Clinical manifestations

Presentation and course

When we assess memory at the bedside, we are examining four subtypes of memory, according to the following table:

Table 1. The Four Subtypes of Memory

	Immediate memory	Working memory	Recent memory	Remote memory
Synonyms or conceptually similar terms	Primary memory or registration		Secondary memory	Semantic or long-term memory
Method of bedside assessment	Auditory attention span for up to seven digits	Digits forward, serial subtraction	Memory for three items after 3 minutes	History of public events, or vocabulary

Immediate memory (primary memory, attention, or registration). Immediate memory is tested by asking patients to repeat word lists or number lists. It involves short-term storage for only a few seconds. Memory storage in this system has limited capacity and is highly susceptible to interference. The quantity of information that a normal person can retrieve in immediate memory is limited to about six or seven digits. Patients with impaired immediate memory are acutely confused, or they have moderate to severe dementia.

Working (declarative or episodic) memory. Working memory is a system for temporarily storing the information needed to carry out a cognitive task. It is related to immediate memory, but it involves the additional task of concurrently manipulating information while recalling it. Forward digit span is a prototypical method to assess working memory. The average memory span for a random number of digits in normal adults is about seven digits (the length of a phone number). Other examples of episodic memory tests are the East Boston Story and Logical Memory Story tests (237) and the Free and Cued Selective Reminding Test (58). Deficits in episodic memory in Alzheimer patients have been shown to correlate with tau accumulation and cortical atrophy in the medial temporal lobes and angular gyri (11). Deficits in episodic memory among cognitively normal older adults can predict progression to incident cognitive impairment within a mean follow-up of 7 years (59). Changes in episodic memory (immediate recall on the ModRey test) over 1 to 3 years were the primary outcome measures used in a clinical trial testing the benefit of multivitamin supplementation in older adults (240).

Recent memory. Recent memory is tested at the bedside when we ask patients to remember three items after a three-minute distraction task. Disorders of recent memory include classic examples such as Wernicke-Korsakoff syndrome, Alzheimer disease, and transient global amnesia. Deficits in recent memory are due to an inability to learn new information and to retrieve it after a delay of a few minutes. The 24-item Grober and Buschke test was used in one study to compare recent and delayed recall performance of patients with Alzheimer disease with those who had other types of dementia (22). Patients with Alzheimer disease did poorly on both free and cued recall, suggesting both encoding and storage problems. The free recall score from the Free and Cued Selective Reminding Test has been shown to be better than the Logical Memory-Immediate Recall Test at identifying older adults with memory complaints who will go on to develop Alzheimer disease over the next 2 to 4 years (36). Memory tasks are performed better in the early stages of dementia with Lewy bodies than in the early stages of Alzheimer disease (88). Patients with pure LATE had fewer memory complaints than those with Alzheimer disease or the combination of LATE and Alzheimer disease (18).

Remote memory (semantic memory or long-term memory). Remote memory is assessed by asking patients about important public events that took place decades earlier (eg, “what happened in November of 1963? September of 2001?”). Semantic memory also includes things that are common knowledge (“What is the capital of England? Capital of France?”). If the patient is an older veteran, he can be asked, “Who were we fighting in World War II?” The Boston Naming Test can be used as a measure of semantic memory. In a large prospective study, semantic memories were shown to be in particular decline during the 5 to 6 years just prior to the diagnosis of Alzheimer disease (233). Patients with Alzheimer disease with small social networks are the ones most likely to lose semantic memories in the early stages of the disease (13). Remote memory was noted to decrease significantly over a 2-year period in a study of patients with subjective cognitive decline (171). Semantic memory deficits in Alzheimer patients correlate with tau accumulation and cortical atrophy in the left anterior temporal lobe (11).

Delayed recall. Neuropsychologists have used the Rey Complex Figure Test (RCFT) to assess delayed recall in patients with subcortical vascular dementia (82). The Selective Reminding Test has been applied to comparisons of delayed recall in progressive supranuclear palsy and Parkinson disease (41). The 24-item Grober and Buschke test was used to assess free and cued recall in patients with Alzheimer disease and other types of dementia (22). Delayed (cued) recall was better in vascular and frontotemporal dementia than in Alzheimer disease, suggesting a problem with retrieval, rather than a problem with encoding.

Verbal memory. The Buschke Selective Reminding Test (BSRT) has been used by neuropsychologists to assess verbal memory in those who have dementia with Lewy bodies and Alzheimer disease (147). The California Verbal Learning Test-SF was applied to the evaluation of verbal episodic memory in a study comparing dementia with Lewy body patients with other synucleinopathies (92). The Rey Auditory Verbal Learning Test (RAVLT), a multi-trial list learning and memory test, was utilized to assess verbal episodic memory in patients with mild cognitive impairment and Alzheimer disease (205).

Visual and spatial memory. The Benton Visual Retention Test (BVRT) has been applied to studies of visual memory in those with dementia with Lewy bodies and Alzheimer disease (147). The Rey-Osterrieth complex figure test with a 10-minute free recall delay has been used to assess nonverbal episodic memory in dementia with Lewy bodies, Parkinson disease, and multiple system atrophy (92). In early phases of Alzheimer disease, patients are known to lose navigational skills and spatial memory. A study examined patients with early Alzheimer disease in virtual environments while they were being tested in fMRI or PET scanners to determine that early brain changes were occurring in the right anterior hippocampus (17). Authors who identified visual and spatial memory problems in Alzheimer patients found that there were associated areas of tau accumulation on tau-PET in the right (more than left) temporal-occipital areas (11).

Global cognitive assessments. It is critical that every new patient with a memory complaint has at least one global assessment of cognitive function in the chart, whether the initial diagnosis is mild cognitive impairment or dementia (49; 190). Optimal cognitive screening for at-risk surgical patients should include both preoperative and postoperative evaluations with a standard global cognitive assessment instrument (97). The Mini-Mental State Examination (MMSE) is a 30-question test used in clinic settings as a screening tool for older patients who are suspected of having memory problems. In a large Cochrane Systematic Review, the accuracy of the MMSE for assisting in the diagnosis of dementia was greatest (sensitivity 0.85; specificity 0.90) if the chosen cut-point was 24 or less (31). Higher education is associated with false-negative misclassification using the MMSE, and lower education with false-positive misclassification (170). Other false-positive interpretations of the MMSE can occur in those with non-Caucasian ethnicity or in those who have visual impairment. Another 30-question global assessment measure is the Montreal Cognitive Assessment (MoCA), which has been shown to be comparable to the MMSE in documenting mild cognitive impairment (sensitivity 0.89; specificity 0.75) (215; 97). Because the MoCA has more measures of executive function compared to the MMSE, it is preferred by those who manage patients with vascular dementia (242) and many who manage patients with Parkinson disease and other movement disorders. For those who use MoCA to assess patients with traumatic brain injury, it is important to take into account the influence of pain and lack of sleep on test performance (228). The Saint Louis University Mental Status Examination (SLUMS) is also effective in identifying patients with mild cognitive impairment and dementia (208). The paper Self-administered Gerocognitive Examination (SAGE) is a valid and reliable cognitive assessment tool that can assist in identifying patients with mild cognitive impairment or early dementia. A new tablet-based version (eSAGE) has shown a strong association with the validated paper SAGE and a neuropsychological battery (187). Both have the advantage of self-administration, brevity, and four interchangeable forms. The Clinical Dementia Rating (CDR) is a global assessment measurement that captures both cognitive and functional impairments (136). The patient is tested on memory and orientation, and the caregiver is questioned about judgement, community affairs, home and hobbies, and personal care. After each of these six categories is ranked on a severity scale of 0 (normal) to 3 (severe), the “sum of boxes” score (range from 0 to 18) is referred to as the CDR-SB. O’Bryant and others proposed to cross-validate the staging guidelines of the CDR-SB using the National Alzheimer’s Coordinating Center dataset of 12,462 participants (5115 controls, 2551 patients with mild cognitive impairment, and 496 patients with dementia of all types) (149). They found that the CDR-SB successfully classified the vast majority of participants across all levels of cognitive impairment (kappa=0.91).

