Cerebro-spinal fluid biomarker levels: phosphorylated tau (T) and total tau (N) as markers for rate of progression in Alzheimer’s disease

Background We investigated the potential associations between cerebro-spinal fluid (CSF) levels of phosphorylated tau (P-tau) and total tau (T-tau) with short-term response to cholinesterase inhibitor (ChEI) treatment, longitudinal outcome and progression rates in Alzheimer’s disease (AD). Methods This prospective, observational study included 129 participants clinically diagnosed with mild-to-moderate AD, who underwent a lumbar puncture. The CSF biomarkers amyloid-β1–42 (Aβ42), P-tau and T-tau were analysed with xMAP technology. Cognitive, global, instrumental and basic activities of daily living (ADL) capacities at the start of ChEI therapy and semi-annually over 3 years were evaluated. Results All patients had abnormal Aβ42 (A+). Fifty-eight individuals (45%) exhibited normal P-tau and T-tau (A+ T– (N)–), 12 (9%) abnormal P-tau/normal T-tau (A+ T+ (N)–), 17 (13%) normal P-tau/abnormal T-tau (A+ T– (N)+) and 42 (33%) abnormal P-tau and T-tau (A+ T+ (N)+). The participants with A+ T+ (N)+ were younger than A+ T– (N)+ at the estimated onset of AD and the initiation of ChEIs. The proportion of 6-month responders to ChEI and deterioration/year after start of treatment did not differ between the AT(N) profiles in any scales. A higher percentage of globally improved/unchanged patients was exhibited in the A+ T– (N)– group after 12, 30 and 36 months of ChEI therapy but not at other assessments. In apolipoprotein E (APOE) ε4-carriers, linear relationships were found between greater cognitive decline/year and higher tau; Mini-Mental State Examination score – T-tau (rs = − 0.257, p = 0.014) and Alzheimer’s Disease Assessment Scale–cognitive subscale – P-tau (rs = − 0.242, p = 0.022). A correlation between faster progression in instrumental ADL (IADL) and higher T-tau was also detected (rs = − 0.232, p = 0.028). These associations were not demonstrated in non-ε4-carriers. Conclusions Younger age and faster global deterioration were observed in AD patients with pathologic tau and neurodegeneration, whereas more rapid cognitive and IADL decline were related to higher P-tau or T-tau in APOE ε4-carriers only. The results might indicate an association between more pronounced tau pathology/neuronal injury and the APOE ε4-allele leading to a worse prognosis. Our findings showed that the AT(N) biomarker profiles have limited utility to predict AD progression rates and, thus, measure change and interpreting outcomes from clinical trials of future therapies.

Acute treatment of psychotic symptoms in a newly diagnosed Lewy body dementia patient with an accelerated titration schedule of rivastigmine and de-escalation of antipsychotics

A 76-year-old man presented with complaints of increased confusion, visual hallucinations and decline in memory. He was admitted to the hospital and started on quetiapine 50 mg daily for symptom management. Shortly after, he was diagnosed with Lewy body dementia and started on rivastigmine, a cholinesterase inhibitor (ChEI), at 1.5 mg two times per day. The patient’s symptoms continued to worsen and antipsychotics increased for aggressive behaviour. After he became physically aggressive, an extensive medication management review was conducted, prompting an alternative treatment strategy. The quetiapine dose was reduced from 150 mg daily to 12.5 mg daily, his rivastigmine was increased to 3 mg two times per day and all other antipsychotics were discontinued. The up-titration of his rivastigmine after 10 days of therapy was well tolerated with no adverse effects. He demonstrated a clear clinical response to optimised ChEI therapy and low dose quetiapine, showing improvements in alertness and functioning.

Longitudinal Associations between Survival in Alzheimer's Disease and Cholinesterase Inhibitor Use, Progression, and Community-Based Services

Background/Aims: Factors including rate of disease progression, different aspects of cholinesterase inhibitor (ChEI) treatment, and use of community-based services might affect the longitudinal outcome of Alzheimer's disease (AD). Whether these factors alter life expectancy in AD is unclear. We therefore examined the association between long-term ChEI therapy and survival. Methods: The present study included 1,021 patients with a clinical diagnosis of AD and a Mini-Mental State Examination score of 10-26 at baseline from a 3-year, prospective, multicenter study of ChEI therapy in clinical practice. The relationship of potential predictors with mortality was analyzed using Cox regression models. Results: After up to 16 years of follow-up, 841 (82%) of the participants had died. In the Alzheimer's Disease Assessment Scale-cognitive subscale, a mean decline of ≥4 points/year or ≥2 points/year on the Physical Self-Maintenance Scale was a risk factor for an earlier death. In the multivariate models, longer survival was associated with higher ChEI dose and longer duration of treatment. Users of community-based services at baseline exhibited a 1-year shorter mean life expectancy than nonusers. Conclusion: A longer survival time can be anticipated for AD patients with slower deterioration who receive and tolerate higher ChEI doses and a longer duration of treatment.