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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.

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.

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of ‘brain insulin resistance’ and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.

The Religious Orders Study is a longitudinal clinical-pathologic cohort study of aging and Alzheimer’s disease (AD). In this manuscript, we summarize the study methods including the study design and describe the clinical evaluation, assessment of risk factors, collection of ante-mortem biological specimens, brain autopsy and collection of selected post-mortem data. The results: 1) review the relation of neuropathologic indices to clinical diagnoses and cognition proximate to death; 2) examine the relation of risk factors to clinical outcomes; 3) examine the relation of risk factors to measures of neuropathology; and 4) summarize additional study findings. We then discuss and contextualize the study findings.

Diabetes mellitus may be associated with an increased risk of developing AD and may affect cognitive systems differentially.

Background Mixed pathologies are common in older persons with dementia. Little is known about mixed pathologies in probable AD and about the spectrum of neuropathology in mild cognitive impairment (MCI). Objective Investigate single and mixed common age-related neuropathologies in persons with probable AD and MCI. Methods The study included 483 autopsied participants from the Religious Orders Study and the Rush Memory and Aging Project with probable AD (NINCDS-ARDA criteria), MCI (amnestic and non-amnestic) or no cognitive impairment. We excluded 41 persons with clinically possible AD and 14 with other dementias. We documented the neuropathology of AD (NIA-Reagan Criteria), macroscopic cerebral infarcts, and neocortical Lewy body (LB) disease. Results Of 179 persons (average age = 86.9) with probable AD, 87.7% had pathologically-confirmed AD and 45.8% had mixed pathologies, most commonly AD with macroscopic infarcts (n= 54), followed by AD with neocortical Lewy body disease (n=19) and both (n=8). Of the 134 persons with MCI, 54.4% had pathologically-diagnosed AD, (58.7% in amnestic; 49.2% in non-amnestic); 19.4% had mixed pathologies (22.7% in amnestic; 15.3% in non-amnestic). Macroscopic infarcts without pathologically-diagnosed AD accounted for 4.5% of probable AD, 13.3% of amnestic and 18.6% of non-amnestic MCI. Pure neocortical LB disease was uncommon in all persons with cognitive impairment (<6%). Microscopic infarcts (without macroscopic infarcts) were common as a mixed pathology, but rarely accounted for a clinical diagnosis of probable AD (n=4) or MCI (n=3). Interpretation Clinically-diagnosed probable AD and MCI, even amnestic MCI, are pathologically heterogeneous disorders with many persons exhibiting mixed pathologies.

ementia is a common public health problem. 1 Worldwide, approximately 47 million people have dementia, and this number is expected to increase to 131 million by 2050. 1 Reductions in age-adjusted incidence of dementia have occurred in the United States and other developed countries over the last 20 years, perhaps associated with increasing formal educational attainment. However, without improved treatments or preventive therapy, the adverse consequences of dementia will continue to increase. 2 In the United States, the prevalence of dementia is 15% in people older than 68 years. 3 Alzheimer disease (AD) affects 5.8 million people, and 13.8 million are projected to have the diagno-sis of AD by the year 2050. 4 AD is the sixth leading cause of death and the fifth leading cause among people older than 65 years. 5,6 This review summarizes diagnosis and management of dementia, defined as significant cognitive impairment in 2 or more cognitive domains. MethodsWe conducted a literature search in PubMed, using the search terms "dementia and (diagnosis or management)" in the title field. The following inclusion criteria were applied: publication date from 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 fa...