Prognosis and complications

Subjective cognitive decline. These patients progress to dementia at a rate of 6.7% per year (171). MMSE scores and Hamilton Depression Scale scores do not change significantly, but remote memory scores change significantly, when these patients are followed over a period of 2 years. Memory complaints in those with subjective cognitive decline have been associated with depression, regardless of age of onset (21). In those patients with subjective cognitive decline over 60 years of age, there are more complaints if there are signs of brain atrophy and subtle problems with instrumental activities of daily living. A metaanalysis study demonstrated that progression of subjective cognitive decline to MCI or dementia was more likely (OR=11.36) in those who had the full Alzheimer biomarker profile (signs of both amyloid and tau pathology) (177).

Mild cognitive impairment. This condition progresses to dementia at a rate of about 10% to 17% per year (158). Those who have amnestic mild cognitive impairment (prodromal Alzheimer disease) or prodromal vascular dementia (those who have had at least one stroke) make the conversion to dementia at an even more rapid rate of 17% to 20% per year. The best predictors of conversion from amnestic mild cognitive impairment to Alzheimer disease were the results of baseline FDG-PET and episodic memory test scores. Other predictors of conversion, from mild cognitive impairment to dementia, are lower average sleep efficiency or greater variability in sleep time (39). Longitudinal studies with the Framingham cohort also showed that midlife systolic hypertension is a risk factor for conversion to incident dementia (HR 1.57; 95% CI 1.05-2.35) (125). A working group has proposed a mild cognitive impairment stage for dementia with Lewy bodies that includes a delirium-onset condition, a psychiatric-onset presentation, as well as an idiopathic REM sleep disorder type of presentation (128). In the IDEAS longitudinal cohort of 11,409 patients with mild cognitive impairment or dementia, 55.3% of the mild cognitive impairment patients had amyloid positive PET scans at baseline (167). In the BIOCARD longitudinal cohort of 273 participants who were cognitively normal at baseline, CSF A-beta 42/40 was a better predictor of developing mild cognitive impairment symptoms at 7 years than CSF p-tau or total-tau (57). In the MEMENTO longitudinal cohort of 2323 outpatients with subjective cognitive decline or mild cognitive impairment, the best blood biomarkers to predict dementia risk over a 5-year followup period were the A-beta 42/40 ratio, concentrations of p181-tau, and NfL levels (163).

Alzheimer disease. Longitudinal studies of autopsy-verified Alzheimer disease have shown that it follows three phases in many patients: a gradual onset over the first two to three years, then a slow progression over the next 5 to 10 years, followed by a rapid decline over the last 3 to 4 years (237). In another longitudinal study, the mean increase in CDR-SB score for patients with mild Alzheimer disease was 1.6 points per year, whereas the mean decline in MMSE score was 1.9 points per year (45). The higher the baseline CDR-SB score, the more rapid the rate of progression. Those patients with Alzheimer disease who have all their vascular risk factors treated decline less rapidly than those who do not manage their hypertension, diabetes, or hyperlipidemia (37). In one study of tau-PET scans, the authors identified three subtypes of Alzheimer disease besides the typical limbic- predominant, older-onset type with an amnestic presentation, APOE-e4 carrier status, and presence of TDP-43 (225; 134). These included the medial temporal lobe-sparing subtype, which is characterized by male predominance, younger onset, APOE-e4 noncarrier status, and a nonamnestic syndrome (47; 225; 197). In the posterior occipito-temporal subtype (30%), the onset of Alzheimer disease is usually at an older age (often with visuo-spatial impairment), and the progression is slower (225). In the lateral-temporal lobe subtype (12%), left-sided lateralization is more likely to be present, and language is more likely to be impaired. In a series of autopsy-verified cases, risk factors for early-onset Alzheimer disease included male sex, the APOE-e4 allele, and late-life depression (185). In the primary progressive aphasia subtype of Alzheimer disease (PPA-AD), or those with logopenic primary progressive aphasia, episodic memory is preserved on initial testing, and memory showed no decline on retesting 2.5 years later (131). Patients with progressive aphasia subtype of Alzheimer disease are less likely to be carriers of the APOE-e4 allele. There is a behavioral variant of Alzheimer disease (bv-AD) that presents with behavioral changes that are worse than typical Alzheimer disease (tAD), but less severe than patients with behavioral variant of frontotemporal dementia (bvFTD) (154). Neuroimaging in behavioral variant of Alzheimer disease patients follows two patterns: the most prevalent pattern spares the frontal lobes, and the less-common pattern is FTD-like. Alzheimer disease continuum patients with enlarged perivascular spaces in the centrum semi-ovale (a sign of small vessel disease) have been shown to have a more rapid cognitive decline over the first 5 years, compared to those who do not have enlarged spaces (83).

Limbic predominant age-related TDP-43 encephalopathy (LATE). In a longitudinal study that included autopsy-verified diagnoses, age at death in patients with pure LATE was several years later (mean, 89.5) than that of those with Alzheimer disease (mean, 85.4) or those with the combination of LATE and Alzheimer disease (mean, 85.7) (18).

Vascular cognitive impairment. Patients with vascular dementia have shorter lifespans than those with Alzheimer disease because of earlier gait problems, more frequent falls, and more deadly vascular comorbidities, such as stroke, peripheral vascular disease, congestive heart failure, chronic kidney disease, and myocardial infarction (72). The Rush Alzheimer Disease Center Study showed that there was a synergistic interaction between subcortical infarcts and Alzheimer disease because infarcts did not simply add to the cognitive effects of Alzheimer disease but multiplied the effects (189). Incidental lacunes on MRI predict a steeper rate of decline in executive function and psychomotor speed (85). In a study of 142 subcortical vascular cognitive impairment patients, the early-onset group was more likely than the late-onset group to show signs of frontal-executive impairment (82). There were more lacunes in the deep white matter of the frontal lobes in the early-onset patients. Occasionally, patients with vascular cognitive impairment return to normal cognitive and functional performance levels provided their medical comorbidities, such as heart failure and atrial fibrillation, are well managed (38). In one study of patients with hypoxic-ischemic encephalopathy after cardiac arrest, seven of 50 patients were noted to recover to their cognitive baseline (110).

Dementia with Lewy bodies. A longitudinal clinical study compared dementia with Lewy body disease and Alzheimer disease and found similar rates of cognitive decline within the first few years (71). A pathological study showed that those with Lewy body disease had shorter disease duration from symptom onset to death, compared to those with Alzheimer disease (55). Shorter disease duration was particularly noted in men, in those who had later age at onset, and in those who had the diffuse neocortical Lewy body subtype; the severity of associated Alzheimer plaques or tangles did not appear to influence disease duration (55). Several autopsy studies have reported that 75% to 80% of Lewy body brains show signs of having concomitant Alzheimer changes in variable amounts, explaining the wide range of disease severity and survival expectations (73). A longitudinal study by Wilson and colleagues demonstrated that those with neocortical Lewy bodies at autopsy had slowly progressive cognitive changes over the first 5 to 10 years, then marked cognitive decline over the last 2 to 4 years (237). Late-life depression is a predictor for earlier onset of both Lewy body disease and mixed Alzheimer disease plus Lewy body disease (185). In the early stages of dementia, those who have dementia with Lewy bodies are more likely to have lower scores on attention and executive function tasks, compared to those with early Alzheimer disease (88).

