Alzheimer Disease

Abstract

Alzheimer’s disease (AD) was originally conceived as a rare disease that caused presenile dementia but has come to be understood as the most prevalent cause of dementia at any age worldwide. It has an extended preclinical phase characterized by sequential changes in imaging and cerebrospinal fluid biomarkers with subtle memory decline beginning more than a decade before the emergence of symptomatic memory loss heralding the beginning of the mild cognitive impairment stage. The apolipoprotein Eε4 allele is a prevalent and potent risk factor for AD that has facilitated research into its preclinical phase. Cerebral Aβ amyloid levels build from preclinical through early dementia stages followed by hyperphosphorylated tau-related pathology, the latter driving cognitive deficits and dementia severity. Structural and molecular imaging can now recapitulate the neuropathology of AD antemortem. Autosomal dominant forms of early onset familial AD gave rise to the amyloid hypothesis of AD that in turn has led to therapeutic trials of immunotherapy designed to clear cerebral amyloid but to date results have been disappointing. Genome wide association studies have identified multiple additional risk factors but to date none have yielded an effective alternate therapeutic target. Current and future trials aimed at presymptomatic individuals either harboring cerebral amyloid or at genetically high risk offer the hope that earlier intervention might yet succeed where trials in patients with established dementia have failed. A major looming challenge will be that of expensive, incompletely effective disease modifying therapy: who and when to treat, and how to pay for it.

Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer’s disease dementia

“…Post-hoc paired Bonferroni significance testing significant (p<0.05) for all groups vs control except ADD vs control, and significant for ADD, ADLB and ADD/DLB vs PDD+AD and PDD-AD. 4 . Post-hoc paired Bonferroni testing significant (p < 0.05) for all groups vs control and for ADD and for all groups vs PDD-AD.…”

Involvement of Astrocytes in Alzheimer’s Disease from a Neuroinflammatory and Oxidative Stress Perspective

“…The cholinesterase inhibitors are approved for symptomatic treatment of mild-to-moderate stages of AD, while the NMDA antagonist is used for moderate-to-late stages. Regrettably none of these drugs is able to halt the progression of the disease and its uses are aimed at maximizing the quality of life of patients though broad symptom management ( Caselli et al, 2017 ). Is therefore of great importance to design and develop new treatments which offer better therapeutic outcomes and disease-modifying responses to the patients with AD.…”

Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer’s disease

“…These changes possibly begin subcortically, with the first cortical appearance observable in the transentorhinal region, before spreading toward neocortical regions [ 30 ], which correlates spatially better with areas undergoing degeneration than does the propagation of amyloid plaques. Amyloid plaque deposition initially begins in polymodal association cortices and spreads toward the allocortex (for summaries see [ 34 , 38 , 110 ]). Additionally, the deposition of amyloid plaques plateaus in later life [ 121 ] whereas the rate of neurodegeneration accelerates [ 124 ], suggesting the clinical symptoms couple to neurodegeneration, rather than Aβ deposition.…”