Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses

Abstract

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by both amnestic and non-amnestic clinical manifestations. It accounts for approximately 60-70% of all dementia cases worldwide. With the increasing number of AD patients, elucidating underlying mechanisms and developing corresponding interventional strategies are necessary. Hypotheses about AD such as amyloid cascade, Tau hyper-phosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic, and vascular hypotheses are not mutually exclusive, and all of them play a certain role in the development of AD. The amyloid cascade hypothesis is currently the most widely studied; however, other hypotheses are also gaining support. This article summarizes the recent evidence regarding major pathological hypotheses of AD and their potential interplay, as well as the strengths and weaknesses of each hypothesis and their implications for the development of effective treatments. This could stimulate further studies and promote the development of more effective therapeutic strategies for AD.

Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank

“…While abundant evidence underscores the role of neuroinflammation in the pathogenesis of AD, its position as a cause and consequences remain undetermined [ 48 ]. Besides the early changes of inflammatory proteins, GFAP has also been linked to brain Aβ pathology [ 49 ].…”

“…Evidence from a large genome-wide association study has also shown a causal relationship between neuroinflammation and ADRD [ 50 ]. However, neuroinflammation can be triggered by the neurodegenerative processes of AD, such as tau dysfunction and Aβ deposition [ 48 , 51 , 52 ], potentially rendering it a non-specific response. In our study with ~ 50,000 participants, we found robust correlations between peripheral GFAP and NfL expression with AD-GRS APOE*E4 alleles, suggesting shared genetic factors driving early neuroinflammation and neurodegenerative changes in dementia.…”

Food-Derived Peptides: Beneficial CNS Effects and Cross-BBB Transmission Strategies

“…However, the pathogenesis of AD is not clear. At present, there are three leading hypotheses, namely the cholinergic, amyloid, and tau hypotheses . As there is no specific drug to treat AD, intervention implemented in the early stage of memory impairments is currently the only therapeutic strategy to alleviate the symptoms and development of AD.…”

“…At present, there are three leading hypotheses, namely the cholinergic, amyloid, and tau hypotheses. 12 As there is no specific drug to treat AD, intervention implemented in the early stage of memory impairments is currently the only therapeutic strategy to alleviate the symptoms and development of AD. Many peptides of plant 13 and animal 14 origin are known to improve memory impairments against the above hypothesis.…”

New Multitarget Molecules Derived from Caffeine as Potentiators of the Cholinergic System

“…In the central nervous system, it is involved in growth, development, and aging-regulating neural plasticity, differentiation, proliferation, and clearance of aged neurons . It is also involved in a large variety of pathophysiological conditions, such as different myasthenic syndromes, myasthenia gravis, in particular, Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder in the elderly characterized by progressive cognitive decline, Tourette syndrome, and nocturnal frontal lobe epilepsies, among others. − Although the occurrence of these different pathophysiological conditions is due to different causes–multifactorial events in some cases–from a therapeutic point of view, they can be classified into two main groups. One group includes the first two above-mentioned pathological conditions, among others, sharing the “cholinergic hypothesis” that is related to a deficit of functional nAChR, and hence nAChR function potentiation is the therapeutic goal (muscle nAChR in the case of myasthenic syndromes and neuronal nAChR for AD, becoming α7 nAChR increasingly more important for AD pathology).…”