores declined over the follow-up (-0.12 point/month, standard error [SE] = 0.03). A lower MMSE at baseline was associated with lower levels of CSF Aβ 1–42 and p-Tau 181/Tau ratio. pPKR level was associated with longitudinal MMSE changes over the follow-up, higher pPKR levels being related with an exacerbated cognitive deterioration. Other CSF biomarkers were not associated with MMSE changes over time. In aMCI patients, mean CSF biomarker levels were not different in patients who converted to AD from those who did not convert.These results suggest that at the time of AD diagnosis, a higher level of CSF pPKR can predict a faster rate of cognitive decline.

Migraine and cognitive decline among women: prospective cohort study

Objective To evaluate the association between migraine and cognitive decline among women.Design Prospective cohort study.Setting Women’s Health Study, United States.Participants 6349 women aged 65 or older enrolled in the Women’s...

Diabetes is associated with cognitive impairment no dementia in the aging, demographics, and memory study (ADAMS)

Individuals with diabetes mellitus have a 1.39 times increased risk of Alzheimer's disease, a 2.38 times increased risk of vascular dementia, and a faster rate of cognitive decline compared to individuals without diabetes (Lu et al., 2009). In a study, over a 9-year follow-up diabetes was associated with accelerated progression from mild cognitive impairment (MCI) to dementia, but was not associated with progression from no impairment to MCI (Xu et al., 2010). Many previous studies on cognitive impairment and diabetes are limited by the use of cognitive screens to diagnose and assess cognitive impairment. A few studies diagnosing cognitive impairment with comprehensive neuropsychological batteries provide mixed results. For instance, Luchinger et al. (2007) found that diabetes was correlated with the presence of MCI, whereas diabetes was not associated with the presence of dementia versus no dementia in the Aging, Demographics, and Memory Study ADAMS; (Llewellyn et al., 2010).

Is there a bidirectional relationship between depressive symptoms and cognitive ability in older people? A prospective study using the English Longitudinal Study of Ageing

BackgroundCross-sectional surveys of older people commonly find associations between higher levels of depressive symptoms and poorer cognitive performance, but the direction of effect is unclear. We examined whether there was a bidirectional relationship between depressive symptoms and general cognitive ability in non-demented older people, and explored the role of physical health, smoking, exercise, social class and education as potential confounders of this association and as possible determinants of the rate of change of cognitive decline and depressive symptoms.MethodThe English Longitudinal Study of Ageing consists of people aged 50 years and over. Cognitive function and self-reported depressive symptoms were measured in 2002–2003, 2004–2005, 2006–2007 and 2008–2009. We fitted linear piecewise models with fixed knot positions to allow different slopes for different age groups. Analyses are based on 8611 people.ResultsMean cognitive function declined with age; there was no trend in the trajectory of depressive symptoms. Better cognitive function was associated with less depression up to the age of 80 years. Greater depression was associated with a slightly faster rate of cognitive decline but only in people aged 60–80 years. There were no consistent associations across age groups between sex, smoking, education, social class, exercise or number of chronic physical illnesses and the rate of change of cognitive decline or depressive symptoms.ConclusionsIn this longitudinal study of older people, there was no consistent evidence that being more depressed led to an acceleration in cognitive decline and no support for the hypothesis that there might be reciprocal dynamic influences between cognitive ability and depressive symptoms.

CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer's disease.

