Advances in Alzheimer's Dementia: An update for clinicians

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. AD is a progressive disease and pathological changes starting sometimes decades before symptoms. AD involves the accumulation of extra-cellular beta amyloid plaques and intracellular tau protein tangles leading to neuronal dysfunction and degeneration. Interestingly, socioeconomic disparities in the US lead to missed diagnosis especially in the underrepresented racial and ethnic groups such as the Black and Hispanic Americans, who are more likely to have AD. Women are disproportionately affected by the disease, as they represent higher number of patients and caregivers. Geographical disparities have key implications towards access of care and clinical outcomes.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. 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. CSF and blood-based biomarkers are key in early and accurate diagnosis accelerating drug development and clinical care in dementia. 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. pTau217, pTau181, Glial fibrillary acidic protein (GFAP) and Neurofilament light (NFL) show promise of accuracy in both CSF and plasma. There is emerging evidence highlighting the difference in the biomarker levels based on sex and race.MRI provides structural information of the brain including focal hippocampal atrophy. The ability of MRI to detect other causes of dementia, absence of radiation exposure, and insurance coverage are additional advantages. It sometimes lacks the specificity to distinguish AD from other degenerative processes. Fluorodeoxyglucose (18F) or FDG PET scan demonstrates patterns of metabolism in the brain distinguishing AD from another cortical dementia. Amyloid PET and tau PET allow the indirect visualization of amyloid plaques and aggregated tau neurofibrillary tangles respectively. They are not covered by most health insurance plans, which limits their clinical use, but used extensively in clinical trials. In contrast to amyloid PET, tau PET is able to show that tau accumulation correlates with cognitive decline. Even though the individual utilization of AD imaging biomarkers is helpful, their combined use or a multimodal approach is even more powerful.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 accelerated FDA approval in June 2021. In addition, there are multiple trials on other mechanisms like reducing tau, attenuating inflammation and improving synaptic transmission.