Zoe Arvanitakis

OBJECTIVE: To examine the spectrum of neuropathology in persons from the Rush Memory and Aging Project, a longitudinal community-based clinical-pathologic cohort study. METHODS: The study includes older persons who agreed to annual clinical evaluation and brain donation. We examined the neuropathologic diagnoses, including Alzheimer disease (AD) (NIA-Reagan Criteria), cerebral infarctions, and Parkinson disease/Lewy body disease (PD/LBD), in the first 141 autopsies. We calculated the frequency of each diagnosis alone and mixed diagnoses. We used logistic regression to compare one to multiple diagnoses on the odds of dementia. RESULTS: Twenty persons (14.2%) had no acute or chronic brain abnormalities. The most common chronic neuropathologic diagnoses were AD (n = 80), cerebral infarctions (n = 52), and PD/LBD (n = 24). In persons with dementia (n = 50), 38.0% (n = 19) had AD and infarcts, 30.0% (n = 15) had pure AD, and 12% each had vascular dementia (n = 6) and AD with PD/LBD (n = 6). In those without dementia (n = 91), 28.6% (n = 26) had no chronic diagnostic abnormalities, 24.2% (n = 22) had pure AD, and 17.6% (n = 16) had infarctions. In persons with dementia, over 50% had multiple diagnoses (AD, PD/LBD, or infarcts), whereas, in persons without dementia, over 80% had one or no diagnosis. After accounting for age, persons with multiple diagnoses were almost three times (OR = 2.8; 95% CI = 1.2, 6.7) more likely to exhibit dementia compared to those with one pathologic diagnosis. CONCLUSION: The majority of community-dwelling older persons have brain pathology. Those with dementia most often have multiple brain pathologies, which greatly increases the odds of dementia.

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

Importance: Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million. Observations: Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the United States, Alzheimer disease, one cause of dementia, affects 5.8 million people. Dementia is commonly associated with more than 1 neuropathology, usually Alzheimer disease with cerebrovascular pathology. Diagnosing dementia requires a history evaluating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a thorough mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment. However, if the assessment is inconclusive (eg, symptoms present, but normal examination findings), neuropsychological testing can help determine whether dementia is present. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional evaluation with cerebrospinal fluid assays or genetic testing may be considered in atypical dementia cases, such as age of onset younger than 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients may benefit from nonpharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For Alzheimer disease, this includes an acetylcholinesterase inhibitor such as donepezil for mild to severe dementia, and memantine (used alone or as an add-on therapy) for moderate to severe dementia. Rivastigmine can be used to treat symptomatic Parkinson disease dementia. Conclusions and Relevance: Alzheimer disease currently affects 5.8 million persons in the United States and is a common cause of dementia, which is usually accompanied by other neuropathology, often cerebrovascular disease such as brain infarcts. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both nonpharmacologic and pharmacologic approaches, although efficacy of available treatments remains limited.

OBJECTIVE: To examine the relation of National Institute on Aging-Reagan (NIA-Reagan) neuropathologic criteria of Alzheimer disease (AD) to level of cognitive function in persons without dementia or mild cognitive impairment (MCI). METHODS: More than 2,000 persons without dementia participating in the Religious Orders Study or the Memory and Aging Project agreed to annual detailed clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed five cognitive domains, including episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. A total of 134 persons without cognitive impairment died and underwent brain autopsy and postmortem assessment for AD pathology using NIA-Reagan neuropathologic criteria for AD, cerebral infarctions, and Lewy bodies. Linear regression was used to examine the relation of AD pathology to level of cognitive function proximate to death. RESULTS: Two (1.5%) persons met NIA-Reagan criteria for high likelihood AD, and 48 (35.8%) met criteria for intermediate likelihood; 29 (21.6%) had cerebral infarctions, and 18 (13.4%) had Lewy bodies. The mean Mini-Mental State Examination score proximate to death was 28.2 for those meeting high or intermediate likelihood AD by NIA-Reagan criteria and 28.4 for those not meeting criteria. In linear regression models adjusted for age, sex, and education, persons meeting criteria for intermediate or high likelihood AD scored about a quarter standard unit lower on tests of episodic memory (p = 0.01). There were no significant differences in any other cognitive domain. CONCLUSIONS: Alzheimer disease pathology can be found in the brains of older persons without dementia or mild cognitive impairment and is related to subtle changes in episodic memory.