Alzheimer's disease, a multifactorial disorder seeking multitherapies

Abstract

Alzheimer's disease (AD) is multifactorial and apparently involves several different etiopathogenic mechanisms. There are at least five subgroups of AD based on cerebrospinal fluid levels of Abeta(1-42), a marker of beta-amyloid (Abeta) plaques, and tau and ubiquitin, two markers of neurofibrillary tangles. These different AD subgroups may respond differently to a given disease-modifying drug, and hence, different therapeutic drugs for different disease subgroups might be required. Stratification of AD patients by disease subgroups in clinical trials is critical to the successful development of potent disease-modifying drugs. Levels of disease markers in the cerebrospinal fluid are promising, both in identifying various subgroups of AD and in monitoring the response to therapeutic drugs.

Figure 1. Causes and subgroups of AD

Less than 1% of AD cases are familial and are caused by certain mutations in βAPP (mAPP), presenilin 1 (mPS1), or presenilin 2 (mPS2) genes which are transmitted in an autosomal dominant fashion and the resulting gene products, the mutated proteins, are dysfunctional. Over 99% of AD cases are sporadic and have not, to date, been associated with any mutated protein, but several risk factors including the presence of one or two copies of APOE₄ allele, inflammation, head trauma, diabetes/low brain glucose metabolism, and as yet unknown environmental and or metabolic factors have been implicated. Based on CSF levels of Aβ_1–42, a marker of Aβ plaques, and tau and ubiquitin, the two markers of neurofibrillary tangles, five subgroups of AD have been identified. These subgroups, AELO, ATEO, LEBALO, HARO, and ATURO, represent distinct clinical profiles. These different subgroups of AD probably involve different etiopathogenic mechanisms and may respond differently to any one given disease modifying drug. AELO: AD cases with low Aβ_1–42, high incidence of APOE₄, and late onset. ATEO: AD cases with low Aβ_1–42, high tau, and early onset. LEBALO: AD cases with high incidence of Lewy bodies, low Aβ_1–42, and late onset. HARO: AD with high Aβ_1–42, and recent onset. ATURO: AD with low Aβ_1–42, high tau, high ubiquitin, and recent onset.