Clinicopathologic Studies of Alzheimer’s Disease and Related Dementias

Alzheimer’s disease (AD) is the single most common cause of dementia, but AD alone accounts for less than half of all cases. A variety of other brain pathologies can cause cognitive impairment either alone or in combination with AD. A clinical diagnosis often fails to capture this complexity, so evaluation of brain pathology at autopsy remains the gold standard for establishing the underlying causes of dementia. As disease-modifying therapeutics targeting the underlying mechanisms of neurodegenerative diseases are developed, there is a pressing need for clinicopathologic studies to identify distinct clinical presentations that rise from these various pathologies in order to simplify differential diagnosis, improve prognosis of future decline, and help better target interventions.Here, I present a series of clinicopathologic studies that characterize and compare the dementia syndromes associated with neuropathologically-verified AD, Hippocampal Sclerosis, Lewy body disease, and their interactions. The first study demonstrates that Hippocampal Sclerosis, alone or in combination with AD, produces a dementia syndrome that is virtually indistinguishable from AD. The generally slower longitudinal trajectory of cognitive decline in patients with Hippocampal Sclerosis, however, may help clinically distinguish the disorder from AD. The second study revealed double-dissociations in patterns of cognitive deficits and longitudinal declines between Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD) that likely reflect subtle differences in pathology. These results suggest that pooling DLB and PDD patients in clinical trials targeting Lewy body pathology may reduce the power to see an effect of treatment unless the appropriate cognitive domain for each is targeted by the trial outcome measures. The final two studies demonstrate considerable variability in clinical and cognitive presentation across age of onset within those with severe AD at autopsy, and show that this variability is (at least partly) mediated by the distribution of neurofibrillary tangle (NFT) pathology. Those with younger onset AD have disproportionately greater neocortical NFT pathology relative to their degree of hippocampal NFT pathology. These findings help explain the paradox that those patients with younger onset of symptoms tend to have higher likelihood of atypical clinical presentations of AD, even though they tend to have less concomitant non-AD neuropathology