Chemokine (C-C motif) receptor 2 (CCR2)-signaling can mediate accumulation of microglia at sites affected by neuroinflammation. CCR2 and its main ligand CCL2 (MCP-1) might also be involved in the altered metabolism of beta-amyloid (Aβ) underlying Alzheimer's disease (AD). We therefore measured the levels of CCL2 and three other CCR2 ligands, i.e. CCL11 (eotaxin), CCL13 (MCP-4) and CCL26 (eotaxin-3), in the cerebrospinal fluid (CSF) and plasma of 30 controls and 119 patients with mild cognitive impairment (MCI) at baseline. During clinical follow-up 52 MCI patients were clinically stable for five years, 47 developed AD (i.e. cases with prodromal AD at baseline) and 20 developed other dementias. Only CSF CCL26 was statistically significantly elevated in patients with prodromal AD when compared to controls (p = 0.002). However, in patients with prodromal AD, the CCL2 levels in CSF at baseline correlated with a faster cognitive decline during follow-up (r s = 0.42, p = 0.004). Furthermore, prodromal AD patients in the highest tertile of CSF CCL2 exhibited a significantly faster cognitive decline (p<0.001) and developed AD dementia within a shorter time period (p<0.003) compared to those in the lowest tertile. Finally, in the entire MCI cohort, CSF CCL2 could be combined with CSF Tau, P-tau and Aβ42 to predict both future conversion to AD and the rate of cognitive decline. If these results are corroborated in future studies, CCL2 in CSF could be a candidate biomarker for prediction of future disease progression rate in prodromal AD. Moreover, CCR2-related signaling pathways might be new therapeutic targets for therapies aiming at slowing down the disease progression rate of AD.

Phenotypic differences between apolipoprotein E genetic subgroups: research and clinical implications

With the recent interest in Alzheimer's disease course modification and earlier, even preclinical, intervention, questions have arisen regarding the potentially confounding impact of apolipoprotein E (APOE) genotype on study design, therapeutic outcomes, and even clinical practice. APOE e4 carriers have a faster rate of cognitive decline both preclinically and during the mild cognitive impairment (MCI) stage, and a higher burden of cerebrovascular amyloid that may be the basis for the observed gene-dose-related increased frequency of immunomodulatory therapy-induced meningoencephalitis and cerebral microhemorrhages. To date, this has impacted study design in some research trials but not clinical practice.

Factors that influence survival in a probable Alzheimer disease cohort

IntroductionThis longitudinal study examined multiple factors that influence survival in a cohort of Alzheimer patients followed over two decades.MethodsTime to death after symptom onset was determined in 641 probable AD patients who were evaluated annually until death or loss to follow-up, and information was entered into a longitudinal database. Date of death was available for everyone including those eventually lost. Baseline variables included age, sex, race, disease severity, a calculated index of rate of initial cognitive decline from symptom onset to cohort entry (pre-progression rate or PPR), years of education, and medical comorbidities (diabetes, hypertension, hyperlipidemia, coronary disease, cerebrovascular disease). Multivariable Cox proportional hazard regression analysis was used to analyze the baseline and/or time dependent association in Mini-mental Status Exam (MMSE) severity, Physical Self Maintenance Scale (PSMS), Persistency Index (PI) of exposure to antipsychotic and antidementia drugs, and psychotic symptoms (hallucinations, delusions) with mortality.ResultsBaseline covariates significantly associated with increased survival were younger age (p = .0016), female sex (p = .0001), and a slower PPR (p < .0001). Overall disease severity at baseline, medical comorbidities, and education did not influence time to death. Time-dependent changes in antipsychotic drug use, development of psychotic symptoms, antidementia drug use, and observed MMSE change were not predictive. In the final model the only time-dependent covariate that significantly decreased survival was worsening of functional ability on the PSMS (hazard ratio = 1.10; CI: 1.07-1.11).ConclusionsIn this large AD cohort survival is influenced by age, sex, and the development of functional disability during follow-up. The most important predictor of mortality was a faster rate of cognitive decline at the initial patient visit (PPR). The currently available antidementia drugs do not prolong survival in Alzheimer patients.

Serum concentration of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive decline in elderly individuals

