Disease-modifying therapies for Alzheimer disease

Abstract

Prevention of Alzheimer disease (AD) is a national and global imperative. Therapy is optimally initiated when individuals are asymptomatic or exhibit mild cognitive impairment (MCI). Development of therapeutically beneficial compounds requires the creation of clinical trial methodologies for primary and secondary prevention. Populations in primary prevention trials selected only on the basis of age will have low rates of emergent MCI or AD. Epidemiologically based risk factors or biomarkers can be used to enrich trials and increase the likelihood of disease occurrence during the trial. Enrichment strategies for clinical trials with MCI include use of biomarkers such as amyloid imaging, MRI with demonstration of medial temporal lobe atrophy, bilateral parietal hypometabolism on PET, and reduced amyloid beta peptide and increased tau protein in CSF. Neuropsychological measures appropriate for trials of MCI may not be identical to those measures most suited for AD trials. Attention to these and other features of trial design, clinical assessment, and use of biomarkers is critical to improving the detection of disease-modifying effects of emerging therapies in presymptomatic or minimally symptomatic populations. The neurologic health of the growing aging population demands disease-modifying therapies and the development of methods to identify and test promising candidate agents.

Cholinergic Stimulation Enhances Neural Activity Associated with Encoding but Reduces Neural Activity Associated with Retrieval in Humans

“…This suggests that memory deficits within the group of healthy older subjects may be at least in part based on a deficit in the cholinergic system. Whereas an abundance of research studies has concentrated on elucidating neuropharmacological alterations in AD (Ladner and Lee, 1998;Selkoe, 2002;Cummings et al, 2007;Bentley et al, 2008), there is comparatively little information about the development of neurotransmitter systems in healthy human aging. A cholinergic deficit as the underlying reason for poorer memory performance in healthy older subjects seems plausible, since it is the cholinergic system which primarily degenerates in AD as the prototypical disease affecting recent episodic memory Figure 3.…”

Current and future uses of neuroimaging for cognitively impaired patients

“…[111][112][113][114] Some of these approaches might provide disease-modifying effects and slow progression of neurodegeneration. Although a neuroimaging biomarker for insoluble brain amyloid β might measure the biological effects of the intervention, a clinical trial design that would assess the progression of AD (eg, randomised withdrawal or randomised start design) would be necessary to prove diseasemodifying effects.…”

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

“…Furthermore, the AD subjects recruited to these trials may have been very heterogeneous and not all may have had evidence of amyloid plaques [17]. Finally, a widely held belief is that intervening at the dementia stage may be too late, and that putative disease-modifying agents, particularly anti-amyloid therapies, should be initiated earlier in the disease process [18][19][20][21]. The recent solanezumab trials provided some support to this theory, since there was a suggestion of beneficial treatment effects in patients with mild AD but not in those with moderate forms [22].…”