Frontotemporal dementia. The onset of the behavioral variant of frontotemporal dementia is usually before the age of 65, so this makes it the second most common form of pre-senile dementia (199; 46; 30). The most rapidly progressing subtype of frontotemporal dementia is associated with motor neuron disease, where death occurs within three to five years of symptom onset (229). In contrast, those with semantic dementia can survive for 10 years or more (mean survival is 9.1 years) (30). As the slower frontotemporal dementias progress (behavioral variant, progressive nonfluent aphasia, and semantic dementia), they become more difficult to distinguish from each other, and they acquire features that are common to all patients with dementia (wandering, intrusive behaviors, apathy, incontinence, dysphagia, etc.) (229).

Wernicke-Korsakoff syndrome. Some of the symptoms of Wernicke-Korsakoff syndrome respond over days to weeks to intravenous thiamine replacement therapy (nystagmus, dysarthria, and ataxia, for example), but the memory disorder is likely to persist over several months to years, even when patients take daily oral replacement therapy (191; 14).

Traumatic encephalopathy syndrome and chronic traumatic encephalopathy. Besides memory and executive problems, patients can experience language and visuospatial problems. In addition to behavioral dysregulation, such as impulsive or explosive behavior, they can also develop apathy and depression (96).

Transient global amnesia. This clinical syndrome of anterograde amnesia usually clears within 24 hours. It is thought by many to be of vascular or migraine origin. An 8-year, case-controlled, longitudinal study showed an increased risk of dementia (HR=2.23) in those who experienced transient global amnesia, compared to a non–transient global amnesia cohort adjusted for age, sex, and comorbidity (78).

Acute amnestic syndrome. Like transient global amnesia, this condition also presents with anterograde amnesia, but the memory problems often persist and result in functional disability because of infarction of the fornix (53).

Clinical vignette

A 64-year-old man was admitted because of memory loss, dysarthria, and ataxia for the past two months. He had a 20-year history of alcoholism, drinking one to two shots of hard liquor and six beers each day. On examination, he looked his stated age but was unkempt. He was alert and fully oriented; he was able to name, repeat, and follow commands. His speech was moderately dysarthric. He could register three items after one trial, but he could not recall any of these three items at three minutes. Nystagmus was noted on right lateral gaze, but there was no evidence of ophthalmoplegia or gaze palsy. He had dysmetria on heel-to-shin testing in both legs but no dysmetria on the finger-nose-finger test. He had decreased appreciation for pin sensation in both legs in a stocking distribution. Reflexes were hypoactive throughout, and his toes were downgoing to plantar stimulation. Postural instability was noted in the Romberg position with eyes open. Gait was wide-based and ataxic. After one day of intravenous thiamine, this patient’s nystagmus disappeared. After a week of daily intravenous thiamine replacement therapy, the ataxia and dysarthria improved. Even with continued daily oral thiamine replacement as an outpatient, this patient’s recent memory problems and neuropathy persisted for several years.

Comment. This is a typical story for Wernicke-Korsakoff syndrome, which results from a deficiency in vitamin B1 (thiamine). In developed countries, most cases of this disorder are related to the misuse of alcohol, but several cases have been attributed to gastric bypass surgery, anorexia, hyperemesis, intestinal obstruction, AIDS, and total parenteral nutrition. Genetic defects are likely to combine with dietary factors to explain why only a fraction of those with chronic alcoholism acquire this disease (191).

Biological basis

Anatomic localization

Hippocampal formation. The hippocampi and mesial temporal lobes are the regions of the brain most consistently responsible for consolidating recent memories for dates, faces, and events. The most famous patient with memory loss was H. M., who at the age of 27 developed sudden memory loss after a surgical procedure where both his hippocampi were removed for intractable seizures (03; 123). After the procedure, H. M. had marked loss of recent memories, but his semantic (long-term) memories for the years preceding the event were preserved. He had dampened expression of emotion and lack of initiative, which may relate to the removal of both the anterior hippocampus and the amygdala (03).

Hippocampal volume loss is a predictor for the development of amnestic mild cognitive impairment among cognitively normal older adults (91; 69). Noh and colleagues showed that in early-onset Alzheimer disease patients, the first atrophic changes were in the parietal lobes, consistent with the early changes in language and visuospatial problems. The late-onset Alzheimer cases in this series had more memory complaints, consistent with either diffuse cortical or bilateral hippocampal atrophy (148; 47). In amnestic Alzheimer patients, there was reduced hippocampal-to-cortical connectivity, as measured by resting-state functional MRI. This was in contrast to patients with aphasic Alzheimer disease (primary progressive aphasia), where there was reduced connectivity from the left inferior frontal gyrus to the cortex (121). Individuals unaware of cognitive decline are more likely to have lower grey matter volume in the left hippocampus (181).

Reduced volume in the right hippocampus is seen in patients who have the subjective cognitive impairment that precedes mild cognitive impairment (188). Jack and colleagues reported that hippocampal atrophy begins to slowly progress in normal controls after the age of 30, paralleling the slow deterioration of memory function in middle-aged individuals (81). The hippocampus and entorhinal cortex are affected early on by tangle pathology, even in cognitively normal older adults, and this process is associated with poor performance on tests of episodic memory (213). Guo and others showed that memory decline over time occurs faster in normal elderly adults who have a higher amyloid burden as measured by PET on the banks of the superior temporal sulcus (63). Poor episodic memory scores were associated with higher amyloid imaging burden and lower volumes in the hippocampi, entorhinal cortices, and inferior temporal lobes in cognitively unimpaired individuals (mean age = 71.3 years) who were part of a large cross-sectional imaging study (58). A study showed that the rate of hippocampal volume loss in clinically normal older adults appeared to occur independently of amyloid or tau accumulation and was more related to non-Alzheimer pathology, such as TDP-43 and vascular changes (69). Other studies defined LATE with neuropathological change as being associated with atrophy of the hippocampi with or without involvement of the neocortices (142; 179).

The anterograde amnesia that develops after cardiopulmonary arrest is due to bilateral lesions in the hippocampi (34). Herpes simplex encephalitis can cause neuronal death in the hippocampi and mesial temporal lobes (93; 234). Football players with and without concussion have smaller hippocampal volumes, compared to age-matched healthy controls (196). Players with concussion have smaller hippocampal volumes than those without concussion. A series of 14 young to middle-aged patients with substance abuse (ages 19 to 52) presented to the emergency department with confusion or unconsciousness. When they woke up, they had anterograde amnesia (09). Their MRI scans showed signs of bilateral hippocampal ischemia.

Thalami, fornix, and mamillary bodies. Brains of patients with Wernicke-Korsakoff show areas of hemorrhagic necrosis or atrophy in the dorsal medial nuclei of the thalamus and in the mamillary bodies (191; 204). There are links between the hippocampal formations and these midline structures, explaining why anterograde amnesia can result from bilateral thalamic infarcts (120). In a study of a patient with multiple sclerosis, an isolated gadolinium-enhancing plaque in the anterior thalamus was associated with loss of memory, personality change, and hypersomnolence (86). Acute amnestic syndrome can develop in patients who experience ischemic stroke in the fornix, resulting in persistent memory loss that can be associated with functional impairment (53). Memory impairment, apathy, anosognosia, and hypersomnia were reported in a 55-year-old man with bithalamic lesions associated with a dural arteriovenous fistula (67).

Locus coeruleus. This small noradrenergic nucleus in the dorsal pons plays a role in attention, learning, and memory. A study showed that reduced activity in the locus coeruleus in the preclinical stage of Alzheimer disease is associated with tau accumulation in the entorhinal cortex and subsequent memory decline (166).

