Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later

Abstract

Objectives: We compared the ability of molecular biomarkers for Alzheimer disease (AD), including amyloid imaging and CSF biomarkers (Ab 42 , tau, ptau 181 , tau/Ab 42 , ptau 181 /Ab 42 ), to predict time to incident cognitive impairment among cognitively normal adults aged 45 to 88 years and followed for up to 7.5 years.Methods: Longitudinal data from Knight Alzheimer's Disease Research Center participants (N 5 201) followed for a mean of 3.70 years (SD 5 1.46 years) were used. Participants with amyloid imaging and CSF collection within 1 year of a clinical assessment indicating normal cognition were eligible. Cox proportional hazards models tested whether the individual biomarkers were related to time to incident cognitive impairment. "Expanded" models were developed using the biomarkers and participant demographic variables. The predictive values of the models were compared.Results: Abnormal levels of all biomarkers were associated with faster time to cognitive impairment, and some participants with abnormal biomarker levels remained cognitively normal for up to 6.6 years. No differences in predictive value were found between the individual biomarkers (p . 0.074), nor did we find differences between the expanded biomarker models (p . 0.312). Each expanded model better predicted incident cognitive impairment than the model containing the biomarker alone (p , 0.005). Conclusions:Our results indicate that all AD biomarkers studied here predicted incident cognitive impairment, and support the hypothesis that biomarkers signal underlying AD pathology at least several years before the appearance of dementia symptoms. Biomarkers may signal underlying Alzheimer disease (AD) pathology a decade or more before the appearance of dementia symptoms.1,2 Therefore, understanding the temporal relationships between biomarker levels in cognitively normal adults, symptomatic AD (i.e., incident AD), and factors that modify those relationships is imperative.3 The National Institute on Aging/ Alzheimer's Association workgroup urges that the factors that best predict progression from normal cognition to cognitive impairment and dementia due to AD need to be determined. 3The most well-studied and promising molecular biomarkers of AD are those that reflect the presence of the signature lesions of AD: plaques, which comprise the amyloid-b (Ab) protein, and tangles, which comprise the tau protein. Both amyloid imaging, 4 used to identify fibrillar Ab plaques, and CSF biomarkers, 5 which reflect soluble Ab, tau, and phosphorylated tau (ptau), predict incident AD.6-8 However, until now, directly comparing the predictive ability of amyloid imaging with CSF biomarkers was difficult, given the recent development of amyloid imaging 4 and attendant short follow-up times, the lengthy hypothesized time between the appearance of AD

APOE ε4 moderates amyloid-related memory decline in preclinical Alzheimer's disease

“…Thus considered together, the results indicate that in otherwise healthy older adults, evidence of amyloidosis is associated with cognitive decline, mainly in memory, and this decline is increased substantially among 34 carriers. Table 2 Results of linear mixed model, mean slopes (SD), and magnitudes of difference (Cohen's d) Cohen (1988) and Newcombe (2006) The results of this study are not consistent with those from earlier prospective studies which reported that 34 carriage did not increase Ab-related cognitive decline in healthy older adults (Doraiswamy et al, 2012;Lim et al, 2012;Roe et al, 2013). As the samples of Abþ healthy older adults studied in these previous studies were smaller, or studied over shorter time intervals than in the present study and in Mormino et al (2014), the absence of any interaction between 34 and Ab observed in these previous studies is most likely to reflect insufficient statistical power to detect the effect of APOE 34 on Ab-related cognitive decline, especially given the subtlety of this effect (i.e., d ¼ 0.4 for visual memory).…”

“…However, potential interactions between Ab and 34 carriage were suggested by observations in 2 different cohorts that associations between Ab levels and memory performance were evident only in 34 carriers (Kantarci et al, 2012;Lim et al, 2013aLim et al, , 2013bLim et al, , 2013c. Initial prospective studies in preclinical AD showed that rates of Ab-related memory decline were not increased when 34 carrier status was added to predictive models (Doraiswamy et al, 2012;Lim et al, 2012;Roe et al, 2013), suggesting that the risk for memory decline and AD posed by 34 carrier status was a consequence of 34 carriage accelerating Ab accumulation. However, a recent analysis of data aggregated from 3 different prospective studies of early AD observed that 34 carrier status increased substantially the rate of memory decline over a median of 1.5 years in Ab positive (Abþ) healthy individuals (Mormino et al, 2014).…”

Cortical gyrification and its relationships with cortical volume, cortical thickness, and cognitive performance in healthy mid-life adults

“…These relationships also survived corrections for cortical volume and thickness and were independent of age and sex, suggesting that despite sharing a large proportion of variance with volume and thickness, there is a unique relationship between cognitive function and cortical gyrification in the lateral frontal cortex. Our results in this population are also relevant in the context of cognitive aging, as there are indications that the cognitive difficulties that are observed in older adulthood are related to brain [48] and cognitive health [49,50] much earlier in the lifespan. Given the age-related vulnerability of the frontal cortex to volume decrease and its important role in cognitive aging, it is of value to document if prefrontal gyrification relates to cognitive function, especially in a midlife population who are still underinvestigated in the literature.…”

TREM2, Microglia, and Neurodegenerative Diseases

“…AD is characterized histologically by an abundance of extracellular amyloid-b (Ab) plaques (see Glossary) in the brain as well as the widespread presence of hyperphosphorylated tau (microtubule-associated protein tau, MAPT) aggregates within neurons (neurofibrillary tangles) [1-3]. Accumulation of amyloid plaque in the brain takes place over many years and typically precedes tau tangles and cognitive decline by a decade or more [4][5][6][7].…”

“…AD is characterized histologically by an abundance of extracellular amyloid-b (Ab) plaques (see Glossary) in the brain as well as the widespread presence of hyperphosphorylated tau (microtubule-associated protein tau, MAPT) aggregates within neurons (neurofibrillary tangles) [1-3]. Accumulation of amyloid plaque in the brain takes place over many years and typically precedes tau tangles and cognitive decline by a decade or more [4][5][6][7].Another histological feature of AD is the presence and accumulation of reactive astrocytes and microglia (Box 1) around plaques [8,9], loosely called 'neuroinflammation' but more aptly classified as astrogliosis and microgliosis [10][11][12]. Microglia are a self-renewing population of myeloid cells that establish permanent brain residence during embryonic development and function as the innate immune cells of the brain throughout life [13].…”