We present here both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of 15 patients with Alzheimer's disease and 9 neuropathologically normal subjects. The statistical data show only weak correlations between psychometric indices and plaques and tangles, but the density of neocortical synapses measured by a new immunocytochemical/densitometric technique reveals very powerful correlations with all three psychological assays. Multivariate analysis by stepwise regression produced a model including midfrontal and inferior parietal synapse density, plus inferior parietal plaque counts with a correlation coefficient of 0.96 for Mattis's Dementia Rating Scale. Plaque density contributed only 26% of that strength.

Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment.

Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.

Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder

To map presynaptic cholinergic terminal densities in normal aging (n = 36), Alzheimer's disease (AD) (n = 22), and Parkinson's disease (PD) (n = 15), we performed single-photon emission computed tomography using [123I]iodobenzovesamicol (IBVM), an in vivo marker of the vesicular acetylcholine transporter. We used coregistered positron emission tomography with [18F]fluorodeoxyglucose for metabolic assessment and coregistered magnetic resonance imaging for atrophy assessment. In controls (age, 22-91 years), cortical IBVM binding declined only 3.7% per decade. In AD, cortical binding correlated inversely with dementia severity. In mild dementia, binding differed according to age of onset, but metabolism did not. With an onset age of less than 65 years, binding was reduced severely throughout the entire cerebral cortex and hippocampus (about 30%), but with an onset age of 65 years or more, binding reductions were restricted to temporal cortex and hippocampus. In PD without dementia, binding was reduced only in parietal and occipital cortex, but demented PD subjects had extensive cortical binding decreases similar to early-onset AD. We conclude that cholinergic neuron integrity can be monitored in living AD and PD patients, and that it is not so devastated in vivo as suggested by postmortem choline acetyltransferase activity (50-80%).

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In vivo mapping of cholinergic terminals in normal aging, Alzheimer's disease, and Parkinson's disease

Various cytoskeletal proteins have been implicated in the cellular pathology of Alzheimer's disease. A monoclonal antibody (SMI32) that recognizes nonphosphorylated epitopes on the medium (168 kDa) and heavy (200 kDa) subunits of neurofilament proteins has been used to label and analyze a specific subpopulation of pyramidal neurons in the prefrontal and inferior temporal cortices of normal and Alzheimer's disease brains. In Alzheimer's disease, the distribution of neuropathological markers predominates in layers III and V in these association areas. In these neocortical regions, SMI32 primarily labels the perikarya and dendrites of large pyramidal neurons, predominantly located within layers III and V. In Alzheimer's disease, a dramatic loss of SMI32-immunoreactive (ir) cells was observed, affecting particularly the largest cells (i.e., cells with a cross-sectional perikaryal area larger than 350 microns 2). The staining intensity of the largest SMI32-ir neurons was significantly reduced in Alzheimer's disease cases, suggesting that an inappropriate phosphorylation of these cytoskeletal proteins may take place in the course of the pathological process. In addition, the SMI32-ir neuron loss and total neuron loss were highly correlated with neurofibrillary tangle counts, whereas such a correlation was not observed with neuritic plaque counts. These quantitative data suggest that SMI32-ir neurons represent a small subset of pyramidal cells that share certain anatomical and molecular characteristics and are highly vulnerable in Alzheimer's disease. Other studies have suggested that SMI32-ir neurons are likely to furnish long corticocortical projections. Thus, their loss would substantially diminish the effectiveness of the distributed processing capacity of the neocortex, resulting in a neocortical isolation syndrome as reflected by the clinical symptomatology observed in these patients. Such correlations between the expression of a selective cellular pathology and specific elements of cortical circuitry will increase our understanding of the molecular and cellular characteristics underlying a given neuronal subclass vulnerability in Alzheimer's disease or other neurodegenerative disorders.

Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer's disease: I. Superior frontal and inferior temporal cortex.

The literature on cognitive markers in preclinical AD is reviewed. The findings demonstrate that impairment in multiple cognitive domains is typically observed several years before clinical diagnosis. Measures of executive functioning, episodic memory and perceptual speed appear to be most effective at identifying at-risk individuals. The fact that these cognitive domains are most implicated in normal cognitive aging suggests that the cognitive deficit observed preclinically is not qualitatively different from that observed in normal aging. The degree of cognitive impairment prior to the diagnosis of Alzheimer's disease (AD) appears to generalize relatively well across major study characteristics, including sample ascertainment procedures, age and cognitive status of participants, as well as time to diagnosis of dementia. In episodic memory, there is evidence that the size of the preclinical deficit increases with increasing cognitive demands. The global cognitive impairment observed is highly consistent with observations that multiple brain structures and functions are affected long before the diagnosis of AD. However, there is substantial overlap in the distribution of cognitive scores between those who will and those who will not be diagnosed with AD, hence limiting the clinical utility of cognitive markers for early identification of cases. Future research should consider combining cognitive indicators with other types of markers (i.e. social, somatic, genetic, brain-based) in order to increase prediction accuracy.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2004.01386.x

Multiple cognitive deficits during the transition to Alzheimer's disease.

Complement C4 phenotype distribution was studied in 64 patients with dementia of the Alzheimer type. In contrast to reported findings we failed to find a significant association between C4B2 gene frequency and Alzheimer's dementia.

P. Eikelenboom

Papers

Complement C4 phenotypes in dementia of the Alzheimer type.