Cerebral cortex. The nucleus basalis of Meynert is the major source of cholinergic innervation for the cerebral cortex and is significantly diminished in Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and Wernicke-Korsakoff syndrome (04; 61). One MRI study showed as much atrophy in the nucleus basalis of Meynert (20% to 25%) in patients with dementia with Lewy bodies as in those with Alzheimer disease (61). In Alzheimer disease, the magnitude of thinning of the cerebral cortex correlates well with the severity of both cognitive and functional impairment (08). In early-onset Alzheimer disease patients, the visuospatial and language problems seen in the early stages can be associated with bilateral atrophy of the parietal association cortices (148; 47). In addition, there is more likely to be a parietal pattern of amyloid accumulation in Alzheimer patients who have a younger age at onset (27). A review pointed out that the basal forebrain cholinergic neurons in frontotemporal dementia seem to be less vulnerable to tauopathy compared to the basal forebrain cholinergic neurons in either Alzheimer disease or dementia with Lewy bodies (52). Medial frontal cortical neurons in patients with early-onset Alzheimer disease have a higher density of neurofibrillary tangles than what is found in patients with late-onset Alzheimer disease (197).

Frontostriatal system. In early stages of various extrapyramidal diseases, such as progressive supranuclear palsy, short-term memory is normal, but memory retrieval is a problem. This is due to dysfunction in the frontostriatal system, rather than in the hippocampus. The Selective Reminding Test can be used to demonstrate memory retrieval problems in progressive supranuclear palsy, Parkinson disease, and Huntington disease; on the other hand, patients with Alzheimer disease have poor recall, even after being given a cue (161; 41). In cases of subcortical vascular cognitive impairment, delayed recall (as measured by the Rey Complex Figure Test) correlates with the number of lacunes. Frontal lobe dysfunction (as measured by the Stroop color reading test) also correlates with lacune number in these patients (82). In an amyloid-PET/MRI study, basal forebrain volume loss was associated with memory dysfunction among Alzheimer spectrum patients (241). In Lewy body spectrum disorder patients, on the other hand, basal forebrain atrophy correlated with more widespread cognitive dysfunction.

Cerebellum. Although the cerebrum and hippocampus are important for consolidating and storing declarative memories, the cerebellum is key for storing procedural memories, such as riding a bicycle or playing the piano (152; 06). The combined activation of two synaptic inputs to the Purkinje cells depresses the transmission efficacy of those neurons. This long-term depression is thought to be the cellular basis for motor learning.

Pathophysiology

Alzheimer disease. Extracellular accumulation (plaques) of beta-amyloid and intracellular accumulation (tangles) of tau are thought to be the neuropathologic hallmarks of Alzheimer disease (11; 05; 80; 210). The accumulation of these two proteins is thought to cause memory problems by disrupting normal synaptic function. Studies have shown elevated levels of synaptic proteins in the CSF of patients with mild cognitive impairment who had Alzheimer biomarkers compared to controls (212). As Alzheimer disease pathology increases, CSF markers (high levels of tau and low levels of A-beta 42) have been shown to be good predictors of the conversion from amnestic mild cognitive impairment to Alzheimer disease (68). Longitudinal prediction of dementia of the Alzheimer type has also been associated with hypometabolism on FDG-PET, APOE genotype (e4 allele), smaller whole brain volumes, lower hippocampal volume, reduced thickness of the parietal cortex, elevated amyloid burden on PET, elevated tau burden on PET, and higher cerebrospinal fluid tau levels (175; 81; 11; 201; 28). The work of Soldan and colleagues pooled data from four cohort studies in which changes in CSF amyloid, brain tau, and neurodegeneration were followed in 814 cognitively normal older adults over 7 years (200). The results were consistent with the hypothesis that both reduced CSF amyloid and elevated CSF tau were necessary to observe significant neurodegeneration and cognitive decline over time. Late-onset Alzheimer disease is more likely than early-onset disease to show mixed pathological features of one of the non-Alzheimer disease dementias, such as vascular cognitive impairment (197).

Limbic-predominant age-related TDP-43 encephalopathy (LATE). Five genes have been associated with LATE, including one whose allele (APOE-e4) is a risk factor for late-onset Alzheimer disease and one (progranulin, GRN) that is also a risk factor for frontotemporal dementia (142).

Mild cognitive impairment. In several studies in which amyloid was detected in brains with PET, patients with mild cognitive impairment had more rapid progression to Alzheimer disease, compared to cases where there was no amyloid (167; 105). Patients with mild cognitive impairment who have large areas of connectivity on fMRI during memory tasks show slower progression to Alzheimer disease than those who have small areas of connectivity (159). The first biomarker to become abnormal in most patients with mild cognitive impairment is brain A-beta 42 (measured by the PIB-PET scan), and the next is temporoparietal hypometabolism (assessed with FDG-PET), followed by the presence of hippocampal atrophy (MRI scan) (165). In a longitudinal study, tau changes on PET were greater in the nondemented participants who progressed to mild cognitive impairment than in those who did not (68; 28).

Wernicke-Korsakoff syndrome. Thiamine deficiency is the cause of the hemorrhagic necrosis and brain atrophy in Wernicke-Korsakoff syndrome (191; 204). These lesions occur in the dorsal medial nuclei of the thalamus, fornix, mamillary bodies, and the periaqueductal gray matter, all of which have relatively high metabolic rates. If there is not enough thiamine for the pivotal enzyme pyruvate dehydrogenase, then lactate is produced from glucose, instead of ATP. Navarro and colleagues have used nuclear magnetic spectroscopy to demonstrate lactate accumulation in the brains of patients with Wernicke encephalopathy (141).

Vascular cognitive impairment. This is a heterogeneous group of cognitive disorders that results from either small vessel disease, large vessel disease, cardioembolic infarction, or some combination of these three (72; 138; 54; 35; 38). The most common form of vascular cognitive impairment is mixed vascular cognitive impairment/Alzheimer disease, where there are signs of both Alzheimer disease and vascular dementia (189; 243; 35; 82; 38). The most common “pure” vascular dementia is Binswanger disease, or subcortical vascular dementia, which is associated with chronic hypertension, subcortical arteriosclerosis, hypoperfusion, and subsequent bilateral demyelination of subcortical white matter (72; 109; 35). Pure vascular dementia is related to severe white matter intensities on MRI, reduced fractional anisotropy, younger age, greater number of lacunes, and lesser amount of medial temporal atrophy (99; 242). In a study, patients with early-onset subcortical vascular cognitive impairment had deeper frontal lacunes, whereas the late-onset cases had more cortical and hippocampal atrophy on MRI and more amyloid accumulation on Pittsburgh compound B-PET scans (82).

Dementia with Lewy bodies. These patients have a cholinergic deficiency in the basal forebrain and other brain areas that is often more severe than that seen in Alzheimer disease (231). This explains why patients with Lewy body can have a more dramatic early benefit with cholinesterase inhibitors than is noted in most Alzheimer patients. Volumetric MRI studies showed the volume of the nucleus basalis of Meynert to be reduced by 20% to 25% in dementia with Lewy body patients, which was comparable to the volume loss seen in the Alzheimer cohort in one study (61). As in Parkinson disease, another condition of misfolded alpha-synuclein proteins, Lewy bodies accumulate in the neurons of the substantia nigra, but in dementia with Lewy bodies, they also accumulate in the cortex. Reduced levels of alpha-synuclein in the CSF of patients with Lewy body probably reflect the accumulation of alpha-synuclein in the brain (95). Dementia with Lewy bodies and its core features aggregate in families (143). Pure Lewy body pathology exists in only 20% to 30% of those who have symptoms of dementia with Lewy bodies, with most brains showing comorbid Alzheimer findings such as plaques and tangles (129; 73).

Frontotemporal dementia. This is a heterogeneous group of disorders that comprise about 10% to 20% of all dementias worldwide. Mutations in three of the tau genes (MAPT, GRN, and C9orf72) have been significantly associated with the frontotemporal dementias (46). Most cases begin between 55 and 65 years of age. The most common syndromes are the behavioral variant and the language variants (progressive nonfluent aphasia and semantic dementia). The GGGGCC repeat expansion in the C9orf72 gene is the most common cause of familial frontotemporal dementia (29). When the C9orf72 gene is associated with behavioral variant frontotemporal dementia, the disease can present with hallucinations and delusions. This gene is also associated with the parkinsonism/ALS phenotype of frontotemporal dementia. Larger volumes of white matter hyperintensities are associated with behavioral variant frontotemporal dementia than with Alzheimer disease or controls (79). These white matter hyperintensities are associated with disease severity but not with vascular risk.

