Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease

Abstract

BACKGROUND The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

“…The levels of tau in CSF are being used as a complementary biomarker, and the quantification of both t‐tau and p‐tau (threonine 181) have been validated by frequent testing of human CSF samples in several clinical studies. Increased concentration of tau was detected almost 15 years before the onset of symptoms was expected in the CSF of AD patients 38. A growing number of studies point to the roles of oligomeric assemblies of pathogenic proteins in toxicity and propagation of AD.…”

Aging and APOE‐ε4 are determinative factors of plasma Aβ42 levels

“…Prior major cohort studies have reported that plasma A β is a risk factor or predictive marker for AD onset in healthy older community members aged at least 55 years 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. In contrast, after analyzing fasting blood samples from healthy individuals of a wide age range, we observed the natural course of and factors affecting plasma A β 40 and A β 42.…”

“…The Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN) have confirmed the efficacy of neuropsychiatric tests and neuroimaging using cerebrospinal fluid (CSF) biomarkers, including amyloid PET, demonstrating that signatures of brain A β amyloidosis can be found approximately 30 years before the onset of dementia 10, 11. Recent studies have clarified that the plasma A β 42/40 ratio is inversely correlated with cortical amyloid burden in AD, which can be converted into MCI,12, 13 and that the plasma A β 42/40 ratio is a useful screening marker for brain A β amyloidosis in normal individuals 14, 15.…”

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

“…The accumulation of amyloid‐β (Aβ) plaques in the brain is one of the first events in the pathological cascade leading to Alzheimer's disease (AD) (Bateman et al., 2012; Hardy & Selkoe, 2002; Sperling et al., 2010). Aβ disrupts synaptic functioning, resulting in aberrant brain connectivity at the synaptic level (Selkoe, 2002; Spires‐Jones & Hyman, 2014), as well as on the whole‐brain connectivity level (Delbeuck, der Linden, & Collette, 2003; Hedden et al., 2009).…”