Here is an article on the current state of Alzheimer’s researcher by an international expert in the field, Dr. Sam Gandy.
Sam Gandy, MD, PhD, is Mount Sinai Professor of Alzheimer’s Disease Research, Professor of Neurology and Psychiatry, Associate Director of the Mount Sinai Alzheimer’s Disease Research Center in New York City, and Chairman Emeritus of the National Medical and Scientific Advisory Council of the Alzheimer’s Association. You can read his bio here: http://www.mountsinai.org/profiles/samuel-e-gandy.
I have posted a number of articles by Dr. Gandy on DementiaToday because his work is so important.
The article, “Toward the Treatment and Prevention of Alzheimer’s Disease,” is the most important article I have read all year on the state of AD research. It is long, thorough, and can be complex. Bookmark this page and read a little bit a time. You will find, that by the end of the article, many of your questions on AD will be answered. It is well worth the read. I hope you find it of great interest too.
The source article is here http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625402/ if you prefer to read it on the NIH gov site.
Annual Review of Medicine
Vol. 64: 367-383
Toward the Treatment and Prevention of Alzheimer’s Disease: Rational Strategies and Recent Progress
Alzheimer’s disease (AD) is the major cause of late-life brain failure. In the past 25 years, autosomal dominant forms of AD were found to be primariy attributable to mutations in one of two presenilins, polytopic proteins that contain the catalytic site of the γ-secretase protease that releases the amyloid beta (Aβ) peptide. Some familial AD is also due to mutations in the amyloid precursor protein (APP), but recently a mutation in APP was discovered that reduces Aβ generation and is protective against AD, further implicating amyloid metabolism. Prion-like seeding of amyloid fibrils and neurofibrillary tangles has been invoked to explain the stereotypical spread of AD within the brain. Treatment trials with anti-Aβ antibodies have shown target engagement, if not significant treatment effects. Attention is increasingly focused on presymptomatic intervention, because Aβ mismetabolism begins up to 25 years before symptoms begin. AD trials deriving from new biological information involve extraordinary international collaboration and may hold the best hope for success in the fight against AD.
ALZHEIMER’S DISEASE IS AN EPIDEMIC
The demographics of the post–World War II “baby boomer” generation and the increased incidence and prevalence of dementia in the seventh decade and beyond have made Alzheimer’s disease (AD) a major health care threat. As discussed below, research is now focusing on prevention as well as symptomatic treatment. In the United States, 40% of people ages 85 years and above are cognitively impaired (1); AD pathology probably contributes to 75%–80% of these cases. Thus, the discovery of compounds to slow the development and progression of AD is a major imperative for federal agencies and pharmaceutical companies.
In the 1970s, researchers in Great Britain discovered that the AD brain is deficient in acetylcholine (2), leading to the development of a strategy using cholinesterase inhibition. Although this strategy forms the basis for the main medications to treat AD today, it took almost 20 years for the first cholinesterase inhibitor drug to be approved. In the 1990s, the increased availability of neuroimaging and the advances in genetics led to discovery of pathogenic mutations in three genes that produce early-onset autosomal dominant familial AD (EOFAD) (3). The convergence of all three EOFAD gene products on the biosynthetic pathway underlying amyloid precursor protein (APP) metabolism affirmed the amyloid hypothesis of AD originally articulated by Glenner, Masters and Beyreuther (4, 5). These findings stimulated broad therapeutic efforts to suppress amyloid beta (Aβ) generation or to remove amyloid from the brain. Brain amyloid imaging (BAI), described first in 2004, confirmed that AD pathology emerges more than a decade prior to any clinical symptoms, offering a wide opportunity for interventions that would either delay or prevent onset of clinical symptoms. In addition to the EOFAD mutations, genetic factors that confer increased risk have been identified, including the most powerful common genetic risk factor, the APOE ε4 allele of apolipoprotein E (APOE), which contributes to approximately 40%–50% of cases of AD (6). The molecular pathogenesis of AD is defined by this and other identified genes; however, no other genetic factor has an effect on AD risk to rival that associated with APOE ε4.
GAMMA-SECRETASE AND THE RETROMER REPRESENT POTENTIAL THERAPEUTIC TARGETS IN DEVELOPING DRUGS TO TREAT OR PREVENT ALZHEIMER’S DISEASE
γ-Secretase is the high-molecular-weight complex of four proteins [presenilin 1 or 2 (PS1, PS2), nicastrin, APH1, PEN2] that releases Aβ from APP and specifies the length of the Aβ peptide as either 40 or 42 amino acids. Aβ42 initiates Aβ deposition in all forms of AD. New data indicate that γ-secretase can also perform an exopeptidase function, trimming the initial ε cleavage product at its carboxyl terminus and generating various Aβ carboxyl termini (7) (Figure 1). In this proposed model, excess long Aβ species occur as a result of inadequate trimming or “processivity,” a concept consistent with data indicating that pathogenic PS1 mutants lead to reduction in γ-secretase catalytic activity (8). In two elegant in vitro γ-secretase reconstitution papers (7, 9), Wolfe and colleagues clarified the relationships between mutant PS1 action and altered processivity and between membrane lipid composition and processivity. Notably, modulation of γ-secretase processivity by cholesterol may explain at least some of the recognized but poorly understood role(s) of cholesterol in the etiology of AD (for a comprehensive review of the role of cholesterol in AD, see References 10, 11).
Figure 1 Polyacrylamide gel electrophoresis reveals a family of amyloid beta (Aβ) peptides generated by the processivity (trimming) function of γ-secretase following ε cleavage. (a) Effects of presenilin 1 (PS1) mutations (L166P, A246E, …
Protein trafficking is a key issue in AD pathogenesis, as exemplified by the multiple links between the vacuolar protein sorting (Vps) family of proteins and the risk of AD. Genetic linkage to SORL1 was reported in 2007 (12), and pathogenic dominant mutations in SORL1 were reported recently (12, 13). Lane et al. (14) showed that another Vps protein, SorCS1, was linked functionally to the AD phenotype as well as to the phenotype associated with type 2 diabetes insulin resistance in a pathway that converges on the retromer, the protein complex responsible for retrograde transport of cargos from the endosomal system backward to the trans-Golgi network (15). Willnow and colleagues (16) showed that SorL1 requires another retromer component, Vps26, to control Aβ metabolism, further strengthening the connection between the retromer and AD. These observations suggest that a novel pathway may underlie links between type 2 diabetes and AD and, as proposed by Small & Gandy (17), that the SorL1 and SorCS1 links to AD are mediated by the retromer (Figure 2).
Figure 2 Schematized pathway showing the sorting of amyloid precursor protein (APP) (red dumbbell ) and BACE (β-secretase) (blue dumbbell ) into post-trans-Golgi network (TGN) compartments. The retromer retrieves endosomal proteins and conveys them to …