Ophelia syndrome. This is an unusual neuropsychiatric disorder that is characterized by loss of memory, depression, hallucinations, and bizarre behavior, otherwise known as limbic encephalopathy (106). It is caused by circulating antibodies to neuronal surface antigens (mGluR5), and it is reversible in patients for whom the cause is Hodgkin lymphoma.

Chronic traumatic encephalopathy. Clinically, this condition is manifested by behavioral and personality changes, parkinsonism, and speech and gait disorder (203). Pathologically, it is characterized by diffuse atrophy of the cerebral cortices, the mammillary bodies, and a fenestrated cavum septum pellucidum. It is distinguished from other tauopathies in that there is a propensity for tau deposits in the depths of the sulci and in astrocytes, as well as neurons (126). Studies have shown that serum biomarkers of axonal injury (total tau) and astroglial injury (S-100 calcium binding protein B) were elevated in concussed professional hockey players compared to preseason values (193). Plasma from both acute and chronic traumatic brain injury patients has shown elevated concentrations of p-tau and p-tau/t-tau, compared to controls (178).There were no significant changes measured in neuron-specific enolase levels, arguing for a larger acute effect on axons and glia rather than neurons. Football players with and without concussion have been shown to have smaller hippocampal volumes, compared to age-matched controls (196). Those with concussion had smaller hippocampal volumes than those without concussion. Fractional anisotropy showed evidence of decreased white matter integrity across all tracts in professional athletes with multiple concussions who had elevated CSF total tau levels compared to concussed athletes in the normal total tau group (207). Those in the high total tau group scored lower on the Trail Making Test, part B, a test of executive function.

Epidemiology

Mild cognitive impairment. It is estimated that five to 11.6 million Americans are affected by mild cognitive impairment, larger numbers than the four to five million who have Alzheimer disease (158). The Rush Alzheimer Center followed a large group of normal older persons and found an accelerated cognitive decline three to four years prior to the diagnosis of mild cognitive impairment (233). Cognitive decline accelerated again five to six years prior to the diagnosis of Alzheimer disease. The prevalence of mild cognitive impairment is age-dependent: 6.7% for ages 60 to 64 years, 10.1% for ages 70 to 74 years, and 25.2% for ages 80 to 84 years (158).

Dementia. In a large epidemiologic study of insured patients in northern California, dementia diagnoses were taken from inpatient and outpatient medical encounters from 2000 to 2013 (124). It showed that Asian Americans had a lower risk of dementia (15.2 out of 1000 person-years), compared to Latinos (19.6 out of 1000 person-years), whites (19.3 out of 1000 person-years), or African Americans (26.6 out of 1000 person-years). The cumulative risk for dementia at age 65 was 38% for African Americans, 32% for Latinos, 30% for whites, and 28% for Asian Americans. Although vascular disease was one possible explanation for the elevated dementia risk in African Americans, the racial/ethnic inequalities persisted after adjustment for vascular comorbidities. It is possible that differences in education could contribute to the different dementia risks among the various racial/ethnic groups (not measured in this study). Illiteracy was shown to be independently associated with a higher risk of both prevalent and incident dementia (172). Lower education is also associated with more adverse financial events (missing payments on credit accounts) as early as 6 years before developing Alzheimer disease or related dementias (146). In a large longitudinal Japanese study, the prevalence of Alzheimer disease and all-cause dementia increased from 1985 (6.8%) to 2012 (11.3%) due to increased incidence and survival (150). In a large longitudinal population-based study in Finland, major traumatic brain injury was shown to be associated with an increased risk of dementia after a median follow-up of 15.8 years (168). The effect was diluted somewhat after adjusting for age, educational status, smoking status, alcohol consumption, and leisure time physical activity. In a large multiethnic population-based study in New York City, overdiagnosis of dementia was observed among 4.4% of those who had submitted Medicare claims (244). These misdiagnoses were more common in minority participants than among those who were White.

Alzheimer disease. Alzheimer disease is the most common type of dementia (it is listed as the sixth leading cause of death in the United States). According to the 2015 statistics from the Alzheimer’s Association, one in nine Americans aged 65 and older has been diagnosed with Alzheimer disease or another dementing disorder (182). It is estimated that 14.7% of people older than 70 in the United States has dementia. Although the major risk factor for Alzheimer disease is age, there are other risks, such as the apolipoprotein-4 allele, lower level of education, physical inactivity, smaller social networks, hippocampal atrophy, CSF tau, and abnormal amyloid PET (12; 81; 145). Typical Alzheimer disease accounts for 55% of cases (more female), whereas early-onset (hippocampal-sparing Alzheimer disease) accounts for 17% (more male), and limbic predominant Alzheimer disease accounts for 21% (more female) (47). Mortality risks in patients with Alzheimer disease are higher in males and those with lower MMSE, higher numbers of medications, and older age (50).

Vascular cognitive impairment. In a 20-year prospective population-based study, it was shown that a higher degree of atherosclerosis in midlife was associated in later years with an increased risk of vascular dementia (HR=1.32) and small vessel disease (HR=1.47), but not with Alzheimer disease (HR=0.95) (64). In an 8-year follow-up study of patients who had experienced transient global amnesia (vs. non-TGA controls), the risk for developing dementia was increased in the transient global amnesia group (HR=2.23) after adjusting for age, gender, and comorbidities (78). Age and diabetes were factors that significantly increased the risk.

Dementia with Lewy bodies. Mortality risk is higher in dementia with Lewy bodies than in Alzheimer disease (HR=1.64) (50).

Frontotemporal dementia. Mortality risk is higher in frontotemporal dementia than in Alzheimer disease (HR=1.91) (50). Survival in patients with frontotemporal dementia depends on the clinical subtype. For example, the shortest survival (two to five years) is seen in those who have the motor neuron disease subtype (229). Those with the most common subtype (the behavioral variant) live longer (five to eight years), and the language subtypes (semantic dementia, primary progressive aphasia) live the longest (10 to 12 years). Although most types of frontotemporal dementia begin before the age of 65, there are still about 25% that begin in later years (192). In particular, the behavioral variant of frontotemporal dementia has a mean age of onset of 64, whereas the semantic variant begins at 67, and the logopenic variant of primary progressive aphasia begins around 73 (30).

Chronic traumatic encephalopathy. The longer an American football player works at the game, the greater the risk of their developing the pathology of chronic traumatic encephalopathy (odds ratio = 1.3 per year) (132). Those patients with the pathological diagnosis were 10 times as likely to have played more than 14.5 years, compared to participants in the study who did not show the pathology of chronic traumatic encephalopathy.

Differential diagnosis

Confusing conditions

Transient memory loss. In metabolic and hypoxic encephalopathies (eg, acute confusional states, delirium), memory loss is a common complaint. Other deficits can be seen in patients with delirium, such as change in level of consciousness. Transient global amnesia can produce transient confusion and both anterograde and retrograde amnesia that may last up to 24 hours (78). Those receiving electroconvulsive therapy may notice a brief period of memory loss, but they almost always recover (26). After closed-head injury, it is not uncommon for the patient to experience both retrograde and anterograde amnesia for at least 1 to 2 days (119).

