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  • Updated 02.16.2024
  • Released 11.24.1997
  • Expires For CME 02.16.2027

Memory loss



In this article, the authors provide an overview of memory loss and its most common presentations in the clinical setting (mild cognitive impairment, Alzheimer disease, vascular cognitive impairment, vascular dementia, dementia with Lewy bodies, Wernicke-Korsakoff syndrome, and chronic traumatic encephalopathy). Risk factors for mild cognitive impairment are reviewed, along with lifestyle changes that have been suggested to slow progression from mild cognitive impairment to dementia.

Key points

• Late-life changes in memory and other cognitive functions have been shown to reflect changes associated with pathological processes, such as those of common neurodegenerative diseases and cerebrovascular processes, rather than those of normal age-related changes. The pathological processes that cause late-life changes in memory include Alzheimer disease, Lewy body disease, hippocampal sclerosis, and atherosclerosis.

• Chronic traumatic encephalopathy and traumatic encephalopathy syndrome cause early memory loss in boxers, football players, and war veterans. The neurofibrillary tangles in the brains of patients with chronic traumatic encephalopathy at autopsy are similar to those seen in the brains of Alzheimer disease patients. In addition to elevated CSF levels of total tau, there is also loss of white matter integrity across all tracts in professional athletes who have had multiple concussions.

• Pathological and imaging studies have shown that male sex, presence of the APOE-e4 allele, and enlarged perivascular spaces are all predictors of an earlier onset of Alzheimer disease, but not Lewy body disease. Late-life depression and mild behavioral impairment predict an earlier onset of Alzheimer disease, Lewy body disease, and mixed Alzheimer disease and Lewy body disease.

• Longitudinal studies in older adults have demonstrated that higher levels of total daily physical activity and cognitive activity are associated with reduced risk of cognitive decline and Alzheimer disease. Control of hypertension and diet quality, as well as avoiding head injury and exposure to air pollution, are other important strategies to reduce the risk of mild cognitive impairment and dementia. Animal studies have shown that both exercise and sleep accelerate glymphatic clearance of beta amyloid from the brain and reduce the accumulation of amyloid plaques.

• Several longitudinal cohort studies have followed biomarker profiles of brain amyloid, brain tau, and neurodegeneration in cognitively normal older adults over a mean of seven years and have found that abnormal markers of both amyloid and tau are necessary for the development of the accelerated neurodegeneration and memory loss that precede Alzheimer disease. Subtle cognitive changes can be measured before or concurrently with early Alzheimer biomarker changes before signs of mild cognitive impairment appear.

Historical note and terminology

Wernicke-Korsakoff syndrome. In 1881, Carl Wernicke described two male alcoholics and one female with persistent vomiting who presented with acute confusion and ataxia (all three died by the end of two weeks). In 1887, Sergei Korsakoff reported 20 patients with either alcoholism or vomiting who developed chronic memory loss and polyneuropathy. We now use the term “Wernicke-Korsakoff syndrome” to describe this biphasic illness, where the acute phase is called Wernicke encephalopathy, and the chronic disorder is known as Korsakoff syndrome (191). MRI signs of Wernicke-Korsakoff syndrome include the chronic signs of shrunken mammillary bodies and acute signs of hyperintense T2 signal in thalami and periaqueductal grey (204).

Vascular cognitive impairment. In 1894, Otto Binswanger wrote about eight patients who were middle-aged when they developed acute confusion, then chronic memory loss, focal neurologic signs, gait disorder, and functional impairment. Their memory disorder fluctuated over time, but at autopsy all of them showed evidence of diffuse subcortical demyelination with sparing of cortical neurons. Hypertension and diabetes are the most important risk factors for vascular dementia, especially the subtype known as Binswanger disease (72; 138). “Vascular cognitive impairment” is now the preferred term as it includes the full range of severity of cognitive deficits, from mild cognitive impairment to dementia (38).

Alzheimer disease. In 1906, Alois Alzheimer described two women who experienced the insidious onset of memory problems in their 50s. Their memory disorders steadily progressed, and when they died several years later, Dr. Alzheimer found microscopic changes (tangles and plaques) in and around cortical neurons. Genetic analysis from one of these first patients identified a point mutation in the presenilin 1 gene, leading to a Phe176Leu amino acid substitution (139). This could explain the early memory loss in this first case.

In 2007, research criteria were developed to capture patients with Alzheimer disease at their very earliest stage when there is a problem with episodic memory, but before full-blown dementia appears. These criteria stipulated that in addition to memory loss, there must be an abnormality in at least one or more biomarker, including thinning of the entorhinal cortex (MRI), amyloid or tau accumulation (PET), or an abnormality in CSF protein (beta-amyloid or tau) (43). In 2019, another research framework was developed for the biological definition of Alzheimer disease in which an asymptomatic or mildly symptomatic older adult could be identified as falling along the Alzheimer continuum if they had positive signs of amyloid accumulation (PET or CSF), pathological tau (PET or CSF p-tau), or neurodegeneration (MRI, FDG-PET, or CSF total tau) (05; 80; 210). This framework is important for designing clinical trials that use new disease-modifying therapies and for choosing patients who might be eligible for anti-amyloid treatment (162).