BackgroundAdvanced glycations end products increase oxidant stress, inflammation, and neurotoxicity. Serum levels are increased in diabetes and aging. We examined the relationship between serum methylglyoxal derivatives (sMG), and cognitive decline, in 267 non-demented elderly. MethodsTobit mixed regression models assessed the association of baseline sMG with cognitive decline in the Mini Mental State Exam (MMSE) over time, controlling for sociodemographic factors (age, sex, and years of education), cardiovascular risk factors (diabetes and presence of an ApoE4 allele), and kidney function. sMG was assessed by ELISA. ResultsThe fully adjusted model showed an annual decline of 0.26 MMSE points per unit increase in baseline sMG (p=0.03). Significance was unchanged as additional risk factors were added to the model. The interactions of sMG with diabetes, sex, age, kidney function, and ApoE4 genotype were not significant. ConclusionsHigher levels of baseline sMG were associated with a faster rate of cognitive decline, after adjusting for several sociodemographic and clinical characteristics. This relationship did not differ by sex, ApoE4 genotype, or diabetes status suggesting its generality. Since subjects were cognitively normal at the beginning of the study, elevated sMG may be indicative of brain cell injury initiated before clinically evident cognitive compromise.

Race and cognitive decline among community-dwelling elders with mild cognitive impairment: Findings from the Memory and Medical Care Study

Objective: Previous studies have reported conflicting findings on the relationship between race and cognitive decline in elders with dementia. Few studies have examined the role of race in cognitive decline in mild cognitive impairment (MCI). We investigate the relationship between race and cognitive decline in participants with MCI in a community-based, longitudinal study of cognitively impaired elders. Method: Based on a validated method utilizing a neuropsychiatric battery, 133 subjects [mean age: 78.7 years (SD = 6.5); female: 112 (76.7%); black: 59 (44.4%)] out of 512 participants in the Memory and Medical Care Study were diagnosed with MCI. The main outcome measure was the Telephone Interview for Cognitive Status (TICS) score over three years. Other baseline subject characteristics (demographics, health-related variables, behavioral, and psychiatric symptoms) were included in the analysis. Results: Overall, the three-year decline in mean TICS score was significantly higher among African Americans than non-African Americans [3.31 (SD: 7.5) versus 0.96 (SD: 3.0), t-value = 1.96, p-value = 0.05]. General estimating equation analyses revealed that African American race was associated with a faster rate of cognitive decline in all models. Conclusion: The rate of cognitive decline in MCI appears to be faster in African Americans than non-African Americans in the community. Diagnosis of MCI among African American elders could lead to early interventions to prevent or delay cognitive decline in the future.

O1-4.4 Framingham stroke risk profile and cognitive decline in middle age: the Whitehall II study

BackgroundThe relationship between stroke risk and cognitive ageing has not been adequately studied in non-elderly populations. The objective of this study was to examine whether 10-year risk for incident stroke...

Relationship between changes of body mass index (BMI) and cognitive decline in Parkinson's disease (PD)

Decreased BMI has been reported that it may be associated with cognitive decline in the elderly. Weight loss is common in patients with PD. However, studies comparing cognitive changes according to BMI changes in PD have not been done yet. We performed this study to know a relationship between BMI changes and the rate of cognitive decline in PD. PD patients were recruited retrospectively. The patients (n=104) were divided into two groups according to BMI changes during initial 6 months of follow-up: decreased (n=52) vs. stable BMI groups (n=52). Cognitive functions were repeated until 36 months of follow-up using the Korean version of the Mini-Mental State Examination (K-MMSE) and the modified Mini-Mental State (3MS) test. We calculated the rate of cognitive decline (K-MMSE and 3MS score changes/month) and compared it between the two groups. The decreased BMI group showed lower level of cognitive function than that of stable BMI group, especially at the 36th month of follow-up (p<0.05). In addition, the rate of cognitive decline was also significantly faster in the decreased BMI group, particularly at the 36th month of follow-up (p<0.05). This study suggests that decreased BMI during initial 6 months of follow-up in PD might be a useful indicator for future risk of dementia and let clinicians predict faster rate of cognitive decline in patients with PD.