Depression. Memory loss is a common complaint in those with depression. About 8% of elderly individuals in the community have depression, and even higher percentages are reported in those with Alzheimer disease, vascular dementia, and dementia with Lewy bodies. Symptoms of depression and dementia overlap considerably: irritability, nighttime behavior changes, anxiety, appetite changes, agitation, and apathy. Three longitudinal studies found that symptoms of depression were seen earlier in patients who developed signs of mild cognitive impairment or dementia than in those who remained in the control group, suggesting that depression accompanies early signs of cognitive impairment (122; 185). One large study comparing patients with amyloid-PET-positive (85%) and amyloid-negative (15%) Alzheimer disease showed that amyloid-negative patients were more likely to be taking medications for depression and to have higher depression scores (107). These amyloid-negative patients were older; their disease progressed more slowly, and they were more likely to be APOE-e4 negative. One study showed that late-onset depression was a predictor for an earlier onset of Alzheimer disease, dementia with Lewy bodies, and mixed Alzheimer disease and Lewy body dementia (185).

Malingering. On rare occasions, memory loss may be due to malingering. The clinical history may help to suggest this possibility, but a neuropsychological assessment is usually needed to verify this diagnosis. Unfortunately, memory loss can be falsely portrayed in such a way that it is often difficult to detect (66; 186).

Age-related cognitive decline. For years, it was thought that age was one of the causes of declining memory in the elderly. However, work by the Rush Alzheimer Disease Center showed that “age-related cognitive decline” was due to early stages of one of the three common dementing illnesses: Alzheimer disease, vascular dementia, or dementia with Lewy bodies (236). Data from another large longitudinal study have demonstrated that memory function declines steadily in normal adults after the age of 30 and that hippocampal atrophy also progresses after that age (81). Nevertheless, subsequent data have shown that late-life cognitive loss mainly reflects the changes associated with common pathological processes rather than normative age-related processes (237).

A greater steepness of age-related cognitive decline appears to be related to lower baseline IQ in males, and education does not seem to be associated with rate of cognitive decline in either males or females (02). These findings are contrary to the previous “cognitive reserve” observations of Groot and colleagues, where those who eventually develop dementia are more likely to have lower education, lower cognitive scores, and greater cerebral atrophy compared to those in the predementia stage (60).

Associated or underlying disorders

Mild cognitive impairment. This clinical syndrome is a transitional state between normal aging and dementia (157; 158; 49) in which objective signs of memory difficulties are seen in the absence of any change in functional abilities. Studies have emphasized the importance of adequately treating hypertension, diabetes, obesity, and hyperlipidemia in midlife as a way of preventing cognitive impairment in later years (174; 155; 125). Several studies have pointed out how important it is to take a careful medication history in patients with memory complaints because many elderly patients have been taking anticholinergic drugs such as tricyclic antidepressants, antihistamines, and bladder antimuscarinics (56; 158; 49). These drugs are associated not only with memory complaints but also with dementia. Other factors that may contribute to mild cognitive impairment include hearing loss; vision loss; medical illnesses, such as chronic kidney disease; heart failure, and sleep disorders, such as obstructive sleep apnea (49). In the mild cognitive impairment phase of cerebral amyloid angiopathy, the cognitive profile resembles vascular cognitive impairment as there are problems with executive dysfunction and processing speed, rather than memory loss (20).

Alzheimer disease. The four most common causes of persistent memory loss include mild cognitive impairment, Alzheimer disease, dementia with Lewy bodies, and vascular cognitive impairment. Although those with Alzheimer disease have severe recent memory problems, those with vascular dementia are more impaired on semantic (long-term) memory tasks and executive (frontal lobe) function. When patients with Alzheimer disease and Lewy body dementia are compared using neuropsychology tests, patients with Alzheimer disease have more problems with verbal memory, whereas patients with Lewy body dementia have more difficulty with visual memory. In a comparison of patients with Alzheimer disease and Lewy body dementia who had comparable amounts of basal forebrain atrophy on MRI, the patients with Alzheimer disease had more severe global impairment as determined by MMSE scores, whereas patients with Lewy body dementia had more visuospatial and executive impairment on the trail making test (61). Patients with early-onset Alzheimer disease are more likely to have a nonamnestic syndrome, whereas patients with typical late-onset Alzheimer disease and limbic-predominant Alzheimer disease are both characterized by an amnestic syndrome (47).

Vascular cognitive impairment. Those with pure subcortical vascular dementia (Binswanger disease) perform better on delayed recall tasks than those with presumed Alzheimer disease (109). This explains why many patients with vascular dementia complain more about their gait apraxia than their memory loss. Low ejection fraction in those with heart failure correlates significantly with reduced verbal memory function (48). Those with greater white matter lesion load and larger ventricles on MRI showed slower processing speeds and poorer episodic memory (40). One study of free and cued recall demonstrated that patients with vascular dementia had better cued recall compared to Alzheimer patients, suggesting that their problem was one of memory retrieval, rather than of encoding (22). Patients with dementia associated with transient ischemic attack or recent stroke usually have cognitive and functional impairment associated with the presence of small vessel disease and white matter changes in the frontal lobes (242).

Dementia with Lewy bodies. These patients have memory loss in addition to parkinsonism, visual hallucinations, REM sleep behavior disorder, or fluctuations in their levels of alertness over the course of a day (127). Patients with Lewy body dementia performed worse than patients with Parkinson disease and multiple system atrophy on tests of verbal and visual memory, as well as tests of executive function (92). About 50% of those who have dementia with Lewy bodies have REM sleep behavior disorder that often precedes the memory loss by years or even decades (25; 127). Cagnin and associates did a comparison of patients with early dementia and showed that those with dementia with Lewy bodies were more likely to perform poorly on the intersecting pentagon test, compared to those with early Alzheimer disease (19). They also had more impaired executive functions. Those with Lewy body disease have greater medial temporal atrophy than control subjects, but less than those with Alzheimer disease (127).

Frontotemporal dementia. These patients present with either behavioral changes (behavioral variant), language changes (progressive nonfluent aphasia, semantic dementia), or behavioral changes in combination with motor neuron disease or parkinsonism (229). Memory loss may appear to be superficially similar to Alzheimer disease and vascular dementia, but when free and cued recall was tested with the Grober and Buschke test, patients with frontotemporal dementia had better cued recall than patients with Alzheimer disease (22). This suggested that they had a memory retrieval problem, rather than a memory encoding problem. MRI can be used as an adjunct to the clinical examination in identifying the various subtypes of frontotemporal dementia (209).

Chronic traumatic encephalopathy and traumatic encephalopathy syndrome. These patients usually have a triad of cognitive, behavioral, and mood impairments in addition to headaches and motor disturbances (203; 96). They must have a progressive course. Those who die at an older age (mean: 54.5 years) are more likely to suffer from dementia (54%) and have the APOE-e4 genotype (18%). Those who die at a younger age (mean: 34.5 years) are less likely to have dementia (18%) and rarely have the APOE-e4 genotype (4.5%).

Diagnostic workup

Transient memory loss. Young people with new memory loss are likely to have had recent exposure to a drug or to head injury, so they need a toxicology screen and a head CT or MRI scan. If the acutely confused person has bitten his tongue, lost bladder control, or has unexplained bruises, then an EEG is needed to look for a seizure focus. Anyone with a history of stomach surgery should be suspected of having B12 or B1 deficiency (this is particularly true of those who have had gastric bypass surgery). Those who have had gastric bypass surgery could have Wernicke-Korsakoff syndrome if they have memory loss in addition to nystagmus and gait ataxia (191). An MRI is needed to document the T2 signal changes in the periaqueductal grey matter (204). Thyroid function tests and B12 levels are both needed in elderly subjects with new memory complaints (226). Prescription drugs must be suspected as the cause of transient memory loss in older patients, especially if the newest drug has anticholinergic properties (56; 230). Those young or middle-aged people who have symptoms of limbic encephalopathy need an MRI to document the T2 signal changes in the mesial temporal cortex (106). A cluster of 14 young patients with acute amnestic syndrome associated with substance abuse was reported in Massachusetts in 2012 to 2016 (09). As many as 62% were associated with opiate abuse. MRI scans in these cases showed complete ischemia of both hippocampi. This study would support the practice of obtaining both an MRI and a toxicology screen whenever a patient has an unexplained episode of transient memory loss.

