Advances in Alzheimer's Dementia: An update from Banner Alzheimer's Institute

Abstract

Alzheimer's Disease is the most prevalent cause of neurodegenerative disease accounting for 60-80% of dementia cases. With an aging population, the prevalence of AD is projected to reach 12.7 million. Clinical features for AD include difficulties with memory, language, learning, orientation, mood, communication, judgement, behavior, and eventually physical deterioration in the form of difficulty walking, speaking, and swallowing. AD is a progressive disease and pathological changes sometimes start decades before clinical symptoms manifest. AD involves the accumulation of extra-cellular beta amyloid plaques and intracellular tau protein tangles leading to neuronal dysfunction and degeneration. As age is one of the key risk factors for AD, it tends to predominantly affects older adults. Women are disproportionately affected by the disease, as they represent higher number of patients and caregivers.A confirmatory diagnosis of Alzheimer's disease can be formulated only on autopsy currently. A biomarker is a measurable indicator of the presence or severity of a disease state, and it could be used to improve the diagnosis and management of patients. Fluid- based biomarkers and radiological studies are quickly changing that paradigm in AD management. CSF and blood-based biomarkers are key in early and accurate diagnosis accelerating drug development and clinical care in dementia. Levels of Aβ42, phosphorylated tau (p-tau) proteins, and total tau (t-tau) proteins start to change years, sometimes decades before the appearance of AD symptoms. AD biomarkers include amyloid and tau deposition, neurodegeneration, inflammation, and synaptic dysfunctions. The analysis of core CSF biomarkers (total tau (T-tau), phosphorylated tau (P-tau) and β-amyloid 42 (Aβ42)) have shown excellent diagnostic accuracy in diagnosing AD (especially in atypical presentations), mild cognitive impairment (MCI) due to AD and differentiating AD from other psychiatric disorders (1). pTau217, pTau181, Glial fibrillary acidic protein (GFAP) and Neurofilament light (NFL) show promise of accuracy in both CSF and plasma.Until recently, available treatments for AD (donepezil, galantamine, rivastigmine and memantine) were symptomatic and had modest benefits. Several drugs with the potential to modify the disease process are in various stages of development. Among the promising agents, monoclonal antibodies against amyloid are some of the forerunners. Most recently, one of these drugs, aducanumab (Aduhelm) received FDA approval under accelerated pathway in June 2021. However, due to the Centers for Medicare & Medicaid Services (CMS)’s decision to restrict its coverage, aducanumab has not been accessible to the majority of patients. Nevertheless, other anti-amyloid monoclonal antibodies including donanemab, gantenerumab, and lecanemab are expected to read out topline results in late 2022/2023. In addition, there are multiple trials on other mechanisms like reducing tau, attenuating inflammation, and improving synaptic transmission.