COVID-19 and Alzheimer’s Disease Share Common Neurological and Ophthalmological Manifestations: A Bidirectional Risk in the Post-Pandemic Future

Abstract

A growing body of evidence indicates that a neuropathological cross-talk takes place between the coronavirus disease 2019 (COVID-19) -the pandemic severe pneumonia that has had a tremendous impact on the global economy and health since three years after its outbreak in December 2019- and Alzheimer’s Disease (AD), the leading cause of dementia among human beings, reaching 139 million by the year 2050. Even though COVID-19 is a primary respiratory disease, its causative agent, the so-called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is also endowed with high neuro-invasive potential (Neurocovid). The neurological complications of COVID-19, resulting from the direct viral entry into the Central Nervous System (CNS) and/or indirect systemic inflammation and dysregulated activation of immune response, encompass memory decline and anosmia which are typically associated with AD symptomatology. In addition, patients diagnosed with AD are more vulnerable to SARS-CoV-2 infection and are inclined to more severe clinical outcomes. In the present review, we better elucidate the intimate connection between COVID-19 and AD by summarizing the involved risk factors/targets and the underlying biological mechanisms shared by these two disorders with a particular focus on the Angiotensin-Converting Enzyme 2 (ACE2) receptor, APOlipoprotein E (APOE), aging, neuroinflammation and cellular pathways associated with the Amyloid Precursor Protein (APP)/Amyloid beta (Aβ) and tau neuropathologies. Finally, the involvement of ophthalmological manifestations, including vitreo-retinal abnormalities and visual deficits, in both COVID-19 and AD are also discussed. Understanding the common physiopathological aspects linking COVID-19 and AD will pave the way to novel management and diagnostic/therapeutic approaches to cope with them in the post-pandemic future.

Exploring the Pathophysiology of Long COVID: The Central Role of Low-Grade Inflammation and Multisystem Involvement

“…Another aspect of canonical inflammation in LC, which was not included in the aims and objectives of our study, is considering LC as a risk factor for the onset of various inflammatory diseases or the progression of existing inflammatory diseases [ 323 , 324 , 325 , 326 , 327 ]. This primarily concerns immune-dependent diseases, whose association has been established, namely various allergic, autoimmune, and infectious diseases, but also should be taken into account in other pathological conditions as well [ 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 ,…”

“…Evidence also suggests that prior SARS-CoV-2 infection may facilitate the emergence or acceleration of canonical neurodegenerative diseases [ 234 , 235 , 236 , 237 ]. Research indicates that tau protein accumulation, a hallmark of neurodegenerative diseases and to a lesser extent in LC, is characteristic [ 238 , 239 ].…”

Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer’s Disease

“…We now know that prolonged memory deficits, concentration difficulties and anxiety associated with COVID-19 infection can last for over 2 years [7][8][9] and have a significant impact on quality of life. A recent review of the literature suggests an increased susceptibility to Alzheimer's disease (AD) after COVID-19 infection [10]. AD is the most common dementia and affects over 6 million Americans 65 years old and above.…”

Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19-Exacerbated Dementia and Alzheimer’s Disease

“…During the period of 2020–2021, the number of deaths from stroke, cardiovascular disease, and human immunodeficiency virus decreased, whereas the number of people who died from AD increased more than 145% [ 2 ]. There is growing evidence that such a significant increase in mortality from AD may be associated with the COVID-19 pandemic in 2020 and 2021 [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. COVID-19 is primarily known as a severe acute respiratory disease caused by the SARS-CoV-2 virus, but it also affects the central nervous system (CNS) and other organs [ 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…The virus hypothesis for AD has been proposed for decades, and despite supportive evidence, virus etiology of AD is still controversial [ 7 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. On the one hand, many clinical observations indicate an increased risk for COVID-19 in people with AD [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. On the other hand, SARS-CoV-2 infection causes long-lasting neurological sequelae [ 18 , 19 , 20 , 21 , 22 , 23 ].…”