Alzheimer disease. Every new patient with mild cognitive impairment or dementia needs a CT or MRI of the head because in 5% of the patients, subdurals, brain tumors, or silent infarcts may be the cause of memory complaints (222). Those with early-onset Alzheimer disease are more likely to have parietal-dominant atrophy, and those with late-onset Alzheimer disease are more likely to have mesial temporal atrophy or diffuse atrophy (148; 47). MRI is also needed to determine which patients are more likely to develop vascular dementia (severe white matter changes and stroke), according to Verdelho and colleagues and others (221; 242). Some have argued that extensive subcortical white matter changes on MRI are a predictor for more rapid cognitive decline and slower processing speeds (220; 40). The sensitivity of hippocampal atrophy on MRI for predicting Alzheimer disease within five years in those with amnestic mild cognitive impairment is 63%, whereas the specificity is 72% (227). Amyloid PET can be used to distinguish those with Alzheimer disease from various non-Alzheimer conditions (81; 107; 167; 210). According to age of onset of the disease, there are three different patterns of amyloid accumulation: frontal and occipital with onset in the 70s, and parietal accumulation with onset in the 60s (27). It is particularly important to use amyloid-PET in studies of new drugs for distinguishing early Alzheimer disease from non-Alzheimer disease conditions (94; 162). Tau pathology, as seen on tau-PET, appears a few years later when patients on the Alzheimer disease continuum begin to show symptoms of memory loss. It shows a close relationship to cortical atrophy and is a good predictor of future cognitive decline (11; 28). Amyloid-PET scans are usually positive several years prior to tau signal being detected on PET; both amyloid-PET and tau-PET scans are positive before much neurodegeneration is evident on MRI or on FDG-PET (80). When four blood biomarkers were compared (p-tau 181, GFAP, NfL, and t-tau), plasma p-tau 181 and GFAP had the highest diagnostic accuracy to distinguish Alzheimer disease from non-Alzheimer causes of dementia (183).

Dementia with Lewy bodies. In contrast with Alzheimer disease, there is relative sparing of medial temporal structures on CT and MRI in dementia with Lewy bodies (127). Reduced dopamine transporter uptake in the basal ganglia on SPECT or PET is another sign that can distinguish dementia with Lewy bodies from Alzheimer disease (127). Another test that supports the diagnosis is polysomnography, if it confirms the diagnosis of REM sleep behavior disorder. EEG can be supportive of the diagnosis of dementia with Lewy bodies when it shows prominent posterior slow-wave activity with periodic fluctuations (127). Amyloid PET scans have also been used to distinguish patients who have dementia with Lewy bodies from those who have Alzheimer disease or those with mixed pathology (dementia with Lewy bodies and Alzheimer disease) (90). Posterior hypoperfusion can be seen on FP-CIT SPECT or FDG-PET (the “cingulate island sign”) in patients who are in the prodromal stages of dementia with Lewy bodies (153).

Depression. Depression is a common, treatable comorbidity in those with mild cognitive impairment and dementia (118). Twelve different behavioral changes in patients with Alzheimer disease, vascular dementia, or dementia with Lewy bodies (depression, irritability, apathy, anxiety, agitation, hallucinations, etc.) can be described and quantified by using the Neuropsychiatric Inventory (33). The advantage of this scale is that it assesses not only the patient’s symptoms, but it also grades the severity of symptoms. Depression is a common complaint in those of all ages who meet the criteria for subjective cognitive decline (21). According to the Mayo Clinic Study of Aging, investigators found that neuropsychiatric symptoms, such as depression and anxiety, were associated with the presence of CSF biomarkers of Alzheimer disease in persons over 50 years of age who were still free of dementia (103). This fits with earlier observations of Sheikh and colleagues where mild behavioral impairment was recorded as being present in 76% of patients with subjective cognitive decline and 85% of those with mild cognitive impairment (195).

Management

Mild cognitive impairment: medications. Cholinesterase inhibitors do not delay the onset of Alzheimer disease overall in patients with mild cognitive impairment, but treatment with donepezil is indicated in those who are clinically depressed (118). Donepezil may help symptomatically delay conversion of those with the apolipoproteinE epsilon4 genotype (about 40% of patients); this was demonstrated in a subanalysis, but not prospectively. In a group of 216 prodromal Alzheimer disease patients, donepezil (vs. placebo) appeared to slow the annual rate of hippocampal atrophy, even though there were no neuropsychological differences between the two treatment groups (42). Control of diabetes is critical, because faster decline in cognitive function was present among African Americans and European Americans following the diagnosis of diabetes in old age (169). Treating hypertension in midlife and later years is also helpful in preventing dementia in later years (125; 232; 202; 111).

Mild cognitive impairment: nonpharmacological interventions. Several studies have emphasized the importance of treating blood pressure, diabetes, obesity, physical inactivity, and hyperlipidemia in addition to stopping cigarette smoking in midlife to prevent cognitive impairment or dementia in later life (62; 110; 145). Active participation in cognitive tasks and physical activities are both effective in reducing the risk of developing dementia in those who have mild cognitive impairment (49; 113; 110). A Mediterranean diet has been shown to prevent both mild cognitive impairment and Alzheimer disease in a multiethnic community study and in a large clinical trial of patients at risk for cognitive decline because of cardiovascular disease (198). The MIND diet (a hybrid of the Mediterranean diet and the DASH diet) emphasizes plant-based foods instead of animal products and is associated with a reduced incidence of cognitive decline (137). In a study of adults with cognitive impairment but no dementia, the largest improvements in executive function were seen in those randomized to both aerobic exercise and the DASH diet (15). There were no significant changes in memory or language function. Dietary omega-3 fatty acids from marine sources have been associated with a reduced risk of progression to dementia in community-dwelling elders (115). A Mediterranean diet supplemented with olive oil or nuts has been associated with improved cognitive function (217). A diet with low inflammatory potential is less likely to be associated with an increased risk of dementia (23). A published multicenter longitudinal study compared U.S. participants who were eligible for the supplemental nutrition assistance program (SNAP) (117); the authors found that SNAP users had worse memory scores at baseline, but slower rates of cognitive decline over 10 to 20 years, compared to nonusers. The authors concluded that SNAP use was associated with slower memory decline in this population of individuals who had lower education and lower socioeconomic status at baseline. More frequent cognitive activity across the lifespan has been associated with a slower late-life cognitive decline that is independent of several common neuropathological conditions, which is consistent with the cognitive reserve hypothesis (235). A large randomized, controlled clinical trial showed that a multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring was effective at improving or maintaining cognitive function in a group of at-risk elderly individuals (144). Weight loss in obese/overweight individuals (resulting in an average BMI decrease of 7 kg/m2) has been shown in a meta-analysis of 13 longitudinal studies and seven randomized controlled trials (n=551 participants) to be associated with a significant improvement in attention and memory (224). Future randomized trials will need to examine whether this effect is explained by improvement in sleep patterns.

