No relationship to premorbid personality traits earlier in life has been established, but an intriguing finding from what has become known as the “nun study” and several similar studies suggests that poorer linguistic capability early in life corresponded to the development of Alzheimer disease with aging (Snowden et al, 1996). In this study, the autobiographies of 93 nuns, written in their twenties, were rated for linguistic and ideational complexity. Of 14 sisters who died in late life, deterioration of cognitive function and neuropathologically proven Alzheimer disease occurred in 7 who had a low “idea density” in their writings and in none of 7 whose writings were cognitively more complex. Obviously this type of correlation is subject to several interpretations, but the general notion of “cognitive reserve” having either a protective property or simply hiding mental decline, has emerged from numerous other studies. Also, there has been a general perception, confirmed by a few studies such as the one by Verghese and colleagues, that an active mental life may reduce the severity of mental decline with aging, but firm conclusions about causation cannot be made from the available information.
Neurotransmitter abnormalities Considerable interest was created in the late 1970s by the finding of a marked reduction in choline acetyltransferase (ChAT) and acetylcholine in the hippocampus and neocortex of patients with Alzheimer disease. This loss of cholinergic synthetic capacity was attributed to a reduction in the number of cells in the basal forebrain nuclei (mainly the nucleus basalis of Meynert), from which the major portion of neocortical cholinergic terminals originate (Whitehouse et al, 1981). However, a 50 percent reduction in ChAT activity has been found in regions such as the caudate nucleus, which shows neither plaques nor tangles. The specificity of the nucleus basalis cholinergic changes has been questioned for other reasons as well. For one, Alzheimer brain also shows a loss of monoaminergic neurons and a diminution of noradrenergic, gabanergic, and serotonergic functions in the affected neocortex. The concentration of amino acid transmitters, particularly of glutamate, is also reduced in cortical and subcortical areas (Sasaki et al) and the concentration of several neuropeptide transmitters—notably substance P, somatostatin, and cholecystokinin are likewise low—but it has not been determined whether any of these biochemical abnormalities, including the cholinergic ones, are primary or secondary to heterogeneous neuronal loss. Nevertheless, the administration of cholinomimetics—either acetylcholine precursors (e.g., choline or lecithin), degradation inhibitors (e.g., physostigmine), or muscarinic agonists that act directly on postsynaptic receptors—have had a mild and unsustained therapeutic effect (see further under “Treatment”).
The role of aluminum in the genesis of neurofibrillary tangles, as was once proposed, has never been validated. It has been suggested that the use of estrogen by postmenopausal women or of antiinflammatory agents in men or women delayed the onset of the disease or reduced its occurrence, but neither of these have been corroborated by other studies.