Comparison of diagnostic power of cerebrospinal fluid Aß and Tau variables for Alzheimer's disease diagnosis: proposition of a simple decision tree

Background: Advanced glycations endproducts (AGE) are known to cause increased oxidant stress, inflammation, and neurotoxicity; serum levels are increased in diabetes and aging. We examined the relationship between levels of serum methylglyoxal (sMG), an AGE precursor, and cognitive decline in elderly. Methods: Subjects were 266 initially non-demented elderly who had complete data including at least two MMSEs. Tobit mixed regression models assessed the association of baseline MG with cognitive decline in the Mini Mental State Exam (MMSE) score over time, controlling for sociodemographic factors (age, sex, and years of education), and cardiovascular risk factors (diabetes and presence of anAPOE4 allele). sMGwas assessed by ELISA. Results: The sample averaged 83.5 years of age, 14.3 years of education, 36 months of follow up, and 0.93 nmol/ml of sMG. Average baseline MMSE of 28.2 reflected this cognitively normal sample. Seventy six percent of the sample was male since a major source of recruitment was the Mount Sinai affiliate James J. Peters Veterans Affairs Medical Center; 18% had diabetes and 20% carried an APOE4 allele. The fully adjusted model showed an annual decline of 0.33 MMSE points per unit increase in baseline sMG (p 1⁄4 0.015). Significance improved as additional risk factors were added to the model. The interactions of sMGwith diabetes, sex, age, and APOE4 genotype were not significant and did not substantially improve the model fit. In a small replication sample of 49 younger elderly (average age 70, education 14.6, 18 months of follow up, sMG1⁄4 0.91 nmol/ml, baselineMMSE 28.8, 53%males, 13% had diabetes, 9% carried an APOE4 allele), who had a broad neuropsychological battery, results were essentially identical: for the fully adjusted model: p 1⁄4 0.01 when using the MMSE as outcome measure and p 1⁄4 0.03 when using an overall cognition outcome measure. Conclusions: Higher levels of circulating MG were associated with a faster rate of cognitive decline, after adjusting for several sociodemographic and clinical characteristics. This relationship did not differ by sex, APOE4 genotype, or diabetes status suggesting its generality. Since subjects were cognitively normal at the beginning of the study, elevated circulating MG may be indicative of brain cell injury initiated before clinically evident cognitive compromise. Because levels of MG in blood correlate with those consumed with diet, lowering MG by AGE restricted diet has potential for preventing cognitive compromise.

Faster rate of cognitive decline in essential tremor cases than controls: a prospective study

Mild cognitive deficits have been reported in essential tremor (ET). However, these cognitive deficits have been assessed in cross-sectional rather than longitudinal analyses. To determine whether decline in cognitive test scores occurs at a faster rate in ET cases than controls. In a population-based study of older people (≥ 65 years) in central Spain (Neurological Disorders in Central Spain, NEDICES), non-demented ET cases and controls were followed prospectively. Participants with baseline or incident Parkinson's disease or dementia were excluded as were participants who developed incident ET. At baseline (1994-1995) and at follow-up (1997-1998), a 37-item version of the mini-mental state examination (37-MMSE) was administered. A total of 2319 participants (72.4 ± 5.8 years) included 135 prevalent ET cases and 2184 controls. At baseline, the mean 37-MMSE in cases was 28.8 ± 5.8 vs. 30.2 ± 4.8 in controls (P = 0.02). During the 3-year follow-up period, the 37-MMSE declined by 0.70 ± 3.2 points in cases vs. 0.11 ± 3.8 points in controls (P = 0.03). In analyses that adjusted for age, education, and other potential confounders, the case-control difference remained robust. In this population-based, prospective study of non-demented elders, baseline cognitive test scores were lower in ET cases than controls; moreover, during the 3-year follow-up period, these scores declined at a rate that was seven-times faster in ET cases. This study provides evidence that cognitive deficits in ET are not static, and they appear to be progressing at a faster rate than in elders without this disease.