Alzheimer disease: medications. Several cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) have been shown to improve cognition and behavior at all stages of Alzheimer disease (173; 190). A systematic review found that cholinesterase inhibitors reduced all-cause mortality in patients with dementia (214). Memantine improves cognitive functions in patients with moderate to severe stages of the illness and can also improve some behaviors (173; 190). One study demonstrated that continued treatment with donepezil in patients with moderate to severe Alzheimer disease was associated with both cognitive and functional benefits over a 12-month period (77). Citalopram and trazodone are both useful for managing agitated behaviors in patients with Alzheimer disease (173). Observational studies and clinical trials have shown that better control of systolic blood pressure reduces the incidence of Alzheimer disease and other dementias, especially when blood pressure lowering is started in middle age (232). In a nationwide case-control study in Finland, use of hormone replacement therapy in postmenopausal women was associated with a 9% to 17% increased risk of Alzheimer disease (9% with estradiol only; 17% with estradiol-progesterone) (184). Vaginal estradiol preparations were not associated with an increased risk of Alzheimer disease. There are currently 132 agents in clinical trials for the treatment of Alzheimer disease (32). These include agents to mitigate the damaging effects of beta amyloid, in addition to drugs aimed at treating neuropsychiatric symptoms of the disease. Some of these trials failed because of no clinical benefit, but others (a beta-secretase inhibitor) failed because the experimental drug caused a worse outcome than placebo (101). Aducanumab was marketed in the United States in 2021 for the treatment of mild cognitive impairment and mild Alzheimer disease on the strength of its ability to remove elevated levels of brain amyloid (74; 164). In two phase 3, randomized controlled clinical trials using high-dose aducanumab, 41.3% of participants developed amyloid-related imaging abnormalities (26% had symptoms, such as headache, dizziness, etc.) (180). In February 2024, the manufacturer withdrew aducanumab from the market due to safety concerns. In 2023, lecanemab was approved by the FDA for the treatment of mild cognitive impairment and mild Alzheimer disease, based on data from a large phase 3 clinical trial (218). In this trial, 1795 patients were assigned 1:1 to the intravenous drug (10 mg/kg q2 wks) or to intravenous placebo (same intravenous infusion schedule). The primary outcome measure for lecanemab was change from baseline at 18 months in the CDR-SB score (the drug caused 27% less disease progression compared to placebo at 18 months). Donanemab is another anti-amyloid therapy that has been shown in a phase 3 trial to significantly reduce cognitive decline in a global measure of cognitive functions (CDR sum of boxes) (133). Both lecanemab and donanemab are more effective than previous intravenous anti-Alzheimer therapies in their ability to remove amyloid over 52 to 76 weeks of therapy (102). Medicare (CMS) is still in negotiations concerning whether it has agreed to provide coverage for this drug, but patients can receive it by private payment, if they are enrolled in a clinical trial, or if they are part of alecanemab, provided the patient is involved in an approved prospective registry (194). More information can be accessed at:https://www.CMS.gov.

Alzheimer disease: nonpharmacological interventions. Caregiver support group meetings are particularly helpful in providing education to caregivers about the diseases that cause dementia and in addressing ways to manage behavioral changes (24; 190). Physical activity (especially aerobic exercise) attenuates the neuropathological changes in Alzheimer disease, and it positivity affects cognitive function and sleep, especially when it is started in the early stages of the disease (160; 156; 140; 145; 239). In animal models of Alzheimer disease, physical activity improves spatial learning, reduces markers of oxidative stress, increases levels of BDNF protein, promotes the glymphatic clearance of beta amyloid, and reduces activation of astrocytes and microglia (70; 98). When patients with Alzheimer disease were assigned to home-based exercise twice weekly (vs. usual care) for a year, the exercise group showed improvement in executive function, but verbal fluency and global function did not improve (151). Lifetime cognitive engagement has been associated with lower deposition of beta-amyloid in the brain, according to results of amyloid PET images (108). This suggests that cognitive engagement might influence the onset and progression of Alzheimer disease. One study has shown that lifetime intellectual enrichment (high education, high midlife cognitive activity) is associated with lower amyloid accumulation in the brains of patients with Alzheimer disease who are APOE-e4 carriers (223). In the Rush Memory and Aging Project, early-life and middle-age cognitive activity influenced late-life cognitive decline, regardless of neuropathologic diagnosis, which was consistent with the cognitive reserve hypothesis (238). A 44-year longitudinal population study in women found that cognitive activity in midlife was associated with reduced risk of total dementia (HR 0.68; 95% CI 0.49-0.89) and Alzheimer disease (HR 0.54; 95% CI 0.36-0.82) (140). In the Rush Memory and Aging Project, greater total flavonol intake in mid-life predicted lower risks of incident Alzheimer dementia in later life (75). Examples of foods that contain flavonols are kale, grapes, peaches, berries, tomatoes, broccoli, and tea. Low educational attainment, midlife obesity, and physical inactivity are three of the most prevalent modifiable population-attributable risks for Alzheimer disease in the U.S. (145). Recent studies have shown that incidence of dementia, memory loss measures, and amyloid PET scans are more likely to be positive if older adults live in areas with a greater degree of small particle (PM 2.5) air pollution (01; 116).

Vascular cognitive impairment. Patients who have mild to moderate vascular dementia seem to benefit from cholinesterase inhibitors to a similar extent as those with Alzheimer disease. This is likely due to the fact that the brains of most patients with vascular dementia show mixtures of both vascular pathology and Alzheimer changes (38). Lowering blood pressure is recommended for hypertensive patients who have vascular cognitive impairment because the SPRINT MIND study showed that intensive blood pressure lowering in hypertensive individuals could significantly reduce the combined risk of mild cognitive impairment and dementia (202). In a 6-month randomized controlled trial, aerobic exercise for 3 days per week (vs. usual care and education) provided improvement on the ADAS-cog for 70 adults with vascular cognitive impairment (114). Aerobic and resistance exercise has been shown in longitudinal studies to reduce arterial stiffness and to improve endothelial function over time (98). Physical activity in midlife in women is associated with reduced risk of mixed dementia (HR 0.43; 95% CI 0.22-0.86) and vascular dementia (HR 0.47; 95% CI 0.28-0.78) (140; 190).

Dementia with Lewy bodies. Treatment with rivastigmine, galantamine, and donepezil have been demonstrated to improve cognition and behavioral symptoms (particularly visual hallucinations) in both dementia with Lewy bodies and Parkinson dementia (127; Hershey & Coleman-Jackson 2019; 190). Cholinesterase inhibitors do not cause worsening of the parkinsonism symptoms of these patients. These drugs can be effective at reducing the syncopal episodes and falls that are sometimes seen in this disease. Memantine also improves global function in patients with Lewy body dementia (127; 73).

Frontotemporal dementia. In contrast to its beneficial effects in Alzheimer disease and dementia with Lewy bodies, memantine has not been shown to help patients who have the behavioral or semantic variants of frontotemporal dementia (16). In fact, more patients in the memantine group in this clinical trial developed cognitive adverse events, compared to those assigned to the placebo group. This effect of behavioral worsening with cognitive therapy had been reported earlier when donepezil was used in patients with frontotemporal dementia (130). Trazodone is particularly helpful for managing insomnia and agitated behaviors in patients who have frontotemporal dementia (173). Citalopram, on the other hand, is helpful when these patients exhibit apathy and lack of motivation. Several nonpharmacological methods have been shown to be helpful for managing behavioral symptoms in patients with frontotemporal dementia, including reducing the noise level, lessening clutter, and reducing the number of people involved in public outings (10). Walking the patient on a regular schedule seems to help improve sleep quality, but the benefit of exercise in general has not been uniformly demonstrated in all the clinical trials.

Multiple sclerosis. Randomized trials do not support the use of donepezil in treating memory loss in patients with multiple sclerosis (104).

Outcomes

Alzheimer disease. When patients with Alzheimer disease from three large clinical trials were compared, use of donepezil at 5 mg/day or more was associated with a significant delay in nursing home placement by at least 21 months (51). The models used in this study were adjusted for age, sex, baseline Mini-Mental State Examination score, and whether the caregiver was a spouse or not.

Dementia. Using the Swedish Death Registry (2007-2015), survival prediction tables were developed for those with newly diagnosed dementia. By 2016, 41.6% of the dementia cohort had died, and the most potent predictors of mortality included older age, male sex, greater comorbidity, lower baseline cognitive function, having a diagnosis of non-Alzheimer dementia, living alone, and using more medications (65). In a systematic review, Truong and colleagues found a consistent association between use of cholinesterase inhibitors and a reduction in all-cause mortality (214).