Limbic predominant age-related TDP-43 encephalopathy (LATE). This condition and Alzheimer disease are the two most common neurodegenerative diseases in those over the age of 80 (142; 18). TDP stands for transactive response DNA-binding protein. LATE and Alzheimer disease often coexist. Those with pure LATE are usually older than Alzheimer patients at the time of symptom onset.

Frontotemporal dementia. In the late 19th century, Arnold Pick described the first cases of frontotemporal dementia (229). Now, frontotemporal dementia refers to a diverse group of disorders that involve atrophy of specific areas of the frontal or temporal lobes, or both (brain MRI and neuropsychological testing are both needed for an accurate diagnosis). The presenting features are behavioral changes (behavioral variant), language problems (progressive nonfluent aphasia, semantic dementia), or behavioral changes associated with motor neuron disease rather than memory loss.

Dementia with Lewy bodies. Lennox and others described diffuse Lewy body disease as being different from Alzheimer disease in that it has a more fluctuating clinical course, extrapyramidal signs, well-formed visual hallucinations, and increased sensitivity to neuroleptic drugs (112). Several autopsy studies have shown that dementia with Lewy bodies accounts for at least 20% of the total number of dementia brains, although many of these brains showed features of both Lewy body disease and Alzheimer pathology (89; 76). Besides having dementia, patients with dementia with Lewy body must have at least two of these four clinical features for a probable diagnosis: (a) visual hallucinations, (b) fluctuating levels of alertness, (c) signs of parkinsonism, or (d) REM sleep disorder (127).

Mild cognitive impairment. The initial definition of mild cognitive impairment was that it was a transition state between normal aging and dementia (157). Symptoms can vary depending on whether they are preclinical manifestations of Alzheimer disease (memory complaints), vascular dementia (executive dysfunction), dementia with Lewy bodies (fluctuations in cognition), or other dementias (135; 157). Duff and others showed that nearly 40% of those genetically at risk for Huntington disease meet criteria for mild cognitive impairment (44), just as about 40% of patients with Parkinson have mild cognitive impairment (100). In 2019, the AAN Quality Improvement Committee defined someone with mild cognitive impairment as having acquired objective cognitive deficits that were insufficiently severe to affect most usual daily activities (49). The informant report of memory decline is particularly important for patients in the mild cognitive impairment stage of the Alzheimer disease continuum, where it is strongly associated with signs of elevated brain amyloid on PET (105).

Mild behavioral impairment. Patients with this condition develop persistent neuropsychiatric symptoms later in life that cannot be explained by medications or dementia. In one study from a memory clinic, 85% of these patients had mild cognitive impairment (195). The most common behavioral changes observed included affective dysregulation, impulse control, decreased motivation, and social inappropriateness. Caregiver burden was 3.3 times higher when mild behavioral impairment was present after controlling for age, education, and sex. Late-onset psychosis can be seen in association with normal cognition in patients who have prodromal dementia with Lewy bodies (216).

Chronic traumatic encephalopathy. In 2009, McKee and others described the neuropathology of a condition in football players and war veterans that is now known as chronic traumatic encephalopathy (126). In these brains, there are deposits of neurofibrillary tangles of tau protein and extracellular amyloid plaques that are similar to those seen in Alzheimer disease. These brains also look similar to those of boxers (dementia pugilistica). Jordon and others earlier showed that the risk of dementia was higher in victims of sports injuries if they had one or two of the apolipoprotein E epsilon 4 alleles (87). Traumatic encephalopathy syndrome is the clinical disorder associated with the neuropathologically documented condition, chronic traumatic encephalopathy. It requires (a) substantial exposure to repetitive head injuries, (b) episodic memory loss or executive function impairment, (c) a progressive course, and (d) no other neurologic or psychiatric explanation for the clinical features (96).

Subjective cognitive decline. When patients complain of memory loss, but have unimpaired performance on cognitive tests, we say that they have subjective cognitive decline (188). The newest criteria for subjective cognitive decline have been reported by the Subjective Cognitive Decline Working Group (84). Stage 3 of preclinical Alzheimer disease, for example, is defined by biomarker evidence for Alzheimer disease plus subjective cognitive decline without the objective cognitive impairment that is seen with mild cognitive impairment. One study provided evidence that subtle cognitive decline can sometimes precede the accumulation of beta-amyloid or the thinning of the entorhinal cortex in cases of preclinical Alzheimer disease (211).

Transient global amnesia. This acute episode of severe anterograde amnesia is usually seen in a middle-aged to older person who is alert, but confused (176). The symptoms usually improve slowly after a few hours, and they resolve completely within 24 hours. There are no focal signs of stroke or seizures. Recent studies have demonstrated the usefulness of MRI for identifying hippocampal DWI lesions in the acute or subacute setting (within the first 6 days of symptom onset) (206).

Unaware decliners. These patients experience subtle cognitive changes for which they are unaware. They have worse memory performance than controls, but similar memory performance compared to those with subjective cognitive decline (181). The variability of awareness among decliners has important implications for the reliability of self-report of cognitive dysfunction among patients in the prodromal stages of Alzheimer disease. More amyloid pathology in unaware decliners may be related to increasing anosognosia (219).

Cognitive reserve. Various aspects of an individual’s life experience (education, socioeconomic status, mid-life occupation, later-life social activities, etc.) can have an influence on preserving global cognition, episodic memory, and working memory, even in the presence of various brain pathologies (113; 07; 179).

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