Relationship between changes of body mass index and cognitive decline in Parkinson's disease

Although the relation between body mass index (BMI) changes and risk of dementia is not always associated linearly, decreased BMI has been reported that it may be associated with increased risk of cognitive decline in the elderly. Weight loss is very common in patients with Parkinson's disease (PD) because of changes in appetite due to medication or chewing and swallowing difficulty related with muscular rigidity or higher energy expenditure due to involuntary movement. However, studies comparing BMI changes with cognitive function in PD have not been done yet. We performed this study to evaluate association between BMI changes and rate of cognitive decline and to know whether co-morbid conditions occur more frequently in BMI reduction group of PD. PD patients who measured their height and weight to calculate BMI and evaluated cognitive function regularly at the movement clinic of CNUH were recruited retrospectively. The patients (n = 78) were divided into two groups according to BMI changes during initial 6 months: decreased vs. stable BMI groups. Cognitive functions were evaluated by the Korean versions of Mini-Mental State Examination (MMSE) and the modified Mini-Mental State (3MS) test. Clinical examination, MMSE and 3MS were done at 6-, 12-, 24- and 36-month of follow-up. The rate of cognitive decline (MMSE and 3MS score changes/months) was compared in both groups from the baseline to each follow up. The co-morbid conditions such as pneumonia or bone fracture were evaluated through detailed chart review. The decreased BMI group showed more rapid decline of cognitive function than that of stable BMI group in PD. The rate of cognitive decline measured by both MMSE and 3MS tests was significantly faster especially at the 24- and 36- month of the follow-ups compared with the initial 1-year period of the follow-up in the decreased BMI group. No significant difference in the frequency of co-morbid diseases was found between the two groups. This study suggests that decreased BMI might be a useful indicator for future risk of dementia and let clinicians predict faster rate of cognitive decline in patients with PD.

Diabetes Is Associated with Increased Rate of Cognitive Decline in Questionably Demented Elderly

Background: This study examines whether the association of diabetes with the rate of cognitive decline varies according to dementia severity. Methods: Longitudinal study on subjects residing in nursing homes and assisted living (n = 342). The Mini Mental State Examination (MMSE) was used to measure the rate of cognitive decline in diabetic and nondiabetic subjects who were nondemented (Clinical Dementia Rating, CDR = 0; n = 125), questionably demented (CDR = 0.5; n = 58) or frankly demented (CDR ≧1; n = 89) at baseline. Diagnosis of diabetes was ascertained by review of medical records and history. Results: Diabetes was associated with an increased rate of decline in the MMSE score of questionably demented subjects (p < 0.0001). In frankly demented subjects, diabetes tended to be associated with less cognitive decline (p = 0.04). Diabetes was not associated with the rate of MMSE decline in nondemented subjects (p = 0.89). Conclusion: In individuals with questionable dementia (CDR = 0.5), diabetes is associated with a faster rate of cognitive decline as measured by the MMSE, but not in nondemented (CDR = 0) or frankly demented (CDR ≧1) individuals.

CSF biomarkers predict rate of cognitive decline in Alzheimer disease

CSF biomarkers amyloid beta 1-42 (Abeta(42)), total tau (tau), and tau phosphorylated at threonine 181 (p-tau-181) are useful diagnostic markers for Alzheimer disease (AD). Less is known about these biomarkers as predictors for further cognitive decline in patients with AD. We hypothesized that high tau, especially in combination with relatively low p-tau-181, is a marker of rapid decline, since it has been associated with fast neuronal degeneration. A total of 151 patients with AD of whom we had baseline CSF were included from our memory clinic. All patients had at least 2 Mini-Mental State Examination (MMSE) scores, obtained no less than 1 year apart. Linear mixed models were used to assess associations between CSF biomarkers and the rate of cognitive decline as measured with the MMSE. CSF biomarkers were used in quintiles, random intercept and random slope with time were assumed, and the analyses were corrected for sex and age. The patients with AD (45% women, age 66 +/- 9 years, baseline MMSE 22 +/- 4) had a follow-up period of 2.0 (1.0-5.0) years. Linear mixed models revealed no relations between any CSF biomarker and baseline MMSE. However, CSF biomarkers did predict cognitive decline over time. A low p-tau-181/tau ratio was the strongest predictor with a dose-dependent effect (lowest vs highest quintile: 2.9 vs 1.3 MMSE points annual decline, p for trend <0.001). In addition, low Abeta(42), high tau, and high tau/Abeta(42)-ratio were associated with rapid cognitive decline (p < 0.05). At the time of diagnosis, a combination of high CSF tau without proportionally elevated p-tau-181 is associated with a faster rate of cognitive decline.